119 results on '"Thierry Massfelder"'
Search Results
2. A new tumorgraft panel to accelerate precision medicine in prostate cancer
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Claire Béraud, Nadege Bidan, Myriam Lassalle, Hervé Lang, Véronique Lindner, Clémentine Krucker, Julien Masliah-Planchon, Eric Potiron, Philippe Lluel, Thierry Massfelder, Yves Allory, and Yolande Misseri
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PDX ,prostate cancer ,neuroendocine tumors ,genomic characteristics ,PARP inhibitor ,metabolism ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundDespite the significant advances in the management of advanced prostate cancer (PCa), metastatic PCa is currently considered incurable. For further investigations in precision treatment, the development of preclinical models representing the complex prostate tumor heterogeneity are mandatory. Accordingly, we aimed to establish a resource of patient-derived xenograft (PDX) models that exemplify each phase of this multistage disease for accurate and rapid evaluation of candidate therapies.MethodsFresh tumor samples along with normal corresponding tissues were obtained directly from patients at surgery. To ensure that the established models reproduce the main features of patient’s tumor, both PDX tumors at multiple passages and patient’s primary tumors, were processed for histological characteristics. STR profile analyses were also performed to confirm patient identity. Finally, the responses of the PDX models to androgen deprivation, PARP inhibitors and chemotherapy were also evaluated.ResultsIn this study, we described the development and characterization of 5 new PDX models of PCa. Within this collection, hormone-naïve, androgen-sensitive and castration-resistant (CRPC) primary tumors as well as prostate carcinoma with neuroendocrine differentiation (CRPC-NE) were represented. Interestingly, the comprehensive genomic characterization of the models identified recurrent cancer driver alterations in androgen signaling, DNA repair and PI3K, among others. Results were supported by expression patterns highlighting new potential targets among gene drivers and the metabolic pathway. In addition, in vivo results showed heterogeneity of response to androgen deprivation and chemotherapy, like the responses of patients to these treatments. Importantly, the neuroendocrine model has been shown to be responsive to PARP inhibitor.ConclusionWe have developed a biobank of 5 PDX models from hormone-naïve, androgen-sensitive to CRPC primary tumors and CRPC-NE. Increased copy-number alterations and accumulation of mutations within cancer driver genes as well as the metabolism shift are consistent with the increased resistance mechanisms to treatment. The pharmacological characterization suggested that the CRPC-NE could benefit from the PARP inhibitor treatment. Given the difficulties in developing such models, this relevant panel of PDX models of PCa will provide the scientific community with an additional resource for the further development of PDAC research.
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- 2023
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3. Integrated molecular and pharmacological characterization of patient-derived xenografts from bladder and ureteral cancers identifies new potential therapies
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Hervé Lang, Claire Béraud, Luc Cabel, Jacqueline Fontugne, Myriam Lassalle, Clémentine Krucker, Florent Dufour, Clarice S. Groeneveld, Victoria Dixon, Xiangyu Meng, Aurélie Kamoun, Elodie Chapeaublanc, Aurélien De Reynies, Xavier Gamé, Pascal Rischmann, Ivan Bieche, Julien Masliah-Planchon, Romane Beaurepere, Yves Allory, Véronique Lindner, Yolande Misseri, François Radvanyi, Philippe Lluel, Isabelle Bernard-Pierrot, and Thierry Massfelder
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urothelial carcinoma ,squamous cell carcinoma ,upper-urinary tract carcinoma ,luminal tumors ,basal tumors ,tyrosine kinase receptor ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundMuscle-invasive bladder cancer (MIBC) and upper urinary tract urothelial carcinoma (UTUC) are molecularly heterogeneous. Despite chemotherapies, immunotherapies, or anti-fibroblast growth factor receptor (FGFR) treatments, these tumors are still of a poor outcome. Our objective was to develop a bank of patient-derived xenografts (PDXs) recapitulating the molecular heterogeneity of MIBC and UTUC, to facilitate the preclinical identification of therapies.MethodsFresh tumors were obtained from patients and subcutaneously engrafted into immune-compromised mice. Patient tumors and matched PDXs were compared regarding histopathology, transcriptomic (microarrays), and genomic profiles [targeted Next-Generation Sequencing (NGS)]. Several PDXs were treated with chemotherapy (cisplatin/gemcitabine) or targeted therapies [FGFR and epidermal growth factor (EGFR) inhibitors].ResultsA total of 31 PDXs were established from 1 non-MIBC, 25 MIBC, and 5 upper urinary tract tumors, including 28 urothelial (UC) and 3 squamous cell carcinomas (SCCs). Integrated genomic and transcriptomic profiling identified the PDXs of three different consensus molecular subtypes [basal/squamous (Ba/Sq), luminal papillary, and luminal unstable] and included FGFR3-mutated PDXs. High histological and genomic concordance was found between matched patient tumor/PDX. Discordance in molecular subtypes, such as a Ba/Sq patient tumor giving rise to a luminal papillary PDX, was observed (n=5) at molecular and histological levels. Ten models were treated with cisplatin-based chemotherapy, and we did not observe any association between subtypes and the response. Of the three Ba/Sq models treated with anti-EGFR therapy, two models were sensitive, and one model, of the sarcomatoid variant, was resistant. The treatment of three FGFR3-mutant PDXs with combined FGFR/EGFR inhibitors was more efficient than anti-FGFR3 treatment alone.ConclusionsWe developed preclinical PDX models that recapitulate the molecular heterogeneity of MIBCs and UTUC, including actionable mutations, which will represent an essential tool in therapy development. The pharmacological characterization of the PDXs suggested that the upper urinary tract and MIBCs, not only UC but also SCC, with similar molecular characteristics could benefit from the same treatments including anti-FGFR for FGFR3-mutated tumors and anti-EGFR for basal ones and showed a benefit for combined FGFR/EGFR inhibition in FGFR3-mutant PDXs, compared to FGFR inhibition alone.
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- 2022
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4. Editorial: in vitro and in vivo non-clinical models of kidney cancers
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Valérian Dormoy, Odile Filhol, Carole Sourbier, and Thierry Massfelder
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kidney cancer ,renal cell carcinoma (RCC) ,patient-derived xenograft (PDX) ,tumoroids ,tissue slice culture ,pre-clinical oncology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2022
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5. Biological Biomarkers of Response and Resistance to Immune Checkpoint Inhibitors in Renal Cell Carcinoma
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Claire Masson, Jonathan Thouvenin, Philippe Boudier, Denis Maillet, Sabine Kuchler-Bopp, Philippe Barthélémy, and Thierry Massfelder
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clear cell renal cell carcinoma ,immune checkpoint inhibitors ,immunotherapy ,biomarkers ,resistance ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Renal cell carcinoma (RCC) represents around 2% of cancer-related deaths worldwide per year. RCC is an immunogenic malignancy, and treatment of metastatic RCC (mRCC) has greatly improved since the advent of the new immunotherapy agents, including immune checkpoint inhibitors (ICIs). However, it should be stressed that a large proportion of patients does not respond to these therapies. There is thus an urgent need to identify predictive biomarkers of efficacy or resistance associated with ICIs or ICI/Tyrosine kinase inhibitor (TKI) combinations; this is a major challenge to achieve precision medicine for mRCC in routine practice. To identify potential biomarkers, it is necessary to improve our knowledge on the biology of immune checkpoints. A lot of efforts have been made over the last decade in the field of immuno-oncology. We summarize here the main data obtained in this field when considering mRCC. As for clinical biomarkers, clinician and scientific experts of the domain are facing difficulties in identifying such molecular entities, probably due to the complexity of immuno-oncology and the constant adaptation of tumor cells to their changing environment.
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- 2023
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6. Complete Response in Metastatic Clear Cell Renal Cell Carcinoma Patients Treated with Immune-Checkpoint Inhibitors: Remission or Healing? How to Improve Patients’ Outcomes?
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Jonathan Thouvenin, Claire Masson, Philippe Boudier, Denis Maillet, Sabine Kuchler-Bopp, Philippe Barthélémy, and Thierry Massfelder
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clear-cell-renal-cell carcinoma ,immune-checkpoint inhibitors ,immunotherapy ,complete response ,first-line treatment ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Renal-cell carcinoma (RCC) accounts for 2% of cancer diagnoses and deaths worldwide. Clear-cell RCCs represent the vast majority (85%) of kidney cancers and are considered morphologically and genetically as immunogenic tumors. Indeed, the RCC tumoral microenvironment comprises T cells and myeloid cells in an immunosuppressive state, providing an opportunity to restore their activity through immunotherapy. Standard first-line systemic treatment for metastatic patients includes immune-checkpoint inhibitors (ICIs) targeting PD1, in combination with either another ICI or with antiangiogenic targeted therapy. During the past few years, several combinations have been approved with an overall survival benefit and overall response rate that depend on the combination. Interestingly, some patients achieve prolonged complete responses, raising the question of whether these metastatic RCC patients can be cured. This review will focus on recent therapeutic advances in RCC and the clinical and biological aspects underpinning the potential for healing.
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- 2023
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7. Flavagline synthetic derivative induces senescence in glioblastoma cancer cells without being toxic to healthy astrocytes
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Ezeddine Harmouch, Joseph Seitlinger, Hassan Chaddad, Geneviève Ubeaud-Sequier, Jochen Barths, Sani Saidu, Laurent Désaubry, Stéphanie Grandemange, Thierry Massfelder, Guy Fuhrmann, Florence Fioretti, Monique Dontenwill, Nadia Benkirane-Jessel, and Ysia Idoux-Gillet
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Medicine ,Science - Abstract
Abstract Glioblastoma (GBM) is one of the most aggressive types of cancer, which begins within the brain. It is the most invasive type of glioma developed from astrocytes. Until today, Temozolomide (TMZ) is the only standard chemotherapy for patients with GBM. Even though chemotherapy extends the survival of patients, there are many undesirable side effects, and most cases show resistance to TMZ. FL3 is a synthetic flavagline which displays potent anticancer activities, and is known to inhibit cell proliferation, by provoking cell cycle arrest, and leads to apoptosis in a lot of cancer cell lines. However, the effect of FL3 in glioblastoma cancer cells has not yet been examined. Hypoxia is a major problem for patients with GBM, resulting in tumor resistance and aggressiveness. In this study, we explore the effect of FL3 in glioblastoma cells under normoxia and hypoxia conditions. Our results clearly indicate that this synthetic flavagline inhibits cell proliferation and induced senescence in glioblastoma cells cultured under both conditions. In addition, FL3 treatment had no effect on human brain astrocytes. These findings support the notion that the FL3 molecule could be used in combination with other chemotherapeutic agents or other therapies in glioblastoma treatments.
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- 2020
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8. Recurrent activating mutations of PPARγ associated with luminal bladder tumors
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Natacha Rochel, Clémentine Krucker, Laure Coutos-Thévenot, Judit Osz, Ruiyun Zhang, Elodie Guyon, Wayne Zita, Séverin Vanthong, Oscar Alba Hernandez, Maxime Bourguet, Kays Al Badawy, Florent Dufour, Carole Peluso-Iltis, Syrine Heckler-Beji, Annick Dejaegere, Aurélie Kamoun, Aurélien de Reyniès, Yann Neuzillet, Sandra Rebouissou, Claire Béraud, Hervé Lang, Thierry Massfelder, Yves Allory, Sarah Cianférani, Roland H. Stote, François Radvanyi, and Isabelle Bernard-Pierrot
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Science - Abstract
Activation of the PPARγ/RXRα pathway in luminal bladder cancers has mainly been linked to PPARG gene amplifications and activating point mutations in RXRα. Here, the authors identify recurrent PPARγ mutations with similar effects and elucidate the structural basis for this mutational PPARγ activation.
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- 2019
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9. An FGFR3/MYC positive feedback loop provides new opportunities for targeted therapies in bladder cancers
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Mélanie Mahe, Florent Dufour, Hélène Neyret‐Kahn, Aura Moreno‐Vega, Claire Beraud, Mingjun Shi, Imene Hamaidi, Virginia Sanchez‐Quiles, Clementine Krucker, Marion Dorland‐Galliot, Elodie Chapeaublanc, Remy Nicolle, Hervé Lang, Celio Pouponnot, Thierry Massfelder, François Radvanyi, and Isabelle Bernard‐Pierrot
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BET inhibitors ,bladder cancer ,FGFR3 ,MYC ,p38 ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract FGFR3 alterations (mutations or translocation) are among the most frequent genetic events in bladder carcinoma. They lead to an aberrant activation of FGFR3 signaling, conferring an oncogenic dependence, which we studied here. We discovered a positive feedback loop, in which the activation of p38 and AKT downstream from the altered FGFR3 upregulates MYC mRNA levels and stabilizes MYC protein, respectively, leading to the accumulation of MYC, which directly upregulates FGFR3 expression by binding to active enhancers upstream from FGFR3. Disruption of this FGFR3/MYC loop in bladder cancer cell lines by treatment with FGFR3, p38, AKT, or BET bromodomain inhibitors (JQ1) preventing MYC transcription decreased cell viability in vitro and tumor growth in vivo. A relevance of this loop to human bladder tumors was supported by the positive correlation between FGFR3 and MYC levels in tumors bearing FGFR3 mutations, and the decrease in FGFR3 and MYC levels following anti‐FGFR treatment in a PDX model bearing an FGFR3 mutation. These findings open up new possibilities for the treatment of bladder tumors displaying aberrant FGFR3 activation.
