270 results on '"tumor-cells"'
Search