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- 2018
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10. Data from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
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Thierry Massfelder, Hervé Lang, Jean-Jacques Helwig, Didier Jacqmin, Nicolas Meyer, Sylvie Rothhut, Jacques Steger, Véronique Lindner, Sabrina Danilin, and Carole Sourbier
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Metastatic renal cell carcinoma (RCC) remains refractory to therapies. The nuclear factor-κB (NF-κB) transcription factor is involved in cell growth, cell motility, and vascularization. We evaluated whether targeting NF-κB could be of therapeutic and prognostic values in human RCC. The activation of the NF-κB pathway in human RCC cells and tumors was investigated by Western blot. In vitro, the effects of BAY 11-7085 and sulfasalazine, two NF-κB inhibitors, on tumor cell growth were investigated by cell counting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling, and fluorescence-activated cell sorting. Their specificity toward NF-κB was analyzed by Western blot, confocal microscopy, NF-κB small interfering RNA, and NF-κB transcription assay. In vivo, the effects of BAY 11-7085 on the growth of human RCC tumors were investigated in nude mice. A tissue microarray (TMA) containing 241 cases of human RCC with 12 to 22 years of clinical follow-up and corresponding normal tissues was built up to assess prognostic significance of activated NF-κB. NF-κB is constitutively activated in cultured cells expressing or not the von Hippel-Lindau (VHL) tumor suppressor gene as a consequence of Akt kinase activation and in tumors. In vitro and in vivo NF-κB inhibition blocked tumor cell growth by inducing cell apoptosis. On the TMA, NF-κB activation was correlated with tumor dimension but was not found to be an independent prognostic factor for patient survival. This report provides strong evidence that the mechanisms responsible for the intrinsic resistance of RCC cells to apoptosis converge on NF-κB independently of VHL expression and that targeting this pathway has great anticancer potential. [Cancer Res 2007;67(24):11668–76]
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- 2023
11. Supplementary Legends 1-6 from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
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Thierry Massfelder, Hervé Lang, Jean-Jacques Helwig, Didier Jacqmin, Nicolas Meyer, Sylvie Rothhut, Jacques Steger, Véronique Lindner, Sabrina Danilin, and Carole Sourbier
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Supplementary Legends 1-6 from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
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- 2023
12. Supplementary Figure 4 from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
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Thierry Massfelder, Hervé Lang, Jean-Jacques Helwig, Didier Jacqmin, Nicolas Meyer, Sylvie Rothhut, Jacques Steger, Véronique Lindner, Sabrina Danilin, and Carole Sourbier
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Supplementary Figure 4 from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
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- 2023
13. Supplementary Figure 6 from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
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Thierry Massfelder, Hervé Lang, Jean-Jacques Helwig, Didier Jacqmin, Nicolas Meyer, Sylvie Rothhut, Jacques Steger, Véronique Lindner, Sabrina Danilin, and Carole Sourbier
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Supplementary Figure 6 from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
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- 2023
14. Supplementary Figure 3 from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
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Thierry Massfelder, Hervé Lang, Jean-Jacques Helwig, Didier Jacqmin, Nicolas Meyer, Sylvie Rothhut, Jacques Steger, Véronique Lindner, Sabrina Danilin, and Carole Sourbier
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Supplementary Figure 3 from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
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- 2023
15. Supplementary Figure 2 from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
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Thierry Massfelder, Hervé Lang, Jean-Jacques Helwig, Didier Jacqmin, Nicolas Meyer, Sylvie Rothhut, Jacques Steger, Véronique Lindner, Sabrina Danilin, and Carole Sourbier
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Supplementary Figure 2 from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
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- 2023
16. Supplementary Figure 1 from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
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Thierry Massfelder, Hervé Lang, Jean-Jacques Helwig, Didier Jacqmin, Nicolas Meyer, Sylvie Rothhut, Jacques Steger, Véronique Lindner, Sabrina Danilin, and Carole Sourbier
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Supplementary Figure 1 from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
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- 2023
17. Supplementary Figure 5 from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
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Thierry Massfelder, Hervé Lang, Jean-Jacques Helwig, Didier Jacqmin, Nicolas Meyer, Sylvie Rothhut, Jacques Steger, Véronique Lindner, Sabrina Danilin, and Carole Sourbier
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Supplementary Figure 5 from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
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- 2023
18. Supplementary Tables 1-2 from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
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Thierry Massfelder, Hervé Lang, Jean-Jacques Helwig, Didier Jacqmin, Nicolas Meyer, Sylvie Rothhut, Jacques Steger, Véronique Lindner, Sabrina Danilin, and Carole Sourbier
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Supplementary Tables 1-2 from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
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- 2023
19. Editorial
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Valérian, Dormoy, Odile, Filhol, Carole, Sourbier, and Thierry, Massfelder
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- 2022
20. The Lim1 oncogene as a new therapeutic target for metastatic human renal cell carcinoma
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Imène Hamaidi, Thierry Massfelder, Valérian Dormoy, Hervé Lang, Sylvie Rothhut, Claire Béraud, Mariette Barthelmebs, Véronique Lindner, Nadia Benkirane-Jessel, Sabrina Danilin, Catherine Coquard, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Plasticité de l'épithélium respiratoire dans les conditions normales et pathologiques - UMR-S 903 (PERPMP), Université de Reims Champagne-Ardenne (URCA)-Centre Hospitalier Universitaire de Reims (CHU Reims)-Institut National de la Santé et de la Recherche Médicale (INSERM)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), Hôpital de Hautepierre [Strasbourg], Service d'urologie, CHU Strasbourg, Les Hôpitaux Universitaires de Strasbourg (HUS), Développement et physiopathologie de l'intestin et du pancréas, Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Immunorhumathologie moléculaire, Service de pathologie, Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA)-Groupe Hospitalier de Territoire Haute Alsace (GHTHA), and dormoy, valerian
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0301 basic medicine ,Cancer Research ,Lung Neoplasms ,[SDV]Life Sciences [q-bio] ,CXCR4 ,[SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology ,Metastasis ,0302 clinical medicine ,Invasion ,Cell Movement ,Molecular Targeted Therapy ,RNA, Small Interfering ,mouse xenograft model ,ComputingMilieux_MISCELLANEOUS ,Primary tumor ,Kidney Neoplasms ,3. Good health ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Von Hippel-Lindau Tumor Suppressor Protein ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,RNA Interference ,Lim1 ,Signal Transduction ,Epithelial-Mesenchymal Transition ,Tumor suppressor gene ,human renal cell carcinoma ,LIM-Homeodomain Proteins ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,In vivo ,Cell Line, Tumor ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Genetics ,medicine ,Gene silencing ,Humans ,Neoplasm Invasiveness ,Molecular Biology ,Carcinoma, Renal Cell ,Oncogene ,Cell growth ,Oncogenes ,medicine.disease ,[SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology ,Clear cell renal cell carcinoma ,030104 developmental biology ,Tumorigenesis ,Cancer research ,Transcription Factors - Abstract
International audience; Metastatic clear cell renal cell carcinoma (CCC) remains incurable despite advances in the development of anti-angiogenic targeted therapies and the emergence of immune checkpoint inhibitors. We have previously shown that the sonic hedgehog-Gli signaling pathway is oncogenic in CCC allowing us to identify the developmental Lim1 transcription factor as a Gli target and as a new oncogene in CCC regulating cell proliferation and apoptosis, and promoting tumor growth. In this previous study, preliminary in vitro results also suggested that Lim1 may be implicated in metastatic spread. Here we investigated the potential pro-metastatic role of Lim1 in advanced CCC (1) in vitro using a panel of CCC cell lines expressing or not the von Hippel-Lindau (VHL) tumor suppressor gene either naturally or by gene transfer and (2) ex vivo in 30 CCC metastatic tissues, including lymph nodes, lung, skin, bone, and adrenal metastases, and (3) in vivo, using a metastatic model by intravenous injection of siRNA-transfected cells into Balb/c nude. Our in vitro results reveal that Lim1 knockdown time-dependently decreased CCC cell motility, migration, invasion, and clonogenicity by up to 50% regardless of their VHL status. Investigating the molecular machinery involved in these processes, we identified a large panel of Lim1 targets known to be involved in cell adhesion (paxillin and fibronectin), epithelial-mesenchymal transition (Twist1/2 and snail), invasion (MMP1/2/3/8/9), and metastatic progression (CXCR4, SDF-1, and ANG-1). Importantly, Lim1 was found constitutively expressed in all metastatic tissues. The H-score in metastatic tissues being significantly superior to the score in the corresponding primary tumor tissues (P value = 0.009). Furthermore, we showed that Lim1 silencing decreases pulmonary metastasis development in terms of number and size in the in vivo metastatic model of human CCC. Taken together, these experiments strengthen the potential therapeutic value of Lim1 targeting as a promising novel approach for treating metastatic human CCC.
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- 2019
21. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead
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Dustin G. Brown, Tove Hultman, Judith Weisz, H. Kim Lyerly, Paola A. Marignani, Ann-Karin Olsen, Rabindra Roy, Kim Moorwood, Masoud H. Manjili, Monica Vaccari, Jesse Roman, Hasiah Ab Hamid, Kalan R. Prudhomme, Periyadan K. Krishnakumar, Chenfang Dong, Tiziana Guarnieri, Leandro S. D'Abronzo, Gloria M. Calaf, Amelia K Charles, Emanuela Corsini, Yunus A. Luqmani, Graeme Williams, Louis Vermeulen, Pankaj Vadgama, Sarah N Bay, Véronique Maguer-Satta, Sabine A. S. Langie, Christian C. Naus, Le Jian, Gladys N. Nangami, Lorenzo Memeo, Stephanie C. Casey, Thomas Sanderson, Takemi Otsuki, Nichola Cruickshanks, William H. Bisson, Sudjit Luanpitpong, Jonathan Whitfield, Ahmed Lasfar, Yon Rojanasakul, A. Ivana Scovassi, Shelley A. Harris, Ferdinando Chiaradonna, Richard Ponce-Cusi, Gregory T. Wolf, Valérian Dormoy, Roslida Abd Hamid, Hyun Ho Park, Matilde E. Lleonart, William K. Decker, Maria Romano, Leroy Lowe, Fabio Marongiu, Jan Vondráček, Chiara Mondello, Luc Leyns, Josiah Ochieng, Pratima Nangia-Makker, Edward A. Ratovitski, Zhiwei Hu, Jayadev Raju, Hemad Yasaei, Rafaela Andrade-Vieira, Jordan Woodrick, Hideko Sone, Harini Krishnan, W. Kimryn Rathmell, Andrew Collins, Luoping Zhang, Barry J. Barclay, Amaya Azqueta, Laura Soucek, Marc A. Williams, David O. Carpenter, Roberta Palorini, Rita Nahta, Juan Fernando Martinez-Leal, Firouz Darroudi, Rita Dornetshuber-Fleiss, James E. Klaunig, Elizabeth P. Ryan, Qiang Shawn Cheng, Arthur Berg, Andrew Ward, Gudrun Koppen, Tao Chen, Petr Heneberg, Michael Gilbertson, Amedeo Amedei, Sakina E. Eltom, Ezio Laconi, Joseph Christopher, Hiroshi Kondoh, Neetu Singh, Danielle J Carlin, Marion Chapellier, Michalis V. Karamouzis, Rekha Mehta, Tae-Jin Lee, Annamaria Colacci, Venkata S. Sabbisetti, Mark Wade, Micheline Kirsch-Volders, Patricia Ostrosky-Wegman, Isabelle R. Miousse, Patricia A. Thompson, Philippa D. Darbre, Frederik J. van Schooten, Sofia Pavanello, Igor Koturbash, Binhua P. Zhou, Ranjeet Kumar Sinha, Anna C. Salzberg, Mahara Valverde, Fahd Al-Mulla, Julia Kravchenko, Nicole Kleinstreuer, Carolyn J. Baglole, Menghang Xia, Samira A. Brooks, Amancio Carnero, Gunnar Brunborg, Sandra S. Wise, Daniel C. Koch, John Pierce Wise, Rabeah Al-Temaimi, Laetitia Gonzalez, Lisa J. McCawley, R. Brooks Robey, Gary S. Goldberg, Thierry Massfelder, Linda S M Gulliver, Olugbemiga Ogunkua, Emilio Rojas, Eun-Yi Moon, Lin Li, Silvana Papagerakis, Nik van Larebeke, Adela Lopez de Cerain Salsamendi, Staffan Eriksson, Simona Romano, Dean W. Felsher, Paramita M. Ghosh, Karine A. Cohen-Solal, Paul Dent, Jun Sun, Carmen Blanco-Aparicio, Riccardo Di Fiore, Chia-Wen Hsu, Mahin Khatami, Kannan Badri Narayanan, Francis Martin, Colleen S. Curran, Dale W. Laird, William H. Goodson, Abdul Manaf Ali, Valerie Odero-Marah, Michael J. Gonzalez, Renza Vento, Liang Tzung Lin, Clement G. Yedjou, Hosni Salem, Hsue-Yin Hsu, Zhenbang Chen, Nuzhat Ahmed, Gerard Wagemaker, Sandra Ryeom, Stefano Forte, Debasish Roy, Nancy B. Kuemmerle, Robert C. Castellino, Po Sing Leung, Wilhelm Engström, National Institute of Environmental Health Sciences (US), Research Council of Norway, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Red Temática de Investigación Cooperativa en Cáncer (España), European Commission, Junta de Andalucía, Ministerio de Educación y Ciencia (España), Ministero dell'Istruzione, dell'Università e della Ricerca, University of Oslo, Regione Emilia Romagna, National Institutes of Health (US), Consejo Nacional de Ciencia y Tecnología (México), Associazione Italiana per la Ricerca sul Cancro, National Research Foundation of Korea, Ministry of Education, Science and Technology (South Korea), Fondo Nacional de Desarrollo Científico y Tecnológico (Chile), Ministry of Education, Culture, Sports, Science and Technology (Japan), Japan Science and Technology Agency, Ministry of Science and Technology (Taiwan), Arkansas Biosciences Institute, Czech Science Foundation, Fundación Fero, Swim Across America, American Cancer Society, Research Foundation - Flanders, Austrian Science Fund, Institut National de la Santé et de la Recherche Médicale (France), Natural Sciences and Engineering Research Council of Canada, Farmacologie en Toxicologie, RS: NUTRIM - R4 - Gene-environment interaction, Goodson, William H, Lowe, Leroy, Carpenter, David O, Gilbertson, Michael, Manaf Ali, Abdul, Lopez de Cerain Salsamendi, Adela, Lasfar, Ahmed, Carnero, Amancio, Azqueta, Amaya, Amedei, Amedeo, Charles, Amelia K, Collins, Andrew R, Ward, Andrew, Salzberg, Anna C, Colacci, Annamaria, Olsen, Ann Karin, Berg, Arthur, Barclay, Barry J, Zhou, Binhua P, Blanco Aparicio, Carmen, Baglole, Carolyn J, Dong, Chenfang, Mondello, Chiara, Hsu, Chia Wen, Naus, Christian C, Yedjou, Clement, Curran, Colleen S, Laird, Dale W, Koch, Daniel C, Carlin, Danielle J, Felsher, Dean W, Roy, Debasish, Brown, Dustin G, Ratovitski, Edward, Ryan, Elizabeth P, Corsini, Emanuela, Rojas, Emilio, Moon, Eun Yi, Laconi, Ezio, Marongiu, Fabio, Al Mulla, Fahd, Chiaradonna, Ferdinando, Darroudi, Firouz, Martin, Francis L, Van Schooten, Frederik J, Goldberg, Gary S, Wagemaker, Gerard, Nangami, Gladys N, Calaf, Gloria M, Williams, Graeme, Wolf, Gregory T, Koppen, Gudrun, Brunborg, Gunnar, Lyerly, H. Kim, Krishnan, Harini, Ab Hamid, Hasiah, Yasaei, Hemad, Sone, Hideko, Kondoh, Hiroshi, Salem, Hosni K, Hsu, Hsue Yin, Park, Hyun Ho, Koturbash, Igor, Miousse, Isabelle R, Scovassi, A. Ivana, Klaunig, James E, Vondráček, Jan, Raju, Jayadev, Roman, Jesse, Wise, John Pierce, Whitfield, Jonathan R, Woodrick, Jordan, Christopher, Joseph A, Ochieng, Josiah, Martinez Leal, Juan Fernando, Weisz, Judith, Kravchenko, Julia, Sun, Jun, Prudhomme, Kalan R, Narayanan, Kannan Badri, Cohen Solal, Karine A, Moorwood, Kim, Gonzalez, Laetitia, Soucek, Laura, Jian, Le, D'Abronzo, Leandro S, Lin, Liang Tzung, Li, Lin, Gulliver, Linda, Mccawley, Lisa J, Memeo, Lorenzo, Vermeulen, Loui, Leyns, Luc, Zhang, Luoping, Valverde, Mahara, Khatami, Mahin, Romano, MARIA FIAMMETTA, Chapellier, Marion, Williams, Marc A, Wade, Mark, Manjili, Masoud H, Lleonart, Matilde E, Xia, Menghang, Gonzalez, Michael J, Karamouzis, Michalis V, Kirsch Volders, Micheline, Vaccari, Monica, Kuemmerle, Nancy B, Singh, Neetu, Cruickshanks, Nichola, Kleinstreuer, Nicole, van Larebeke, Nik, Ahmed, Nuzhat, Ogunkua, Olugbemiga, Krishnakumar, P. K, Vadgama, Pankaj, Marignani, Paola A, Ghosh, Paramita M, Ostrosky Wegman, Patricia, Thompson, Patricia A, Dent, Paul, Heneberg, Petr, Darbre, Philippa, Sing Leung, Po, Nangia Makker, Pratima, Cheng, Qiang Shawn, Robey, R. Brook, Al Temaimi, Rabeah, Roy, Rabindra, Andrade Vieira, Rafaela, Sinha, Ranjeet K, Mehta, Rekha, Vento, Renza, Di Fiore, Riccardo, Ponce Cusi, Richard, Dornetshuber Fleiss, Rita, Nahta, Rita, Castellino, Robert C, Palorini, Roberta, Abd Hamid, Roslida, Langie, Sabine A. S, Eltom, Sakina E, Brooks, Samira A, Ryeom, Sandra, Wise, Sandra S, Bay, Sarah N, Harris, Shelley A, Papagerakis, Silvana, Romano, Simona, Pavanello, Sofia, Eriksson, Staffan, Forte, Stefano, Casey, Stephanie C, Luanpitpong, Sudjit, Lee, Tae Jin, Otsuki, Takemi, Chen, Tao, Massfelder, Thierry, Sanderson, Thoma, Guarnieri, Tiziana, Hultman, Tove, Dormoy, Valérian, Odero Marah, Valerie, Sabbisetti, Venkata, Maguer Satta, Veronique, Rathmell, W. Kimryn, Engström, Wilhelm, Decker, William K, Bisson, William H, Rojanasakul, Yon, Luqmani, Yunu, Chen, Zhenbang, Hu, Zhiwei, Goodson, W., Lowe, L., Carpenter, D., Gilbertson, M., Ali, A., de Cerain Salsamendi, A., Lasfar, A., Carnero, A., Azqueta, A., Amedei, A., Charles, A., Collins, A., Ward, A., Salzberg, A., Colacci, A., Olsen, A., Berg, A., Barclay, B., Zhou, B., Blanco-Aparicio, C., Baglole, C., Dong, C., Mondello, C., Hsu, C., Naus, C., Yedjou, C., Curran, C., Laird, D., Koch, D., Carlin, D., Felsher, D., Roy, D., Brown, D., Ratovitski, E., Ryan, E., Corsini, E., Rojas, E., Moon, E., Laconi, E., Marongiu, F., Al-Mulla, F., Chiaradonna, F., Darroudi, F., Martin, F., Van Schooten, F., Goldberg, G., Wagemaker, G., Nangami, G., Calaf, G., Williams, G., Wolf, G., Koppen, G., Brunborg, G., Kim Lyerly, H., Krishnan, H., Hamid, H., Yasaei, H., Sone, H., Kondoh, H., Salem, H., Hsu, H., Park, H., Koturbash, I., Miousse, I., Ivana Scovassi, A., Klaunig, J., Vondráček, J., Raju, J., Roman, J., Wise, J., Whitfield, J., Woodrick, J., Christopher, J., Ochieng, J., Martinez-Leal, J., Weisz, J., Kravchenko, J., Sun, J., Prudhomme, K., Narayanan, K., Cohen-Solal, K., Moorwood, K., Gonzalez, L., Soucek, L., Jian, L., D'Abronzo, L., Lin, L., Li, L., Gulliver, L., Mccawley, L., Memeo, L., Vermeulen, L., Leyns, L., Zhang, L., Valverde, M., Khatami, M., Romano, M., Chapellier, M., Williams, M., Wade, M., Manjili, M., Lleonart, M., Xia, M., Gonzalez, M., Karamouzis, M., Kirsch-Volders, M., Vaccari, M., Kuemmerle, N., Singh, N., Cruickshanks, N., Kleinstreuer, N., Van Larebeke, N., Ahmed, N., Ogunkua, O., Krishnakumar, P., Vadgama, P., Marignani, P., Ghosh, P., Ostrosky-Wegman, P., Thompson, P., Dent, P., Heneberg, P., Darbre, P., Leung, P., Nangia-Makker, P., Cheng, Q., Brooks Robey, R., Al-Temaimi, R., Roy, R., Andrade-Vieira, R., Sinha, R., Mehta, R., Vento, R., Di Fiore, R., Ponce-Cusi, R., Dornetshuber-Fleiss, R., Nahta, R., Castellino, R., Palorini, R., Hamid, R., Langie, S., Eltom, S., Brooks, S., Ryeom, S., Wise, S., Bay, S., Harris, S., Papagerakis, S., Romano, S., Pavanello, S., Eriksson, S., Forte, S., Casey, S., Luanpitpong, S., Lee, T., Otsuki, T., Chen, T., Massfelder, T., Sanderson, T., Guarnieri, T., Hultman, T., Dormoy, V., Odero-Marah, V., Sabbisetti, V., Maguer-Satta, V., Kimryn Rathmell, W., Engström, W., Decker, W., Bisson, W., Rojanasakul, Y., Luqmani, Y., Chen, Z., Hu, Z., Goodson, W.H., Carpenter, D.O., Ali, A.M., de Cerain Salsamendi, A.L., Charles, A.K., Collins, A.R., Salzberg, A.C., Olsen, A.-K., Barclay, B.J., Zhou, B.P., Baglole, C.J., Hsu, C.-W., Naus, C.C., Curran, C.S., Laird, D.W., Koch, D.C., Carlin, D.J., Felsher, D.W., Brown, D.G., Ryan, E.P., Moon, E.-Y., Martin, F.L., Van Schooten, F.J., Goldberg, G.S., Calaf, G.M., Wolf, G.T., Hamid, H.A., Salem, H.K., Hsu, H.-Y., Park, H.H., Miousse, I.R., Klaunig, J.E., Vondracek, J., Wise, J.P., Whitfield, J.R., Christopher, J.A., Martinez-Leal, J.F., Prudhomme, K.R., Narayanan, K.B., Cohen-Solal, K.A., D'Abronzo, L.S., Lin, L.-T., Mccawley, L.J., Romano, M.F., Williams, M.A., Manjili, M.H., Gonzalez, M.J., Karamouzis, M.V., Kuemmerle, N.B., Krishnakumar, P.K., Marignani, P.A., Ghosh, P.M., Leung, P.S., Cheng, Q.S., Sinha, R.K., Castellino, R.C., Hamid, R.A., Langie, S.A.S., Brooks, S.A., Wise, S.S., Bay, S.N., Harris, S.A., Casey, S.C., Lee, T.-J., Engstrom, W., Decker, W.K., Bisson, W.H., sans affiliation, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), We gratefully acknowledge the support of the National Institute of Health-National Institute of Environmental Health Sciences (NIEHS) conference grant travel support (R13ES023276), Glenn Rice, Office of Research and Development, United States Environmental Protection Agency, Cincinnati, OH, USA also deserves thanks for his thoughtful feedback and inputs on the manuscript, William H.Goodson III was supported by the California Breast Cancer Research Program, Clarence Heller Foundation and California Pacific Medical Center Foundation, Abdul M.Ali would like to acknowledge the financial support of the University of Sultan Zainal Abidin, Malaysia, Ahmed Lasfar was supported by an award from the Rutgers Cancer Institute of New Jersey, Ann-Karin Olsen and Gunnar Brunborg were supported by the Research Council of Norway (RCN) through its Centres of Excellence funding scheme (223268/F50), Amancio Carnero’s lab was supported by grants from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028) co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0306-2012), Matilde E. Lleonart was supported by a trienal project grant PI12/01104 and by project CP03/00101 for personal support. Amaya Azqueta would like to thank the Ministerio de Educacion y Ciencia (‘Juande la Cierva’ programme, 2009) of the Spanish Government for personal support, Amedeo Amedei was supported by the Italian Ministry of University and Research (2009FZZ4XM_002), and the University of Florence (ex60%2012), Andrew R.Collins was supported by the University of Oslo, Annamaria Colacci was supported by the Emilia-Romagna Region - Project ‘Supersite’ in Italy, Carolyn Baglole was supported by a salary award from the Fonds de recherche du Quebec-Sante (FRQ-S), Chiara Mondello’s laboratory is supported by Fondazione Cariplo in Milan, Italy (grant n. 2011-0370), Christian C.Naus holds a Canada Research Chair, Clement Yedjou was supported by a grant from the National Institutes of Health (NIH-NIMHD grant no. G12MD007581), Daniel C.Koch is supported by the Burroughs Wellcome Fund Postdoctoral Enrichment Award and the Tumor Biology Training grant: NIH T32CA09151, Dean W. Felsher would like to acknowledge the support of United States Department of Health and Human Services, NIH grants (R01 CA170378 PQ22, R01 CA184384, U54 CA149145, U54 CA151459, P50 CA114747 and R21 CA169964), Emilio Rojas would like to thank CONACyT support 152473, Ezio Laconi was supported by AIRC (Italian Association for Cancer Research, grant no. IG 14640) and by the Sardinian Regional Government (RAS), Eun-Yi Moon was supported by grants from the Public Problem-Solving Program (NRF-015M3C8A6A06014500) and Nuclear R&D Program (#2013M2B2A9A03051296 and 2010-0018545) through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology (MEST) in Korea, Fahd Al-Mulla was supported by the Kuwait Foundation for the Advancement of Sciences (2011-1302-06), Ferdinando Chiaradonna is supported by SysBioNet, a grant for the Italian Roadmap of European Strategy Forum on Research Infrastructures (ESFRI) and by AIRC (Associazione Italiana Ricerca sul Cancro, IG 15364), Francis L.Martin acknowledges funding from Rosemere Cancer Foundation, he also thanks Lancashire Teaching Hospitals NHS trust and the patients who have facilitated the studies he has undertaken over the course of the last 10 years, Gary S.Goldberg would like to acknowledge the support of the New Jersey Health Foundation, Gloria M.Calaf was supported by Fondo Nacional de Ciencia y Tecnología (FONDECYT), Ministerio de Educación de Chile (MINEDUC), Universidad de Tarapacá (UTA), Gudrun Koppen was supported by the Flemish Institute for Technological Research (VITO), Belgium, Hemad Yasaei was supported from a triennial project grant (Strategic Award) from the National Centre for the Replacement, Refinement and Reduction (NC3Rs) of animals in research (NC.K500045.1 and G0800697), Hiroshi Kondoh was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Science and Technology Agency and by JST, CREST, Hsue-Yin Hsu was supported by the Ministry of Science and Technology of Taiwan (NSC93-2314-B-320-006 and NSC94-2314-B-320-002), Hyun Ho Park was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) of the Ministry of Education, Science and Technology (2012R1A2A2A01010870) and a grant from the Korea Healthcare Technology R&D project, Ministry of Health and Welfare, Republic of Korea (HI13C1449), Igor Koturbash is supported by the UAMS/NIH Clinical and Translational Science Award (UL1TR000039 and KL2TR000063) and the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000, Jan Vondráček acknowledges funding from the Czech Science Foundation (13-07711S), Jesse Roman thanks the NIH for their support (CA116812), John Pierce Wise Sr. and Sandra S.Wise were supported by National Institute of Environmental Health Sciences (ES016893 to J.P.W.) and the Maine Center for Toxicology and Environmental Health, Jonathan Whitfield acknowledges support from the FERO Foundation in Barcelona, Spain, Joseph Christopher is funded by Cancer Research UK and the International Journal of Experimental Pathology, Julia Kravchenko is supported by a philanthropic donation by Fred and Alice Stanback, Jun Sun is supported by a Swim Across America Cancer Research Award, Karine A.Cohen-Solal is supported by a research scholar grant from the American Cancer Society (116683-RSG-09-087-01-TBE), Laetitia Gonzalez received a postdoctoral fellowship from the Fund for Scientific Research–Flanders (FWO-Vlaanderen) and support by an InterUniversity Attraction Pole grant (IAP-P7-07), Laura Soucek is supported by grant #CP10/00656 from the Miguel Servet Research Contract Program and acknowledges support from the FERO Foundation in Barcelona, Spain, Liang-Tzung Lin was supported by funding from the Taipei Medical University (TMU101-AE3-Y19), Linda Gulliver is supported by a Genesis Oncology Trust (NZ) Professional Development Grant, and the Faculty of Medicine, University of Otago, Dunedin, New Zealand, Louis Vermeulen is supported by a Fellowship of the Dutch Cancer Society (KWF, UVA2011-4969) and a grant from the AICR (14–1164), Mahara Valverde would like to thank CONACyT support 153781, Masoud H. Manjili was supported by the office of the Assistant Secretary of Defense for Health Affairs (USA) through the Breast Cancer Research Program under Award No. W81XWH-14-1-0087 Neetu Singh was supported by grant #SR/FT/LS-063/2008 from the Department of Science and Technology, Government of India, Nicole Kleinstreuer is supported by NIEHS contracts (N01-ES 35504 and HHSN27320140003C), P.K. Krishnakumar is supported by the Funding (No. T.K. 11-0629) of King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia, Paola A.Marignani is supported by the Dalhousie Medical Research Foundation, The Beatrice Hunter Cancer Institute and CIHR and the Nova Scotia Lung Association, Paul Dent is the holder of the Universal Inc.Chair in Signal Transduction Research and is supported with funds from PHS grants from the NIH (R01-CA141704, R01-CA150214, R01-DK52825 and R01-CA61774), Petr Heneberg was supported by the Charles University in Prague projects UNCE 204015 and PRVOUK P31/2012, and by the Czech Science Foundation projects P301/12/1686 and 15-03834Y, Po Sing Leung was supported by the Health and Medical Research Fund of Food and Health Bureau, Hong Kong Special Administrative Region, Ref. No: 10110021, Qiang Cheng was supported in part by grant NSF IIS-1218712, R. Brooks Robey is supported by the United States Department of Veterans Affairs, Rabindra Roy was supported by United States Public Health Service Grants (RO1 CA92306, RO1 CA92306-S1 and RO1 CA113447), Rafaela Andrade-Vieira is supported by the Beatrice Hunter Cancer Research Institute and the Nova Scotia Health Research Foundation, Renza Vento was partially funded by European Regional Development Fund, European Territorial Cooperation 2007–13 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–13) and grants from the Italian Ministry of Education, University and Research (MIUR) ex-60%, 2007, Riccardo Di Fiore was a recipient of fellowship granted by European Regional Development Fund, European Territorial Cooperation 2007–2013 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–2013), Rita Dornetshuber-Fleiss was supported by the Austrian Science Fund (FWF, project number T 451-B18) and the Johanna Mahlke, geb.-Obermann-Stiftung, Roberta Palorini is supported by a SysBioNet fellowship, Roslida Abd Hamid is supported by the Ministry of Education, Malaysia-Exploratory Research Grant Scheme-Project no: ERGS/1-2013/5527165, Sabine A.S.Langie is the beneficiary of a postdoctoral grant from the AXA Research Fund and the Cefic-LRI Innovative Science Award 2013, Sakina Eltom is supported by NIH grant SC1CA153326, Samira A.Brooks was supported by National Research Service Award (T32 ES007126) from the National Institute of Environmental Health Sciences and the HHMI Translational Medicine Fellowship, Sandra Ryeom was supported by The Garrett B. Smith Foundation and the TedDriven Foundation, Thierry Massfelder was supported by the Institut National de la Santé et de la Recherche Médicale INSERM and Université de Strasbourg, Thomas Sanderson is supported by the Canadian Institutes of Health Research (CIHR, MOP-115019), the Natural Sciences and Engineering Council of Canada (NSERC, 313313) and the California Breast Cancer Research Program (CBCRP, 17UB-8703), Tiziana Guarnieri is supported by a grant from Fundamental Oriented Research (RFO) to the Alma Mater Studiorum University of Bologna, Bologna, Italy and thanks the Fondazione Cassa di Risparmio di Bologna and the Fondazione Banca del Monte di Bologna e Ravenna for supporting the Center for Applied Biomedical Research, S.Orsola-Malpighi University Hospital, Bologna, Italy, W.Kimryn Rathmell is supported by the V Foundation for Cancer Research and the American Cancer Society, William K.Decker was supported in part by grant RP110545 from the Cancer Prevention Research Institute of Texas, William H.Bisson was supported with funding from the NIH P30 ES000210, Yon Rojanasakul was supported with NIH grant R01-ES022968, Zhenbang Chen is supported by NIH grants (MD004038, CA163069 and MD007593), Zhiwei Hu is grateful for the grant support from an institutional start-up fund from The Ohio State University College of Medicine and The OSU James Comprehensive Cancer Center (OSUCCC) and a Seed Award from the OSUCCC Translational Therapeutics Program., Sans affiliation, Courcelles, Michel, Goodson, W, Lowe, L, Carpenter, D, Gilbertson, M, Ali, A, de Cerain Salsamendi, A, Lasfar, A, Carnero, A, Azqueta, A, Amedei, A, Charles, A, Collins, A, Ward, A, Salzberg, A, Colacci, A, Olsen, A, Berg, A, Barclay, B, Zhou, B, Blanco Aparicio, C, Baglole, C, Dong, C, Mondello, C, Hsu, C, Naus, C, Yedjou, C, Curran, C, Laird, D, Koch, D, Carlin, D, Felsher, D, Roy, D, Brown, D, Ratovitski, E, Ryan, E, Corsini, E, Rojas, E, Moon, E, Laconi, E, Marongiu, F, Al Mulla, F, Chiaradonna, F, Darroudi, F, Martin, F, Van Schooten, F, Goldberg, G, Wagemaker, G, Nangami, G, Calaf, G, Williams, G, Wolf, G, Koppen, G, Brunborg, G, Kim Lyerly, H, Krishnan, H, Hamid, H, Yasaei, H, Sone, H, Kondoh, H, Salem, H, Hsu, H, Park, H, Koturbash, I, Miousse, I, Ivana Scovassi, A, Klaunig, J, Vondráček, J, Raju, J, Roman, J, Wise, J, Whitfield, J, Woodrick, J, Christopher, J, Ochieng, J, Martinez Leal, J, Weisz, J, Kravchenko, J, Sun, J, Prudhomme, K, Narayanan, K, Cohen Solal, K, Moorwood, K, Gonzalez, L, Soucek, L, Jian, L, D'Abronzo, L, Lin, L, Li, L, Gulliver, L, Mccawley, L, Memeo, L, Vermeulen, L, Leyns, L, Zhang, L, Valverde, M, Khatami, M, Romano, M, Chapellier, M, Williams, M, Wade, M, Manjili, M, Lleonart, M, Xia, M, Gonzalez, M, Karamouzis, M, Kirsch Volders, M, Vaccari, M, Kuemmerle, N, Singh, N, Cruickshanks, N, Kleinstreuer, N, Van Larebeke, N, Ahmed, N, Ogunkua, O, Krishnakumar, P, Vadgama, P, Marignani, P, Ghosh, P, Ostrosky Wegman, P, Thompson, P, Dent, P, Heneberg, P, Darbre, P, Leung, P, Nangia Makker, P, Cheng, Q, Brooks Robey, R, Al Temaimi, R, Roy, R, Andrade Vieira, R, Sinha, R, Mehta, R, Vento, R, Di Fiore, R, Ponce Cusi, R, Dornetshuber Fleiss, R, Nahta, R, Castellino, R, Palorini, R, Hamid, R, Langie, S, Eltom, S, Brooks, S, Ryeom, S, Wise, S, Bay, S, Harris, S, Papagerakis, S, Romano, S, Pavanello, S, Eriksson, S, Forte, S, Casey, S, Luanpitpong, S, Lee, T, Otsuki, T, Chen, T, Massfelder, T, Sanderson, T, Guarnieri, T, Hultman, T, Dormoy, V, Odero Marah, V, Sabbisetti, V, Maguer Satta, V, Kimryn Rathmell, W, Engström, W, Decker, W, Bisson, W, Rojanasakul, Y, Luqmani, Y, Chen, Z, and Hu, Z
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Cancer Research ,Carcinogenesis ,[SDV]Life Sciences [q-bio] ,METHOXYCHLOR-INDUCED ALTERATIONS ,Review ,Pharmacology ,MESH: Carcinogens, Environmental ,Carcinogenic synergies ,Chemical mixtures ,Neoplasms ,MESH: Animals ,MESH: Neoplasms ,Carcinogenesi ,Risk assessment ,Cancer ,ACTIVATED PROTEIN-KINASES ,Medicine (all) ,Low dose ,1. No poverty ,Cumulative effects ,BREAST-CANCER CELLS ,General Medicine ,Environmental exposure ,MESH: Carcinogenesis ,BIO/10 - BIOCHIMICA ,EPITHELIAL-MESENCHYMAL TRANSITION ,3. Good health ,[SDV] Life Sciences [q-bio] ,Environmental Carcinogenesis ,ESTROGEN-RECEPTOR-ALPHA ,Human ,MESH: Environmental Exposure ,ENDOCRINE-DISRUPTING CHEMICALS ,TARGETING TISSUE FACTOR ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Prototypical chemical disruptors ,Exposure ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Environmental health ,medicine ,[SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health ,Carcinogen ,Environmental carcinogenesis ,[SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health ,MESH: Humans ,Animal ,POLYBROMINATED DIPHENYL ETHERS ,Environmental Exposure ,medicine.disease ,MESH: Hazardous Substances ,Carcinogens, Environmental ,MIGRATION INHIBITORY FACTOR ,VASCULAR ENDOTHELIAL-CELLS ,Hazardous Substance ,Neoplasm - Abstract
Goodson, William H. et al., © The Author 2015. Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology., We gratefully acknowledge the support of the National Institute of Health-National Institute of Environmental Health Sciences (NIEHS) conference grant travel support (R13ES023276); Glenn Rice, Office of Research and Development, United States Environmental Protection Agency, Cincinnati, OH, USA also deserves thanks for his thoughtful feedback and inputs on the manuscript; William H.Goodson III was supported by the California Breast Cancer Research Program, Clarence Heller Foundation and California Pacific Medical Center Foundation; Abdul M.Ali would like to acknowledge the financial support of the University of Sultan Zainal Abidin, Malaysia; Ahmed Lasfar was supported by an award from the Rutgers Cancer Institute of New Jersey; Ann-Karin Olsen and Gunnar Brunborg were supported by the Research Council of Norway (RCN) through its Centres of Excellence funding scheme (223268/F50), Amancio Carnero’s lab was supported by grants from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028) co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0306-2012); Matilde E. Lleonart was supported by a trienal project grant PI12/01104 and by project CP03/00101 for personal support. Amaya Azqueta would like to thank the Ministerio de Educacion y Ciencia (‘Juande la Cierva’ programme, 2009) of the Spanish Government for personal support; Amedeo Amedei was supported by the Italian Ministry of University and Research (2009FZZ4XM_002), and the University of Florence (ex60%2012); Andrew R.Collins was supported by the University of Oslo; Annamaria Colacci was supported by the Emilia-Romagna Region - Project ‘Supersite’ in Italy; Carolyn Baglole was supported by a salary award from the Fonds de recherche du Quebec-Sante (FRQ-S); Chiara Mondello’s laboratory is supported by Fondazione Cariplo in Milan, Italy (grant n. 2011-0370); Christian C.Naus holds a Canada Research Chair; Clement Yedjou was supported by a grant from the National Institutes of Health (NIH-NIMHD grant no. G12MD007581); Daniel C.Koch is supported by the Burroughs Wellcome Fund Postdoctoral Enrichment Award and the Tumor Biology Training grant: NIH T32CA09151; Dean W. Felsher would like to acknowledge the support of United States Department of Health and Human Services, NIH grants (R01 CA170378 PQ22, R01 CA184384, U54 CA149145, U54 CA151459, P50 CA114747 and R21 CA169964); Emilio Rojas would like to thank CONACyT support 152473, Ezio Laconi was supported by AIRC (Italian Association for Cancer Research, grant no. IG 14640) and by the Sardinian Regional Government (RAS); Eun-Yi Moon was supported by grants from the Public Problem-Solving Program (NRF-015M3C8A6A06014500) and Nuclear R&D Program (#2013M2B2A9A03051296 and 2010-0018545) through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology (MEST) in Korea; Fahd Al-Mulla was supported by the Kuwait Foundation for the Advancement of Sciences (2011-1302-06); Ferdinando Chiaradonna is supported by SysBioNet, a grant for the Italian Roadmap of European Strategy Forum on Research Infrastructures (ESFRI) and by AIRC (Associazione Italiana Ricerca sul Cancro; IG 15364); Francis L.Martin acknowledges funding from Rosemere Cancer Foundation; he also thanks Lancashire Teaching Hospitals NHS trust and the patients who have facilitated the studies he has undertaken over the course of the last 10 years; Gary S.Goldberg would like to acknowledge the support of the New Jersey Health Foundation; Gloria M.Calaf was supported by Fondo Nacional de Ciencia y Tecnología (FONDECYT), Ministerio de Educación de Chile (MINEDUC), Universidad de Tarapacá (UTA); Gudrun Koppen was supported by the Flemish Institute for Technological Research (VITO), Belgium; Hemad Yasaei was supported from a triennial project grant (Strategic Award) from the National Centre for the Replacement, Refinement and Reduction (NC3Rs) of animals in research (NC.K500045.1 and G0800697); Hiroshi Kondoh was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Science and Technology Agency and by JST, CREST; Hsue-Yin Hsu was supported by the Ministry of Science and Technology of Taiwan (NSC93-2314-B-320-006 and NSC94-2314-B-320-002); Hyun Ho Park was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) of the Ministry of Education, Science and Technology (2012R1A2A2A01010870) and a grant from the Korea Healthcare Technology R&D project, Ministry of Health and Welfare, Republic of Korea (HI13C1449); Igor Koturbash is supported by the UAMS/NIH Clinical and Translational Science Award (UL1TR000039 and KL2TR000063) and the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000; Jan Vondráček acknowledges funding from the Czech Science Foundation (13-07711S); Jesse Roman thanks the NIH for their support (CA116812), John Pierce Wise Sr. and Sandra S.Wise were supported by National Institute of Environmental Health Sciences (ES016893 to J.P.W.) and the Maine Center for Toxicology and Environmental Health; Jonathan Whitfield acknowledges support from the FERO Foundation in Barcelona, Spain; Joseph Christopher is funded by Cancer Research UK and the International Journal of Experimental Pathology; Julia Kravchenko is supported by a philanthropic donation by Fred and Alice Stanback; Jun Sun is supported by a Swim Across America Cancer Research Award; Karine A.Cohen-Solal is supported by a research scholar grant from the American Cancer Society (116683-RSG-09-087-01-TBE); Laetitia Gonzalez received a postdoctoral fellowship from the Fund for Scientific Research–Flanders (FWO-Vlaanderen) and support by an InterUniversity Attraction Pole grant (IAP-P7-07); Laura Soucek is supported by grant #CP10/00656 from the Miguel Servet Research Contract Program and acknowledges support from the FERO Foundation in Barcelona, Spain; Liang-Tzung Lin was supported by funding from the Taipei Medical University (TMU101-AE3-Y19); Linda Gulliver is supported by a Genesis Oncology Trust (NZ) Professional Development Grant, and the Faculty of Medicine, University of Otago, Dunedin, New Zealand; Louis Vermeulen is supported by a Fellowship of the Dutch Cancer Society (KWF, UVA2011-4969) and a grant from the AICR (14–1164); Mahara Valverde would like to thank CONACyT support 153781; Masoud H. Manjili was supported by the office of the Assistant Secretary of Defense for Health Affairs (USA) through the Breast Cancer Research Program under Award No. W81XWH-14-1-0087 Neetu Singh was supported by grant #SR/FT/LS-063/2008 from the Department of Science and Technology, Government of India; Nicole Kleinstreuer is supported by NIEHS contracts (N01-ES 35504 and HHSN27320140003C); P.K. Krishnakumar is supported by the Funding (No. T.K. 11-0629) of King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia; Paola A.Marignani is supported by the Dalhousie Medical Research Foundation, The Beatrice Hunter Cancer Institute and CIHR and the Nova Scotia Lung Association; Paul Dent is the holder of the Universal Inc.Chair in Signal Transduction Research and is supported with funds from PHS grants from the NIH (R01-CA141704, R01-CA150214, R01-DK52825 and R01-CA61774); Petr Heneberg was supported by the Charles University in Prague projects UNCE 204015 and PRVOUK P31/2012, and by the Czech Science Foundation projects P301/12/1686 and 15-03834Y; Po Sing Leung was supported by the Health and Medical Research Fund of Food and Health Bureau, Hong Kong Special Administrative Region, Ref. No: 10110021; Qiang Cheng was supported in part by grant NSF IIS-1218712; R. Brooks Robey is supported by the United States Department of Veterans Affairs; Rabindra Roy was supported by United States Public Health Service Grants (RO1 CA92306, RO1 CA92306-S1 and RO1 CA113447); Rafaela Andrade-Vieira is supported by the Beatrice Hunter Cancer Research Institute and the Nova Scotia Health Research Foundation, Renza Vento was partially funded by European Regional Development Fund, European Territorial Cooperation 2007–13 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–13) and grants from the Italian Ministry of Education, University and Research (MIUR) ex-60%, 2007; Riccardo Di Fiore was a recipient of fellowship granted by European Regional Development Fund, European Territorial Cooperation 2007–2013 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–2013); Rita Dornetshuber-Fleiss was supported by the Austrian Science Fund (FWF, project number T 451-B18) and the Johanna Mahlke, geb.-Obermann-Stiftung; Roberta Palorini is supported by a SysBioNet fellowship; Roslida Abd Hamid is supported by the Ministry of Education, Malaysia-Exploratory Research Grant Scheme-Project no: ERGS/1-2013/5527165; Sabine A.S.Langie is the beneficiary of a postdoctoral grant from the AXA Research Fund and the Cefic-LRI Innovative Science Award 2013; Sakina Eltom is supported by NIH grant SC1CA153326; Samira A.Brooks was supported by National Research Service Award (T32 ES007126) from the National Institute of Environmental Health Sciences and the HHMI Translational Medicine Fellowship; Sandra Ryeom was supported by The Garrett B. Smith Foundation and the TedDriven Foundation; Thierry Massfelder was supported by the Institut National de la Santé et de la Recherche Médicale INSERM and Université de Strasbourg; Thomas Sanderson is supported by the Canadian Institutes of Health Research (CIHR; MOP-115019), the Natural Sciences and Engineering Council of Canada (NSERC; 313313) and the California Breast Cancer Research Program (CBCRP; 17UB-8703); Tiziana Guarnieri is supported by a grant from Fundamental Oriented Research (RFO) to the Alma Mater Studiorum University of Bologna, Bologna, Italy and thanks the Fondazione Cassa di Risparmio di Bologna and the Fondazione Banca del Monte di Bologna e Ravenna for supporting the Center for Applied Biomedical Research, S.Orsola-Malpighi University Hospital, Bologna, Italy; W.Kimryn Rathmell is supported by the V Foundation for Cancer Research and the American Cancer Society; William K.Decker was supported in part by grant RP110545 from the Cancer Prevention Research Institute of Texas; William H.Bisson was supported with funding from the NIH P30 ES000210; Yon Rojanasakul was supported with NIH grant R01-ES022968; Zhenbang Chen is supported by NIH grants (MD004038, CA163069 and MD007593); Zhiwei Hu is grateful for the grant support from an institutional start-up fund from The Ohio State University College of Medicine and The OSU James Comprehensive Cancer Center (OSUCCC) and a Seed Award from the OSUCCC Translational Therapeutics Program.
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- 2015
22. Abstract 1668: Mutational landscape and pharmacological profiling of a panel of prostate PDX models including hormone-naïve, hormone-sensitive and castrate-resistant prostate cancer specimens
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Myriam Lassalle, Herve Lang, Véronique Lindner, Yves Allory, Claire Béraud, Thierry Massfelder, E. Potiron, Philippe Lluel, and Yolande Misseri
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Cancer Research ,medicine.anatomical_structure ,Oncology ,business.industry ,Prostate ,Castrate-resistant prostate cancer ,Cancer research ,Medicine ,Hormone naive ,business ,Hormone-sensitive - Abstract
Prostate Cancer (PCa) is the second most frequent cancer in men worldwide and the fifth leading cause of cancer death with an incidence rate of 13.5%. PCa is driven by multiple genomic alterations, with distinct patterns and clinical implications. These genomic alterations occurring both early and later in the natural history of the disease (ranging from localized disease, initially responsive to androgen deprivation therapy, to Castrate Resistant Prostate Cancers -CRPC) allow classification of PCa in several molecular subtypes with potential clinical relevance. Patient-Derived Xenograft (PDX) models have become the most reliable in vivo human cancer models. Developing such models that capture the biological heterogeneity and mutational landscape of PCa, remains a challenge, but is essential for delivery of precision medicine in metastatic castrate resistant stages. In this study, we present the genomic and transcriptomic landscapes, as well as the pharmacological status of an established bank of seven (7) prostate PDX models ranging from hormone naïve to hormone-resistance PCa specimens. Samples of PCa along with normal corresponding tissues were obtained directly from patients at surgery. Fragments were subcutaneously xenografted into immunocompromised mice to establish PDX models. After the first growth in mice, they were serially passaged in vivo and considered to be established from P3. To ensure model stability, PDX tumors at multiple passages and patients' primary tumors were processed for histological, transcriptomic (Affymetrix U133 plus 2.0 microarray) and STR profile analyses. Genomic characteristics (WES, CNA) were also investigated. Finally, the responses of the PDX models to androgen deprivation and docetaxel were also evaluated. 7 PDX models were successfully established (> P3 in mice) out of 253 primary prostatic tumors collected from surgery. Within those models, one matched pair of responsive adenocarcinoma and neuroendocrine castration-resistant (NE-CRPC) models from the same patient was generated. Histological, transcriptomic and STR profiling validated the stability of the models compared to the parental tumor. The genomic analyses revealed i) the mutational burden rise with the resistance to treatments of the models, correlating with clinical results ii) an increase of metastatic genes loss in the NE-CRPC compared to the corresponding hormone sensitive adenocarcinoma. Furthermore, for all the PDX models generated, genomic and mutational analyses revealed specific molecular features and allowed molecular classification depending on tumor stage. Based on the molecular taxonomy of primary prostate cancers, the presented panel covers the different progression steps of the pathology. Considering the scarcity of useful models for PCa and the difficulties to develop such models, the prostate PDX models collection presented here should clearly help understanding disease progression and supporting precision medicine approaches for patients with advanced PCa. Citation Format: Myriam Lassalle, Claire Béraud, Hervé Lang, Véronique Lindner, Yves Allory, Eric Potiron, Thierry Massfelder, Philippe Lluel, Yolande Misseri. Mutational landscape and pharmacological profiling of a panel of prostate PDX models including hormone-naïve, hormone-sensitive and castrate-resistant prostate cancer specimens [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1668.
- Published
- 2020
23. Abstract A24: Establishment of a panel of patient-derived tumor xenograft models recapitulating molecular heterogeneity and drug response of muscle-invasive bladder tumors
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Yves Allory, Claire Béraud, Clémentine Krucker, Michel Soulié, Aurélie Kamoun, Isabelle Bernard-Pierrot, François Radvanyi, Elodie Guillon, Thierry Massfelder, Hervé Lang, Xavier Gamé, Aurélien de Reyniès, Philippe Lluel, Véronique Lindner, Myriam Lassalle, and Pascal Rischmann
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Cancer Research ,Chemotherapy ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Muscle invasive ,Cancer ,Immunotherapy ,medicine.disease ,Subtyping ,Basal (phylogenetics) ,Oncology ,medicine ,Cancer research ,Histopathology ,business ,Tumor xenograft - Abstract
Background: Muscle-invasive bladder cancers (MIBCs) constitute a heterogeneous group of tumors with poor outcome. Recently, MIBC molecular subtyping efforts from an international consortium led to the identification of six subtypes, improving prediction of clinical outcomes and treatment responses. FGFR3 alterations (mutations and translocations), observed in 20% of MIBCs, are found mainly in the luminal papillary subtype that respond poorly to chemo- and immunotherapy. Basal tumors represent 35% of MIBCs and were shown to be better responders to chemotherapy. Here, we describe the development and characterization of patient-derived primary MIBC xenografts (PDX) belonging to these main subtypes. Methods: Bladder tumors were obtained from patients at surgery. Tumor fragments were subcutaneously engrafted into immune-compromised mice. Primary tumors and matched PDX tumors at multiple passages were analyzed regarding growth characteristics, histopathology (H&E staining, CK5/6, FOXA1, and GATA3 immunohistochemistry), gene expression (Affymetrix U133 plus 2.0 microarray), and genetic stability (STR profiling). Hotspot oncogenic mutations for FGFR3, PIK3CA, HRAS, KRAS, NRAS, PPARG, and RXRA were also assessed. Additionally, pharmacologic responses to standard-of-care and targeted therapies were characterized. Findings: From 152 MIBC tumors at all stages and grades, 32 PDX models were successfully established (21.1% success rate). This take rate did not seem correlated to any classical tumor characteristics. Importantly, transcriptomic analysis allowed us to identify PDX models belonging to different molecular subtypes, notably the basal-like and luminal papillary subtypes, including PDXs with FGFR3 mutations. All histologic, genetic, and molecular features validated the stability of the PDX models compared to the parental tumors. Histologic analyses correlated with the molecular classification. These models reproduced the response to cisplatin-based therapies observed in the clinic. Basal models, except one harboring a FGFR3 mutation, were sensitive to anti-EGFR therapies but to a lesser extent than to chemotherapy. FGFR3-mutated PDX models, including a basal model, were highly responsive to FGFR3 inhibitors and less responsive to chemotherapy. Conclusion: We have developed and characterized highly relevant preclinical models for MIBCs, including basal and FGFR3-mutated tumors, recapitulating molecular heterogeneity and drug responses as observed in patients with MIBCs. They represent essential tools for developing new, efficient therapies against this deadly disease. Citation Format: Claire Béraud, Hervé Lang, Myriam Lassalle, Véronique Lindner, Aurélie Kamoun, Michel Soulié, Elodie Guillon, Clémentine Krucker, Xavier Gamé, Pascal Rischmann, Aurélien De Reynies, Yves Allory, François Radvanyi, Philippe Lluel, Thierry Massfelder, Isabelle Bernard-Pierrot. Establishment of a panel of patient-derived tumor xenograft models recapitulating molecular heterogeneity and drug response of muscle-invasive bladder tumors [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A24.
- Published
- 2020
24. Parathyroid Hormone–Related Protein Contributes to Early Healing of Habu Snake Venom–Induced Glomerulonephritis in Mice
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Denis Raison, Mazène Hochane, Thierry Massfelder, Sabrina Danilin, Audrey Bethry, Catherine Coquard, Claire Béraud, Mariette Barthelmebs, Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), and univOAK, Archive ouverte
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Male ,0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Kidney Glomerulus ,030232 urology & nephrology ,Inflammation ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Injections ,Pathology and Forensic Medicine ,Proinflammatory cytokine ,03 medical and health sciences ,Glomerulonephritis ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Internal medicine ,Crotalid Venoms ,medicine ,Animals ,Trimeresurus ,Cell Proliferation ,Mesangial cell ,Parathyroid hormone-related protein ,business.industry ,Growth factor ,Parathyroid Hormone-Related Protein ,medicine.disease ,Antibodies, Neutralizing ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Snake venom ,Creatinine ,Mesangial proliferative glomerulonephritis ,medicine.symptom ,business ,hormones, hormone substitutes, and hormone antagonists - Abstract
International audience; Proliferative glomerulonephritis is characterized by local inflammation and mesangial cell deterioration, followed by mesangial proliferation and glomerular healing. Parathyroid hormone-related peptide (PTHrP) is a mesangial cytokine-like growth factor implicated in mesangial proliferation and survival. No data are available about its role in glomerulonephritis. Herein, we analyzed the expression and role of PTHrP in glomerular inflammation and healing in an experimental model of glomerulonephritis induced by i.v. injection of Habu snake venom in mice. The temporal analysis showed marked renal damage in the first days after venom injection and the beginning of recovery within 7 days. Glomerular expression of PTHrP (transcript and protein) was observed in the early phase after venom injection (from day 1 to day 3), along with an inflammatory environment. The inactivation of secreted PTHrP with PTHrP-neutralizing antibody (PTH2E11; 120 μg i.p. daily) reduced the markers of local inflammation (expression of macrophage chemotactic protein-1; regulated upon activation, normal T cell expressed and secreted; cyclooxygenase 2; IL-6; and macrophage infiltration) and abolished the expression of PTHrP itself. Moreover, the glomerular cell proliferation was hampered, and the healing process was prevented on day 7 after venom injection. These results show that PTHrP has antinomic actions in glomerulonephritis, participating in both the proinflammatory condition and the healing process. Our work reveals the essential role of PTHrP in early glomerular repair in an experimental model of glomerulonephritis.
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- 2018
25. Polydiacetylenic nanofibers as new siRNA vehicles for in vitro and in vivo delivery
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V. Lindner, Antoine Kichler, Patrick Neuberg, Marc Nothisen, Alain Wagner, Imène Hamaidi, Thierry Massfelder, Sabrina Danilin, Manon Ripoll, Jean-Serge Remy, Institut de Chimie de Strasbourg, and Centre National de la Recherche Scientifique (CNRS)-Université Louis Pasteur - Strasbourg I-Institut de Chimie du CNRS (INC)
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congenital, hereditary, and neonatal diseases and abnormalities ,Small interfering RNA ,health care facilities, manpower, and services ,education ,LIM-Homeodomain Proteins ,Nanofibers ,Mice, Nude ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Mice ,In vivo ,health services administration ,Cell Line, Tumor ,[CHIM]Chemical Sciences ,Gene silencing ,Animals ,General Materials Science ,Gene Silencing ,RNA, Small Interfering ,ComputingMilieux_MISCELLANEOUS ,Oncogene ,Chemistry ,021001 nanoscience & nanotechnology ,Xenograft Model Antitumor Assays ,In vitro ,Kidney Neoplasms ,Polyacetylene Polymer ,0104 chemical sciences ,Cell biology ,Cell culture ,Nanofiber ,Cancer cell ,Chimie/Chimie thérapeutique ,0210 nano-technology ,Injections, Intraperitoneal ,Transcription Factors - Abstract
Polydiacetylenic nanofibers (PDA-Nfs) obtained by photopolymerization of surfactant 1 were optimized for intracellular delivery of small interfering RNAs (siRNAs). PDA-Nfs/siRNA complexes efficiently silenced the oncogene Lim-1 in the renal cancer cells 786-O in vitro. Intraperitoneal injection of PDA-Nfs/siLim1 downregulated Lim-1 in subcutaneous tumor xenografts obtained with 786-O cells in nude mice. Thus, PDA-Nfs represent an innovative system for in vivo delivery of siRNAs.
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- 2018
26. An FGFR3/MYC positive feedback loop provides new opportunities for targeted therapies in bladder cancers
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Clémentine Krucker, Marion Dorland-Galliot, Mélanie Mahe, F. Radvanyi, Hélène Neyret-Kahn, Isabelle Bernard-Pierrot, Imène Hamaidi, Mingjun Shi, Thierry Massfelder, Elodie Chapeaublanc, Virginia Sanchez‐Quiles, Florent Dufour, Hervé Lang, Celio Pouponnot, Claire Béraud, Aura Moreno-Vega, Rémy Nicolle, Compartimentation et dynamique cellulaires (CDC), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Les Hôpitaux Universitaires de Strasbourg (HUS), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), and Université de Strasbourg (UNISTRA)
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0301 basic medicine ,Medicine (General) ,030232 urology & nephrology ,MYC ,QH426-470 ,Fibroblast growth factor ,p38 Mitogen-Activated Protein Kinases ,[SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology ,0302 clinical medicine ,p38 Subject Categories Cancer ,BET inhibitors ,Research Articles ,Cancer ,Azepines ,musculoskeletal system ,3. Good health ,030220 oncology & carcinogenesis ,Molecular Medicine ,bladder cancer ,Signal transduction ,Research Article ,Signal Transduction ,musculoskeletal diseases ,congenital, hereditary, and neonatal diseases and abnormalities ,Cell Survival ,Urology ,MEDLINE ,Urogenital System ,p38 ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,03 medical and health sciences ,Text mining ,R5-920 ,Cell Line, Tumor ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,medicine ,Genetics ,Humans ,Receptor, Fibroblast Growth Factor, Type 3 ,Viability assay ,Enhancer ,Protein kinase B ,Cell Proliferation ,Bladder cancer ,business.industry ,Cell growth ,Feedback loop ,Triazoles ,medicine.disease ,Bromodomain ,stomatognathic diseases ,030104 developmental biology ,Urinary Bladder Neoplasms ,FGFR3 ,Cancer research ,business ,MYC Positive - Abstract
FGFR3 alterations (mutations or translocation) are among the most frequent genetic events in bladder carcinoma. They lead to an aberrant activation of FGFR3 signaling, conferring an oncogenic dependence, which we studied here. We discovered a positive feedback loop, in which the activation of p38 and AKT downstream from the altered FGFR3 upregulates MYC mRNA levels and stabilizes MYC protein, respectively, leading to the accumulation of MYC, which directly upregulates FGFR3 expression by binding to active enhancers upstream from FGFR3 . Disruption of this FGFR3/MYC loop in bladder cancer cell lines by treatment with FGFR3, p38, AKT, or BET bromodomain inhibitors (JQ1) preventing MYC transcription decreased cell viability in vitro and tumor growth in vivo . A relevance of this loop to human bladder tumors was supported by the positive correlation between FGFR3 and MYC levels in tumors bearing FGFR3 mutations, and the decrease in FGFR3 and MYC levels following anti‐FGFR treatment in a PDX model bearing an FGFR3 mutation. These findings open up new possibilities for the treatment of bladder tumors displaying aberrant FGFR3 activation.
- Published
- 2018
27. Parathyroid hormone-related protein modulates inflammation in mouse mesangial cells and blunts apoptosis by enhancing COX-2 expression
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Claire Béraud, Denis Raison, Sabrina Danilin, Catherine Coquard, Mariette Barthelmebs, Audrey Bethry, Thierry Massfelder, and Mazène Hochane
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0301 basic medicine ,Male ,medicine.medical_specialty ,Time Factors ,Physiology ,Interleukin-1beta ,Peptide ,Inflammation ,Apoptosis ,Biology ,03 medical and health sciences ,Glomerulonephritis ,Internal medicine ,Parathyroid hormone-related peptide ,medicine ,Animals ,Secretion ,Cells, Cultured ,chemistry.chemical_classification ,Parathyroid hormone-related protein ,Tumor Necrosis Factor-alpha ,NF-kappa B ,Parathyroid Hormone-Related Protein ,Cell Biology ,medicine.disease ,Peptide Fragments ,Up-Regulation ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,chemistry ,Cyclooxygenase 2 ,Mesangial Cells ,Cancer research ,medicine.symptom ,Inflammation Mediators ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction - Abstract
Injury of mesangial cells (MC) is a prominent feature of glomerulonephritis. Activated MC secrete inflammatory mediators that induce cell apoptosis. Parathyroid hormone-related peptide (PTHrP) is a locally active cytokine that enhances cell survival and is upregulated by proinflammatory factors in many cell types. The aim of this study was to analyze the regulation of PTHrP expression by inflammatory cytokines and to evaluate whether PTHrP itself acts as a proinflammatory and/or survival factor on male murine MC in primary culture. Our results showed that IL-1β (10 ng/ml) and TNF-α (10 ng/ml) rapidly and transiently upregulated PTHrP expression in MC. The effects of IL-1β were both transcriptional and posttranscriptional, with stabilization of the PTHrP mRNA by human antigen R (HuR). Proteome profiler arrays showed that PTHrP itself enhanced cytokines within 2 h in cell lysates, mainly IL-17, IL-16, IL-1α, and IL-6. PTHrP also stimulated sustained expression (2–4 h) of chemokines, mainly regulated upon activation normal T cell expressed and secreted (RANTES)/C-C motif chemokine 5 (CCL5) and macrophage inflammatory protein-2 (MIP-2)/C-X-C motif chemokine 2 (CXCL2), thymus and activation-regulated chemokine (TARC)/CCL17, and interferon-inducible T cell α-chemoattractant (I-TAC)/CXCL11. Moreover, PTHrP markedly enhanced cyclooxygenase-2 (COX-2) expression and elicited its autoinduction through the activation of the NF-κB pathway. PTHrP induced MC survival via the COX-2 products, and PTHrP overexpression in MC blunted the apoptotic effects of IL-1β and TNF-α. Altogether, these findings suggest that PTHrP functions as a booster of glomerular inflammatory processes and may be a negative feedback loop preserving MC survival.
- Published
- 2017
28. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: focus on the cancer hallmark of tumor angiogenesis
- Author
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Lorenzo Memeo, Monica Vaccari, Roslida Abd Hamid, Jayadev Raju, Rabeah Al-Temaimi, Dustin G. Brown, Thierry Massfelder, W. Kimryn Rathmell, Fahd Al-Mulla, Jordan Woodrick, Liang Tzung Lin, Zhiwei Hu, Lasse Jensen, Samira A. Brooks, Menghang Xia, Leroy Lowe, Kalan R. Prudhomme, William H. Bisson, Stefano Forte, Hosni Salem, Nicole Kleinstreuer, Hsue-Yin Hsu, A. Ivana Scovassi, Chiara Mondello, Neetu Singh, Elizabeth P. Ryan, Amedeo Amedei, Annamaria Colacci, Rabindra Roy, Valérian Dormoy, and Chia Wen Hsu
- Subjects
Cancer Research ,Carcinogenesis ,Angiogenesis ,Review ,medicine.disease_cause ,Hazardous Substances ,Metastasis ,chemistry.chemical_compound ,Cancer stem cell ,Neoplasms ,Tumor Expansion ,medicine ,Animals ,Humans ,Tumor microenvironment ,Neovascularization, Pathologic ,business.industry ,Cancer ,Environmental Exposure ,General Medicine ,medicine.disease ,Carcinogens, Environmental ,Vascular endothelial growth factor ,chemistry ,Immunology ,Cancer research ,business - Abstract
One of the important 'hallmarks' of cancer is angiogenesis, which is the process of formation of new blood vessels that are necessary for tumor expansion, invasion and metastasis. Under normal physiological conditions, angiogenesis is well balanced and controlled by endogenous proangiogenic factors and antiangiogenic factors. However, factors produced by cancer cells, cancer stem cells and other cell types in the tumor stroma can disrupt the balance so that the tumor microenvironment favors tumor angiogenesis. These factors include vascular endothelial growth factor, endothelial tissue factor and other membrane bound receptors that mediate multiple intracellular signaling pathways that contribute to tumor angiogenesis. Though environmental exposures to certain chemicals have been found to initiate and promote tumor development, the role of these exposures (particularly to low doses of multiple substances), is largely unknown in relation to tumor angiogenesis. This review summarizes the evidence of the role of environmental chemical bioactivity and exposure in tumor angiogenesis and carcinogenesis. We identify a number of ubiquitous (prototypical) chemicals with disruptive potential that may warrant further investigation given their selectivity for high-throughput screening assay targets associated with proangiogenic pathways. We also consider the cross-hallmark relationships of a number of important angiogenic pathway targets with other cancer hallmarks and we make recommendations for future research. Understanding of the role of low-dose exposure of chemicals with disruptive potential could help us refine our approach to cancer risk assessment, and may ultimately aid in preventing cancer by reducing or eliminating exposures to synergistic mixtures of chemicals with carcinogenic potential.
- Published
- 2015
29. Targeting FAK scaffold functions inhibits human renal cell carcinoma growth
- Author
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Thierry Massfelder, Didier Jacqmin, Sabrina Danilin, Claire Béraud, Mariette Barthelmebs, Véronique Lindner, Catherine Coquard, Hervé Lang, Mazène Hochane, Valérian Dormoy, and Audrey Bethry
- Subjects
Cancer Research ,Gene knockdown ,Tumor suppressor gene ,Cell growth ,Cell migration ,Biology ,medicine.disease_cause ,3. Good health ,Cell biology ,Focal adhesion ,Oncology ,Cell culture ,medicine ,biological phenomena, cell phenomena, and immunity ,Signal transduction ,Carcinogenesis - Abstract
Human conventional renal cell carcinoma (CCC) remains resistant to current therapies. Focal Adhesion Kinase (FAK) is upregulated in many epithelial tumors and clearly implicated in nearly all facets of cancer. However, only few reports have assessed whether FAK may be associated with renal tumorigenesis. In this study, we investigated the potential role of FAK in the growth of human CCC using a panel of CCC cell lines expressing or not the von Hippel-Lindau (VHL) tumor suppressor gene as well as normal/tumoral renal tissue pairs. FAK was found constitutively expressed in human CCC both in culture cells and freshly harvested tumors obtained from patients. We showed that CCC cell growth was dramatically reduced in FAK-depleted cells or after FAK inhibition with various inhibitors and this effect was obtained through inhibition of cell proliferation and induction of cell apoptosis. Additionally, our results indicated that FAK knockdown decreased CCC cell migration and invasion. More importantly, depletion or pharmacological inhibition of FAK substantially inhibited tumor growth in vivo. Interestingly, investigations of the molecular mechanism revealed loss of FAK phosphorylation during renal tumorigenesis impacting multiple signaling pathways. Taken together, our findings reveal a previously uncharacterized role of FAK in CCC whereby FAK exerts oncogenic properties through a non canonical signaling pathway involving its scaffolding kinase-independent properties. Therefore, targeting the FAK scaffold may represent a promising approach for developing innovative and highly specific therapies in human CCC.
- Published
- 2015
30. MP60-09 LIM1 ONCOGENE AS A NEW THERAPEUTIC TARGET IN ADVANCED HUMAN RENAL CELL CARCINOMA
- Author
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Sabrina Danilin, Véronique Lindner, Thierry Massfelder, Hervé Lang, Catherine Coquard, Imène Hamaidi, Mariette Barthelmebs, Claire Béraud, Sylvie Rothhut, and Valérian Dormoy
- Subjects
Oncology ,medicine.medical_specialty ,Oncogene ,Renal cell carcinoma ,business.industry ,Urology ,Internal medicine ,medicine ,medicine.disease ,business - Published
- 2017
31. MP87-08 ROLE OF THE C-MYC TARGET DNPH1, A NEW N-HYDROLASE, IN KIDNEY AND PROSTATE CANCERS
- Author
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Sylvie Pochet, Thierry Massfelder, Véronique Lindner, Sabrina Danilin, Claire Amiable, Claire Béraud, Hervé Lang, Pierre-Alexandre Kaminski, Sylvie Rothhut, Julie Paoletti, Catherine Coquard, and Imène Hamaidi
- Subjects
Oncology ,Kidney ,medicine.medical_specialty ,medicine.anatomical_structure ,business.industry ,Prostate ,Urology ,Internal medicine ,Hydrolase ,medicine ,business - Published
- 2017
32. MP73-07 INVOLVEMENT OF ANGIOGENIN IN SUNITINIB RESISTANCE IN HUMAN RENAL CELL CARCINOMA
- Author
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Catherine Coquard, Thierry Massfelder, Véronique Lindner, Hervé Lang, Sylvie Rothhut, Laure Pierard, Pascal Mouracade, Claire Béraud, S. Bergerat, and Imène Hamaidi
- Subjects
Angiogenin ,business.industry ,Sunitinib ,Renal cell carcinoma ,Urology ,Cancer research ,Medicine ,business ,medicine.disease ,medicine.drug - Published
- 2017
33. Abstract 92: Characterization of hormone-sensitive and castrate-resistant phenotypes in prostate cancer patient-derived PDX models generated from the same patient
- Author
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Hervé Lang, Claire Beraud, Myriam Lassalle, Véronique Lindner, Eric Potiron, Philippe Lluel, and Thierry Massfelder
- Subjects
Cancer Research ,Oncology - Abstract
Prostate cancer (PCa) is a highly heterogeneous and complex disease, with evolving treatment options over the course of disease progression. Preclinical PCa research is hampered by a lack of predictive models fully capturing all phases of this multistage disease. Despite progresses in the development of genetically-engineered animal models, these ones do not recapitulate faithfully (i) human disease and (ii) tumor heterogeneity. Models obtained by xenografting human tumors in immunodeficient animals (PDX models, for patient-derived tumor xenografts) remain unavoidable tools in PCa translational and preclinical research since they closely conserve cancer characteristics observed in patients. PDX models are thus invaluable tools to evaluate new potential therapeutic agents. We are presenting here the characteristics of two PDX models derived from the same patient before and after acquisition of the hormone-resistance status. Samples of PCa were obtained from patients at surgery and then subcutaneously xenografted into immunocompromised mice to establish PDX models. After the first growth in mice, they were serially passaged in vivo, considering a model established from P3. PDX tumors at multiple passages and patients’ primary tumors from which they are derived were processed for further analyses. Specifically, we performed histological, genetic (AR, PTEN, P53 and ERG status), transcriptomic (Affymetrix U133 plus 2.0 microarray) and STR profiles analyses. In addition, we also evaluated the responses of the PDX models to androgen deprivation and docetaxel. Since 9 years, 252 prostatic tumors have been collected at all stages. Up to now, 7 PDX models were successfully established (> P3 in mice), i.e. 2.7 % success rate. All histological, genetic and molecular analyses validated the stability of the models compared to the parental tumor. Interestingly, we were able to generate one matched pair of responsive and castration resistant models from the same patient. These two PDX models displayed the major molecular features of the disease in humans including PTEN, TP53 and AR modifications. In addition, in vivo results show heterogeneity of response to androgen deprivation and docetaxel, similar to the responses of patients to these treatments. Considering the scarcity of useful PDX models for PCa and the difficulties to develop such models, the PDX models collection presented here should clearly help to open the road of cure for patients with advanced PCa. Citation Format: Hervé Lang, Claire Beraud, Myriam Lassalle, Véronique Lindner, Eric Potiron, Philippe Lluel, Thierry Massfelder. Characterization of hormone-sensitive and castrate-resistant phenotypes in prostate cancer patient-derived PDX models generated from the same patient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 92.
- Published
- 2019
34. Abstract 1930: High specific characterization of patient-derived tumor xenograft models for accelerating drug development in muscle-invasive bladder cancers
- Author
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Hervé Lang, Claire Beraud, Myriam Lassalle, Véronique Lindner, Michel Soulié, Xavier Gamé, Pascal Rischmann, Yves Allory, François Radvanyi, Isabelle Bernard-Pierrot, Philippe Lluel, and Thierry Massfelder
- Subjects
Cancer Research ,Oncology - Abstract
Muscle-invasive bladder cancers (MIBCs) constitute a heterogeneous group of tumors with a poor outcome. Recently, MIBC molecular subtyping efforts from an international consortium led to the identification of six subtypes to improve prediction of clinical outcomes and treatment responses. These subtypes can be schematically divided into luminal (differentiated) and non-luminal subtypes. FGFR3 alterations (mutations and translocations) are among the most frequent genetic events in bladder carcinoma and are found mainly in one subtype, the luminal papillary that respond poorly to chemo- and immuno-therapy. Here we describe the development and characterization of patient-derived primary MIBC xenografts (PDX) belonging to these different subtypes. Bladder primary tumors and normal corresponding tissues were directly obtained from patients at surgery. Tumor fragments were subcutaneously xenografted into immune-compromised mice. After the first growth in mice, they were serially passaged. PDXs tumors at multiple passages and patients’ primary tumors from which they are derived were processed for analyses including growth characteristics, histopathology (H&E, CK5/6, FOXA1 and GATA3), gene expression (Affymetrix U133 plus 2.0 microarray), genetic stability (STR profiling). Specifically, hotspot oncogenic mutations including FGFR3, PIK3CA, HRAS, KRAS, NRAS, and PPARG were also explored. Additionally, pharmacological responses to standards of care and targeted therapies were characterized. Since 10 years, we have collected 152 MIBC tumors at all stages and grades. Up to now, 32 PDX models have been successfully established (> P3 in mice), i.e. 21.1 % success rate. This take rate seems not to be correlated to any classical tumor characteristics. Importantly, transcriptomic analysis allowed us to identify PDX models belonging to the different molecular subtypes including the basal-like and the luminal papillary subtypes (which include several PDX with FGFR3 mutations). All histological, genetic and molecular features validated the stability of the PDX models compared to the parental tumors. Histological analyses were correlated with the molecular classification. These models reproduced the response to cisplatin-based therapies observed in the clinic and FGFR3-mutated PDX models were shown to be highly responder to FGFR3 inhibitors. We have developed highly relevant preclinical models for MIBCs corresponding to the main subtypes which have been described. They represent essential tools for developing adapted and efficient therapies against this deadly disease. Citation Format: Hervé Lang, Claire Beraud, Myriam Lassalle, Véronique Lindner, Michel Soulié, Xavier Gamé, Pascal Rischmann, Yves Allory, François Radvanyi, Isabelle Bernard-Pierrot, Philippe Lluel, Thierry Massfelder. High specific characterization of patient-derived tumor xenograft models for accelerating drug development in muscle-invasive bladder cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1930.
- Published
- 2019
35. Recurrent activating mutations of PPARγ associated with luminal bladder tumors
- Author
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Isabelle Bernard-Pierrot, Florent Dufour, Hervé Lang, Clémentine Krucker, Judit Osz, Yves Allory, E. Guyon, Aurélie Kamoun, L. Coutos-Thevenot, Natacha Rochel, A. De Reynies, O.A. Hernandez, Thierry Massfelder, Roland H. Stote, Maxime Bourguet, Claire Béraud, Sandra Rebouissou, S. Heckler-Beji, K.A. Badawy, Yann Neuzillet, F. Radvanyi, W. Zita, Annick Dejaegere, Carole Peluso-Iltis, R. Zhang, S. Vanthong, Sarah Cianférani, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Compartimentation et dynamique cellulaires (CDC), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Shanghai Jiao Tong University [Shanghai], Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS), PSL Research University (PSL), Institut Curie-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
- Subjects
Male ,0301 basic medicine ,Aucun ,General Physics and Astronomy ,Peroxisome proliferator-activated receptor ,02 engineering and technology ,Sciences du Vivant [q-bio]/Cancer ,Crystallography, X-Ray ,[SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology ,Cohort Studies ,Transcription (biology) ,Medicine ,lcsh:Science ,chemistry.chemical_classification ,Multidisciplinary ,021001 nanoscience & nanotechnology ,3. Good health ,Gain of Function Mutation ,Mutation (genetic algorithm) ,Female ,0210 nano-technology ,Signal Transduction ,Peroxisome proliferator-activated receptor gamma ,Science ,Urology ,Urinary Bladder ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Sciences du Vivant [q-bio]/Médecine humaine et pathologie ,Molecular Dynamics Simulation ,Biology ,Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire ,General Biochemistry, Genetics and Molecular Biology ,Structure-Activity Relationship ,03 medical and health sciences ,Downregulation and upregulation ,Cell Line, Tumor ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Humans ,Protein Interaction Domains and Motifs ,Transcriptional activity ,Tumor microenvironment ,Retinoid X Receptor alpha ,Bladder cancer ,business.industry ,Point mutation ,Sequence Analysis, DNA ,General Chemistry ,medicine.disease ,PPAR gamma ,HEK293 Cells ,030104 developmental biology ,Urinary Bladder Neoplasms ,chemistry ,Mutation ,Cancer research ,lcsh:Q ,business - Abstract
The upregulation of PPARgamma/RXRalpha transcriptional activity has emerged as a key event in luminal bladder tumors. It renders tumor cell growth PPARgamma-dependent and modulates the tumor microenvironment to favor escape from immuno-surveillance. The activation of the pathway has been linked to PPARG gains/amplifications resulting in PPARgamma overexpression and to recurrent activating point mutations of RXRalpha. Here, we report recurrent mutations of PPARgamma that also activate the PPARgamma/RXRalpha pathway, conferring PPARgamma-dependency and supporting a crucial role of PPARgamma in luminal bladder cancer. These mutations are found throughout the protein-including N-terminal, DNA-binding and ligand-binding domains-and most of them enhance protein activity. Structure-function studies of PPARgamma variants with mutations in the ligand-binding domain allow identifying structural elements that underpin their gain-of-function. Our study reveals genomic alterations of PPARG that lead to pro-tumorigenic PPARgamma/RXRalpha pathway activation in luminal bladder tumors and may open the way towards alternative options for treatment.
- Published
- 2019
36. La métabolomique au service de la médecine
- Author
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Valérian Dormoy and Thierry Massfelder
- Subjects
business.industry ,Medicine ,General Medicine ,business ,Humanities ,General Biochemistry, Genetics and Molecular Biology - Published
- 2013
37. Parathyroid Hormone-Related Protein Is a Mitogenic and a Survival Factor of Mesangial Cells from Male Mice: Role of Intracrine and Paracrine Pathways
- Author
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Jean-Jacques Helwig, Mariette Barthelmebs, Denis Raison, Olivier Imhoff, Mazène Hochane, B. Moulin, Catherine Coquard, and Thierry Massfelder
- Subjects
Male ,musculoskeletal diseases ,medicine.medical_specialty ,Intracrine ,Cell Survival ,medicine.medical_treatment ,Mitosis ,Apoptosis ,Biology ,Transfection ,Proto-Oncogene Proteins c-myc ,Mice ,Paracrine signalling ,Glomerulonephritis ,Endocrinology ,Internal medicine ,medicine ,Animals ,E2F1 ,Protein kinase A ,Protein kinase B ,Cell Proliferation ,Parathyroid hormone-related protein ,Parathyroid Hormone-Related Protein ,musculoskeletal system ,Cytokine ,Parathyroid Hormone ,Mesangial Cells ,Cancer research ,Mitogens ,Cyclin-Dependent Kinase Inhibitor p27 ,E2F1 Transcription Factor ,hormones, hormone substitutes, and hormone antagonists - Abstract
Glomerulonephritis is characterized by the proliferation and apoptosis of mesangial cells (MC). The parathyroid-hormone related protein (PTHrP) is a locally active cytokine that affects these phenomena in many cell types, through either paracrine or intracrine pathways. The aim of this study was to evaluate the effect of both PTHrP pathways on MC proliferation and apoptosis. In vitro studies were based on MC from male transgenic mice allowing PTHrP-gene excision by a CreLoxP system. MC were also transfected with different PTHrP constructs: wild type PTHrP, PTHrP devoid of its signal peptide, or of its nuclear localization sequence. The results showed that PTHrP deletion in MC reduced their proliferation even in the presence of serum and increased their apoptosis when serum-deprived. PTH1R activation by PTHrP(1–36) or PTH(1–34) had no effect on proliferation but improved MC survival. Transfection of MC with PTHrP devoid of its signal peptide significantly increased their proliferation and minimally reduced their apoptosis. Overexpression of PTHrP devoid of its nuclear localization sequence protected cells from apoptosis without changing their proliferation. Wild type PTHrP transfection conferred both mitogenic and survival effects, which seem independent of midregion and C-terminal PTHrP fragments. PTHrP-induced MC proliferation was associated with p27Kip1 down-regulation and c-Myc/E2F1 up-regulation. PTHrP increased MC survival through the activation of cAMP/protein kinase A and PI3-K/Akt pathways. These results reveal that PTHrP is a cytokine of multiple roles in MC, acting as a mitogenic factor only through an intracrine pathway, and reducing apoptosis mainly through the paracrine pathway. Thus, PTHrP appears as a probable actor in MC injuries.
- Published
- 2013
38. Tumor suppressor versus oncogenic role of the new N-hydrolase DNPH1 in kidney and prostate cancers
- Author
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C. Amiable, Herve Lang, Sylvie Pochet, P.-A. Kaminski, Sabrina Danilin, J. Paoletti, C. Coquard, Sylvie Rothhut, Thierry Massfelder, Imène Hamaidi, and Véronique Lindner
- Subjects
Oncology ,medicine.medical_specialty ,Kidney ,business.industry ,Urology ,law.invention ,medicine.anatomical_structure ,Prostate ,law ,Internal medicine ,Hydrolase ,medicine ,Suppressor ,business - Published
- 2017
39. Thérapies ciblées dans le cancer du rein : identification des voies/marqueurs de résistance
- Author
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Véronique Lindner, C. Coquard, L. Pierard, Pascal Mouracade, Claire Béraud, S. Bergerat, Herve Lang, and Thierry Massfelder
- Subjects
business.industry ,Urology ,Medicine ,business ,Molecular biology - Abstract
Objectifs Des voies signaletiques proliferatives, anti-apoptotiques et angiogeniques (comme PI3 K/Akt) et certains marqueurs (comme Lim1) sont responsables de la resistance intrinseque du CCC et pourraient egalement etre responsables de la resistance induite par les therapies ciblees. Identifier et inhiber ces voies/marqueurs pourrait permettre de retrouver une sensibilite a ces therapies. Un accent particulier est donne aux mecanismes de resistance a la premiere ligne therapeutique, le sunitinib. Methodes Il est necessaire d’identifier un modele de CCC resistant au sunitinib. Etude in vitro sur cellules humaines de CCC (786-O, A498) par densite cellulaire (coloration CristalViolet) et in vivo sur un modele de souris nude xenogreffees en SC par ces lignees de leur sensibilite au sunitinib. Souris traitees par gavage 3×/semaine a la dose de 60 mg/kg pendant 7 semaines puis sacrifiees. L’effet du traitement sur la croissance tumorale sera mesure. Identification des voies/marqueurs actives par le traitement par analyses moleculaires (Proteome arrays, RT-qPCR et Westernblot), notamment dans les tumeurs in vivo. Validation in vivo des cibles par co-traitement sunitinib + inhibiteurs specifiques des proteines identifiees. Resultats In vitro, les lignees cellulaires de CCC sont sensibles au sunitinib mais resistantes in vivo. L’etude par proteome arrays sur les tumeurs obtenues in vivo montre que le sunitinib diminue l’expression de la P-Akt, et qu’il stimule plusieurs proteines de l’angiogenese notamment l’angiogenine, l’artemine et ADAMTS-1. Ces resultats ont ete confortes in vitro. L’etude par Western blot de leur expression dans des paires de tissus tumoraux et normaux correspondants (> 30 paires) montre que l’angiogenine est surexprimee dans 10 % des CCC alors que celle de l’artemine est deregulee dans 36 % des cas. L’expression de l’ADAMTS-1 est en cours. L’etude de l’effet de l’inhibition de l’angiogenine par siRNA (pas d’inhibiteur chimique disponible) sur la reponse au sunitinib est en cours d’investigation chez la souris nude xenogreffee par la lignee 786-O. Conclusion L’angiogenine, l’artemine et l’ADAMTS-1 ont ete identifiees comme de potentielles cibles impliquees dans les mecanismes de resistance au sunitinib dans le CCC. L’etude de ces cibles, notamment sur des modeles precliniques xenogreffees avec tumeurs humaines, devrait permettre de definir de nouvelles options therapeutiques dans le cancer du rein.
- Published
- 2016
40. Abstract 1035: A comprehensive patient-derived tumor xenograft (PDX) collection representing the heterogeneity of kidney, prostate and bladder cancers
- Author
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Yves Allory, Pascal Rischmann, François Radvanyi, Xavier Gamé, Thierry Massfelder, Michel Soulié, E. Potiron, Hervé Lang, Isabelle Bernard-Pierrot, Claire Béraud, Philippe Lluel, Myriam Lassalle, and Véronique Lindner
- Subjects
Cancer Research ,Kidney ,medicine.anatomical_structure ,Oncology ,business.industry ,Prostate ,Cancer research ,Medicine ,business ,Tumor xenograft - Abstract
Kidney, prostate and bladder cancers (KCa, PCa and BCa, respectively) represent 1 700 000 cases and 450 000 deaths worldwide per year, with an incidence rising yearly by 1-10%. Surgery is usually curative at early and localized stages but there are no efficient therapies at advanced and metastatic stages for any of them. Although genetically-modified and/or chemically-induced avatar models do exist for these cancers and may help to identify new therapeutic targets, they suffer from a lack of an extended biological concordance with the natural history and heterogeneity of the diseases. Patient-derived tumor xenograft models are now well recognized as reliably reproducing tumor heterogeneity and have become over the past few years the preclinical tools of choice to test drugs and identify biomarkers. Since 10 years, we are continuously developing a unique panel of PDX models for these major urological cancers. Tumor tissues along with normal corresponding tissues were obtained from patients at surgery. Patient informed consent and clinical history are available for all patients. Tumor tissues pieces were xenografted subcutaneously in the interscapular space of nude mice, and serially passaged into mice after the first engraftment, up to passage 10. To ensure model stability between primary tumors and tumors growing in mice but also from passage to passage, we performed various analyses at histopathological, genetic (short tandem repeat fingerprinting) and molecular (cDNA profiling) levels. In addition, growth characteristics and responses to standards of care (SOCs) were examined. Finally, specific molecular characteristics were also explored including expression of the androgen receptor, PSA and pan-cytokeratin for PCa models and hotspot mutations of FGFR3, PIK3CA, K/N/H-RAS for BCa models. Up to now, we have xenografted 336 (on 569 samples), 247 and 152 KCa, PCa and BCa tumor tissues, and developed 30 (8.9% success rate), 6 (2.1%) and 30 (19.7%) PDX models, respectively. We recently published part of the KCa PDX models collection (Lang et al., Oncotarget, 2016). Characterization studies showed that PDX models are stable at all levels analyzed considering concordance to primary tumors and from passage to passage; and less than 5% of genes were differentially expressed between the primary tumors and PDX tumors at various passages. Responses to SOCs recapitulated the clinical state. Only for KCa PDX models, the take rate was correlated to tumor stage and grade, and sarcomatoid components. Importantly, several molecular subtypes were defined in our collection of BCa PDX models including PDXs with FGFR3 mutations and PDXs of basal subtype, the most aggressive one. Overall, this panel of PDX models for urological cancers should definitely help to find molecularly guided targeted therapies for these still incurable cancers at metastatic stages. Citation Format: Hervé Lang, Claire Béraud, Myriam Lassalle, Isabelle Bernard-Pierrot, Véronique Lindner, Yves Allory, Michel Soulié, Xavier Gamé, Pascal Rischmann, Eric Potiron, François Radvanyi, Philippe Lluel, Thierry Massfelder. A comprehensive patient-derived tumor xenograft (PDX) collection representing the heterogeneity of kidney, prostate and bladder cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1035.
- Published
- 2018
41. An extensive panel of patient-derived bladder cancer xenografts representing the various molecular subtypes of muscle-invasive bladder cancers (MIBC)
- Author
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F. Radvanyi, Isabelle Bernard-Pierrot, M. Lassalle, N. Sirab, Herve Lang, Véronique Lindner, Yves Allory, Philippe Lluel, Thierry Massfelder, and Claire Béraud
- Subjects
Bladder cancer ,business.industry ,Urology ,Cancer research ,Muscle invasive ,medicine ,medicine.disease ,business - Published
- 2018
42. von Hippel-Lindau tumor suppressor gene-dependent mRNA stabilization of the survival factor parathyroid hormone-related protein in human renal cell carcinoma by the RNA-binding protein HuR
- Author
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Thierry Massfelder, Didier Jacqmin, Jean-Jacques Helwig, Carole Sourbier, Sylvie Rothhut, Lionel Thomas, Hervé Lang, Véronique Lindner, and Sabrina Danilin
- Subjects
Untranslated region ,Cancer Research ,medicine.medical_specialty ,Tumor suppressor gene ,RNA Stability ,RNA-binding protein ,urologic and male genital diseases ,ELAV-Like Protein 1 ,Cell Line, Tumor ,Internal medicine ,Von Hippel–Lindau tumor suppressor ,medicine ,Humans ,RNA, Messenger ,Carcinoma, Renal Cell ,neoplasms ,Messenger RNA ,Parathyroid hormone-related protein ,biology ,Alternative splicing ,Parathyroid Hormone-Related Protein ,RNA-Binding Proteins ,General Medicine ,MRNA stabilization ,Kidney Neoplasms ,female genital diseases and pregnancy complications ,Alternative Splicing ,Endocrinology ,ELAV Proteins ,Von Hippel-Lindau Tumor Suppressor Protein ,Antigens, Surface ,Cancer research ,biology.protein ,Protein Binding - Abstract
We have shown that parathyroid hormone-related protein (PTHrP) is a survival factor for human renal cell carcinoma (RCC) and that its expression is negatively regulated by the von Hippel-Lindau (VHL) tumor suppressor gene at the level of messenger RNA (mRNA) stability, as observed for tumor growth factors (TGFs). Our goals were to analyze the alternative splicing of PTHrP mRNA in human RCC and from these results to identify VHL/hypoxia-induced factor (HIF) system-regulated mRNA-binding proteins involved in PTHrP mRNA stability. We used: (i) a panel of human RCC cells expressing or not VHL; (ii) VHL-deficient 786-0 cells transfected with active or inactive VHL and (iii) human RCC samples and corresponding normal tissues. By quantitative real-time reverse transcription-polymerase chain reaction analysis, the 141 PTHrP mRNA isoform was found to be predominant in all cells and tumors (80%). In cells transfected with VHL, the expressions of all isoforms were decreased by 50%. Eight proteins with molecular weights ranging from 20 to 75 kDa were found to bind to biotinylated transcripts spanning the 141 PTHrP mRNA AU-rich 3'-untranslated region whose abundancy was dependent on VHL expression. The protein having an apparent molecular weight of 30 kDa was identified by western blot as HuR, a RNA-binding protein with stabilizing functions on various mRNA coding for proteins important in malignant transformation including vascular endothelial growth factor and TGF-beta. PTHrP expression studies confirmed the involvement of HuR in PTHrP upregulation in this disease. Common mRNA-binding proteins regulated by the VHL/HIF system may constitute new therapeutic opportunities against human RCC that remains refractory to therapies.
- Published
- 2008
43. Parathyroid hormone-related protein induces cell survival in human renal cell carcinoma through the PI3K Akt pathway: evidence for a critical role for integrin-linked kinase and nuclear factor kappa B
- Author
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Abdelali Agouni, Carole Sourbier, Didier Jacqmin, Thierry Massfelder, Herve Lang, Jean-Jacques Helwig, Sylvie Rothhut, Véronique Lindner, and Sabrina Danilin
- Subjects
Cancer Research ,Tumor suppressor gene ,Cell Survival ,Apoptosis ,Protein Serine-Threonine Kinases ,Transfection ,urologic and male genital diseases ,Phosphatidylinositol 3-Kinases ,Cell Line, Tumor ,Humans ,Integrin-linked kinase ,Carcinoma, Renal Cell ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Phosphoinositide 3-kinase ,biology ,Parathyroid hormone-related protein ,Akt/PKB signaling pathway ,Kinase ,NF-kappa B ,Parathyroid Hormone-Related Protein ,General Medicine ,Kidney Neoplasms ,female genital diseases and pregnancy complications ,Cytoskeletal Proteins ,embryonic structures ,Cancer research ,biology.protein ,RNA Interference ,Carrier Proteins ,Proto-Oncogene Proteins c-akt ,Cell Division ,Molecular Chaperones - Abstract
We have recently shown that parathyroid hormone-related protein (PTHrP), a cytokine-like polyprotein, is critical for human renal cell carcinoma (RCC) growth by inhibiting tumor cell apoptosis. Here, we have explored mechanisms by which PTHrP controls tumor cell survival. Using specific inhibitors of phosphoinositide 3-kinase (PI3K) and depletion of Akt kinase by RNA interference, we established that PTHrP is one of the main factor involved in the constitutive activation of this pathway in human RCC, independently of von Hippel-Lindau (VHL) tumor suppressor gene expression. Interestingly, PTHrP induced phosphorylation of Akt at S473 but had no influence on phosphorylation at T308. Through transfection with integrin-linked kinase (ILK) constructs and RNA interference, we provide evidence that ILK is involved in human RCC cell survival. PTHrP activates ILK which then acts as a phosphoinositide-dependent kinase (PDK)-2 or a facilitator protein to phosphorylate Akt at S473. Among other kinases tested, only ILK was shown to exert this function in RCC. Using specific inhibitors, western blot and transcription assay, we identified nuclear factor kappa B (NF-kappaB) as the downstream Akt target regulated by PTHrP. Since RCC remains refractory to current therapies, our results establish that the PI3K/ILK/Akt/NF-kappaB axis is a promising target for therapeutic intervention.
- Published
- 2007
44. Establishment of a large panel of patient-derived preclinical models of human renal cell carcinoma
- Author
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Hervé Lang, Sylvie Rothhut, Claire Béraud, Sabrina Danilin, Véronique Lindner, Catherine Coquard, Thierry Massfelder, and Audrey Bethry
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Pathology ,renal cell carcinoma ,Tumor suppressor gene ,Mice, Nude ,03 medical and health sciences ,Prostate cancer ,Mice ,0302 clinical medicine ,Renal cell carcinoma ,Internal medicine ,human tumors ,medicine ,Animals ,Humans ,Stage (cooking) ,Neoplasm Metastasis ,Carcinoma, Renal Cell ,Kidney ,business.industry ,medicine.disease ,patient-derived xenograft models ,Primary tumor ,Xenograft Model Antitumor Assays ,Kidney Neoplasms ,Clear cell renal cell carcinoma ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Histopathology ,business ,Neoplasm Transplantation ,Research Paper - Abstract
// Herve Lang 1 , Claire Beraud 2 , Audrey Bethry 2 , Sabrina Danilin 3 , Veronique Lindner 4 , Catherine Coquard 3 , Sylvie Rothhut 3 , Thierry Massfelder 3 1 Department of Urology, Hopitaux Universitaires de Strasbourg, Nouvel Hopital Civil, Strasbourg, 67091 France 2 UROLEAD SAS, School of Medicine, Strasbourg, 67085 France 3 INSERM U1113, Section of Cell Signalisation and Communication in Kidney and Prostate Cancer, University of Strasbourg, School of Medicine, Federation de Medecine Translationnelle de Strasbourg (FMTS), Strasbourg, 67085 France 4 Department of Pathology, Hopitaux Universitaires de Strasbourg, Hopital de Strasbourg-Hautepierre, Strasbourg, 67200 France Correspondence to: Thierry Massfelder, email: massfeld@unistra.fr Keywords: renal cell carcinoma, human tumors, patient-derived xenograft models Abbreviations: CCC, clear cell renal cell carcinoma; PDX, patient-derived tumor xenograft; VHL, von Hippel-Lindau tumor suppressor gene Received: September 08, 2015 Accepted: July 05, 2016 Published: July 18, 2016 ABSTRACT The objective of the present work was to establish a large panel of preclinical models of human renal cell carcinoma (RCC) directly from patients, faithfully reproducing the biological features of the original tumor. RCC tissues (all stages/subtypes) were collected for 8 years from 336 patients undergoing surgery, xenografted subcutaneously in nude mice, and serially passaged into new mice up to 13 passages. Tissue samples from the primary tumor and tumors grown in mice through passages were analyzed for biological tissue stability by histopathology, mRNA profiling, von Hippel-Lindau gene sequencing, STR fingerprinting, growth characteristics and response to current therapies. Metastatic models were also established by orthotopic implantation and analyzed by imagery. We established a large panel of 30 RCC models (passage > 3, 8.9% success rate). High tumor take rate was associated with high stage and grade. Histopathologic, molecular and genetic characteristics were preserved between original tumors and case-matched xenografts. The models reproduced the sensitivity to targeted therapies observed in the clinic. Overall, these models constitute an invaluable tool for the clinical design of efficient therapies, the identification of predictive biomarkers and translational research.
- Published
- 2015
45. The Phosphoinositide 3-Kinase/Akt Pathway: A New Target in Human Renal Cell Carcinoma Therapy
- Author
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Didier Jacqmin, Sabrina Danilin, Carole Sourbier, Eric Schordan, Hervé Lang, Véronique Lindner, Sylvie Rothhut, Jean-Jacques Helwig, Abdelali Agouni, and Thierry Massfelder
- Subjects
Male ,Cancer Research ,Morpholines ,Cell ,Cell Growth Process ,Cell Growth Processes ,Biology ,Transfection ,Substrate Specificity ,Wortmannin ,Mice ,Phosphatidylinositol 3-Kinases ,chemistry.chemical_compound ,Cell Line, Tumor ,medicine ,Animals ,Humans ,LY294002 ,Enzyme Inhibitors ,Phosphorylation ,RNA, Small Interfering ,Carcinoma, Renal Cell ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Phosphoinositide-3 Kinase Inhibitors ,Cell growth ,Xenograft Model Antitumor Assays ,Kidney Neoplasms ,Oncogene Protein v-akt ,medicine.anatomical_structure ,Oncology ,chemistry ,Chromones ,Cancer research ,Signal transduction ,Signal Transduction - Abstract
Metastatic renal cell carcinoma is resistant to current therapies. The phosphoinositide 3-kinase (PI3K)/Akt signaling cascade induces cell growth, cell transformation, and neovascularization. We evaluated whether targeting this pathway could be of therapeutic value against human renal cell carcinoma. The activation of the PI3K/Akt pathway and its role in renal cell carcinoma progression was evaluated in vitro in seven human cell lines by Western blot, cell counting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, terminal deoxyribonucleotide transferase–mediated nick-end labeling assays, and fluorescence-activated cell sorting analysis, using two PI3K inhibitors, LY294002 and wortmannin, as well as by transfection with various Akt constructs and through Akt knockdown by small interfering RNA (siRNA). In vivo nude mice bearing human renal cell carcinoma tumor xenografts were treated with LY294002 (75 mg/kg/wk, 4 weeks, i.p.). Tumor growth was measured and tumors were subjected to Western blot and immunohistochemical analysis. Akt was constitutively activated in all cell lines. Constitutive phosphorylation of glycogen synthase kinase-3 (GSK-3) was observed in all cell lines, whereas forkhead transcription factor and mammalian target of rapamycin, although expressed, were not constitutively phosphorylated. Exposure to LY294002 or wortmannin decreased Akt activation and GSK-3 phosphorylation and reduced cell growth by up to 70% through induction of cell apoptosis. These effects were confirmed by transfection experiments with Akt constructs or Akt siRNA. Importantly, LY294002 induced up to 50% tumor regression in mice through tumor cell apoptosis. Tumor neovascularization was significantly increased by LY294002 treatment. Blood chemistries showed no adverse effects of the treatment. Our results suggest an important role of PI3K/Akt inhibitors as a potentially useful treatment for patients with renal cell carcinoma. (Cancer Res 2006; 66(10): 5130-42)
- Published
- 2006
46. Intravenous Delivery of PTH/PTHrP Type 1 Receptor cDNA to Rats Decreases Heart Rate, Blood Pressure, Renal Tone, Renin Angiotensin System, and Stress-Induced Cardiovascular Responses
- Author
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Michèle Grima, Véronique Lindner, Mariette Barthelmebs, Thierry Massfelder, Sandra Welsch, Samuel Fritsch, Jean-Jacques Helwig, and Sylvie Rothhut
- Subjects
Male ,medicine.medical_specialty ,DNA, Complementary ,Parathyroid hormone ,Blood Pressure ,Vasodilation ,Biology ,Kidney Function Tests ,Cardiovascular System ,Plasma renin activity ,Renal Circulation ,Renin-Angiotensin System ,Heart Rate ,Reference Values ,Risk Factors ,Internal medicine ,Renin–angiotensin system ,medicine ,Animals ,RNA, Messenger ,Rats, Wistar ,Receptor ,Receptor, Parathyroid Hormone, Type 1 ,Kidney ,Reverse Transcriptase Polymerase Chain Reaction ,Parathyroid Hormone-Related Protein ,Blood Pressure Determination ,General Medicine ,Rats ,Disease Models, Animal ,Endocrinology ,medicine.anatomical_structure ,Gene Expression Regulation ,Nephrology ,Injections, Intravenous ,Knockout mouse ,Circulatory system ,Female ,hormones, hormone substitutes, and hormone antagonists - Abstract
While parathyroid hormone type 1 receptor (PTH1R)-mediated vasodilatory, cardiac stimulatory, and renin-activating effects of exogenous PTH/PTH-related protein (PTHrP) are acknowledged, interactions of endogenous PTHrP with these systems remain unclear, mainly because the unavailability of viable PTHrP/PTH1R knockout mice. Transgenic mice overexpressing PTH1R in smooth muscle strongly have supported the PTHrP/PTH1R system as a cardiovascular system (CVS) regulator, but the consequences on renovascular (RVS) and renin-angiotensin systems (RAS) have not been explored in these studies. The aim was to develop a model in which one could study the consequences on CVS, RVS, and RAS of generalized PTH1R overexpression. Systemic PTH1R cDNA plasmid delivery was used in adult rats, a system that is amenable to studies in isolated perfused kidneys and that minimizes development-induced compensatory mechanisms. Intravenous administration of hPTH1R or green fluorescence protein-tagged hPTH1R in pcDNA3 resulted 3 wk later, in generalized expression of hPTH1R (mRNA and protein), especially in vessels, liver, heart, kidney, and central nervous system, where it is expressed physiologically. As expected, PTH1R overexpression decreased BP and renal tone. Unexpected, however, PTH1R overexpression decreased heart rate. These studies also revealed that endogenous PTHrP actually inhibits renin release and that hPTH1R overexpression tends to increase that effect. Striking, liver production and circulatory level of angiotensinogen and hence plasma renin activity were markedly reduced. Thus, abrupt PTH1R overexpression in adult rats profoundly alters the CVS, RVS, and RAS, strongly supporting the PTH/PTHrP/PTH1R system as crucial for heart and vascular tone regulation. In addition, these results revealed that PTH1R-mediated mechanisms might have protective effects against cardiovascular stress-induced responses, including stimulations in heart rate and RAS.
- Published
- 2004
47. Parathyroid Hormone-Related Protein Is an Essential Growth Factor for Human Clear Cell Renal Carcinoma and a Target for the von Hippel-Lindau Tumor Suppressor Gene
- Author
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Jean-Jacques Helwig, Hervé Lang, Véronique Lindner, Patricia Simon-Assmann, Eric Schordan, Thierry Massfelder, Mariette Barthelmebs, Didier Jacqmin, Sandra Welsch, and Sylvie Rothhut
- Subjects
Cancer Research ,von Hippel-Lindau Disease ,Tumor suppressor gene ,Ubiquitin-Protein Ligases ,medicine.medical_treatment ,Transplantation, Heterologous ,Mice, Nude ,Parathyroid hormone ,Apoptosis ,Mice ,Von Hippel–Lindau tumor suppressor ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Growth Substances ,Receptor ,Carcinoma, Renal Cell ,biology ,Parathyroid hormone-related protein ,Reverse Transcriptase Polymerase Chain Reaction ,Cell growth ,Tumor Suppressor Proteins ,Growth factor ,Parathyroid Hormone-Related Protein ,Kidney Neoplasms ,Oncology ,Von Hippel-Lindau Tumor Suppressor Protein ,Clear cell carcinoma ,Cancer research ,biology.protein ,Cell Division ,hormones, hormone substitutes, and hormone antagonists - Abstract
Clear cell renal carcinoma (CCRC) is responsible for 2% of cancer-related deaths worldwide and is resistant to virtually all therapies, indicating the importance of a search for new therapeutic targets. Parathyroid hormone-related protein (PTHrP) is a polyprotein derived from normal and malignant cells that regulates cell growth. In the current study, we show that blocking PTHrP with antibodies or antagonizing the common parathyroid hormone (PTH)/PTHrP receptor, the PTH1 receptor, dramatically blunts the expansion of human CCRC in vitro by promoting cell death. Importantly, in nude mice, anti-PTHrP antibodies induced complete regression of 70% of the implanted tumors by inducing cell death. In addition, we demonstrate that the von Hippel-Lindau tumor suppressor protein, which functions as a gatekeeper for CCRC, negatively regulates PTHrP expression at the post-transcriptional level. These studies indicate that PTHrP is an essential growth factor for CCRC and is a novel target for the von Hippel-Lindau tumor suppressor protein. Taken together, these results strongly suggest that targeting the PTHrP/PTH1 receptor system may provide a new avenue for the treatment of this aggressive cancer in humans.
- Published
- 2004
48. Type 1 Parathyroid Hormone Receptor Expression Level Modulates Renal Tone and Plasma Renin Activity in Spontaneously Hypertensive Rat
- Author
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Andrew F. Stewart, Samuel Fritsch, Anne Eichinger, Nathalie Taesch, Thierry Massfelder, Mariette Barthelmebs, and Jean-Jacques Helwig
- Subjects
medicine.medical_specialty ,Parathyroid hormone ,Blood Pressure ,Vasodilation ,In Vitro Techniques ,Rats, Inbred WKY ,Plasma renin activity ,Renal Circulation ,Spontaneously hypertensive rat ,Rats, Inbred SHR ,Internal medicine ,Renin ,Renin–angiotensin system ,medicine ,Animals ,Humans ,Kidney ,Renal circulation ,business.industry ,Gene Transfer Techniques ,Parathyroid Hormone-Related Protein ,Proteins ,General Medicine ,musculoskeletal system ,Peptide Fragments ,Rats ,Vasomotor System ,Endocrinology ,medicine.anatomical_structure ,Nephrology ,Injections, Intravenous ,cardiovascular system ,Receptors, Parathyroid Hormone ,Vascular Resistance ,business ,hormones, hormone substitutes, and hormone antagonists ,Homeostasis - Abstract
These studies examine whether PTHrP(1-36), a vasodilator, modulates BP and renal vascular resistance (RVR) in spontaneously hypertensive rat (SHR). Within the kidney of normotensive rats, PTHrP(1-36) was enriched in vessels. In vessels of SHR, PTHrP was upregulated by 40% and type 1 PTH receptor (PTH1R) was downregulated by 65% compared with normotensive rats. To investigate the role of endogenous PTHrP in the regulation of BP and RVR, SHR were subjected to somatic human (h)PTH1R gene delivery. Three weeks after a single intravenous injection of pcDNA1.1 plasmid containing the hPTH1R gene under the control of the cytomegalovirus promoter, hPTH1R mRNA was detected in all of the main organs. Within the kidney, the transgene was enriched in vessels. In the isolated perfused kidney, RVR was reduced by 23% and PTHrP(1-36)-induced vasodilation, which is depressed in SHR, was restored and a vasoconstrictory response to PTH(3-34), a PTH1R antagonist, was revealed. These effects were not observed in control SHR treated with empty plasmid. BP remained unchanged, and plasma renin activity increased by 60%. Thus, in SHR renal vessels, a reduced number of PTH1R contributes to the high RVR, despite the higher expression of vasodilatory PTHrP. Moreover, these studies provide evidence for a direct link between the density of PTH1R and plasma renin activity, which might be responsible for the absence of effect of PTH1R gene delivery on BP in SHR. Overall, PTHrP significantly contributes to the homeostasis of renal and systemic hemodynamics in SHR.
- Published
- 2002
49. Targeting FAK scaffold functions inhibits human renal cell carcinoma growth
- Author
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Claire, Béraud, Valérian, Dormoy, Sabrina, Danilin, Véronique, Lindner, Audrey, Béthry, Mazène, Hochane, Catherine, Coquard, Mariette, Barthelmebs, Didier, Jacqmin, Hervé, Lang, and Thierry, Massfelder
- Subjects
Mice ,Carcinogenesis ,Von Hippel-Lindau Tumor Suppressor Protein ,Cell Line, Tumor ,Focal Adhesion Kinase 1 ,Animals ,Heterografts ,Humans ,Phosphorylation ,RNA, Small Interfering ,Carcinoma, Renal Cell ,Kidney Neoplasms - Abstract
Human conventional renal cell carcinoma (CCC) remains resistant to current therapies. Focal Adhesion Kinase (FAK) is upregulated in many epithelial tumors and clearly implicated in nearly all facets of cancer. However, only few reports have assessed whether FAK may be associated with renal tumorigenesis. In this study, we investigated the potential role of FAK in the growth of human CCC using a panel of CCC cell lines expressing or not the von Hippel-Lindau (VHL) tumor suppressor gene as well as normal/tumoral renal tissue pairs. FAK was found constitutively expressed in human CCC both in culture cells and freshly harvested tumors obtained from patients. We showed that CCC cell growth was dramatically reduced in FAK-depleted cells or after FAK inhibition with various inhibitors and this effect was obtained through inhibition of cell proliferation and induction of cell apoptosis. Additionally, our results indicated that FAK knockdown decreased CCC cell migration and invasion. More importantly, depletion or pharmacological inhibition of FAK substantially inhibited tumor growth in vivo. Interestingly, investigations of the molecular mechanism revealed loss of FAK phosphorylation during renal tumorigenesis impacting multiple signaling pathways. Taken together, our findings reveal a previously uncharacterized role of FAK in CCC whereby FAK exerts oncogenic properties through a non canonical signaling pathway involving its scaffolding kinase-independent properties. Therefore, targeting the FAK scaffold may represent a promising approach for developing innovative and highly specific therapies in human CCC.
- Published
- 2014
50. Parathyroid hormone-related protein and its receptors: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets
- Author
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Jean Jacques Helwig, Peter A. Friedman, Thomas L. Clemens, Karen K. Takane, Evelyne Fischer, Caroline Silve, Anne Eichinger, Karlhans Endlich, Andrew C. Karaplis, Andrew F. Stewart, Thierry Massfelder, Sarah Cormier, Klaus Dieter Schlüter, Nathalie Fiaschi-Taesch, and Jerome Rossert
- Subjects
musculoskeletal diseases ,Pharmacology ,medicine.medical_specialty ,Intracrine ,Parathyroid hormone-related protein ,Growth factor ,medicine.medical_treatment ,Kidney metabolism ,Parathyroid hormone ,Biology ,musculoskeletal system ,Paracrine signalling ,Endocrinology ,Internal medicine ,medicine ,Calcium-sensing receptor ,Receptor ,hormones, hormone substitutes, and hormone antagonists - Abstract
The cloning of the so-called 'parathyroid hormone-related protein' (PTHrP) in 1987 was the result of a long quest for the factor which, by mimicking the actions of PTH in bone and kidney, is responsible for the hypercalcemic paraneoplastic syndrome, humoral calcemia of malignancy. PTHrP is distinct from PTH in a number of ways. First, PTHrP is the product of a separate gene. Second, with the exception of a short N-terminal region, the structure of PTHrP is not closely related to that of PTH. Third, in contrast to PTH, PTHrP is a paracrine factor expressed throughout the body. Finally, most of the functions of PTHrP have nothing in common with those of PTH. PTHrP is a poly-hormone which comprises a family of distinct peptide hormones arising from post-translational endoproteolytic cleavage of the initial PTHrP translation products. Mature N-terminal, mid-region and C-terminal secretory forms of PTHrP are thus generated, each of them having their own physiologic functions and probably their own receptors. The type 1 PTHrP receptor, binding both PTH(1-34) and PTHrP(1-36), is the only cloned receptor so far. PTHrP is a PTH-like calciotropic hormone, a myorelaxant, a growth factor and a developmental regulatory molecule. The present review reports recent aspects of PTHrP pharmacology and physiology, including: (a) the identification of new peptides and receptors of the PTH/PTHrP system; (b) the recently discovered nuclear functions of PTHrP and the role of PTHrP as an intracrine regulator of cell growth and cell death; (c) the physiological and developmental actions of PTHrP in the cardiovascular and the renal glomerulo-vascular systems; (d) the role of PTHrP as a regulator of pancreatic beta cell growth and functions, and, (e) the interactions of PTHrP and calcium-sensing receptors for the control of the growth of placental trophoblasts. These new advances have contributed to a better understanding of the pathophysiological role of PTHrP, and will help to identify its therapeutic potential in a number of diseases.
- Published
- 2001
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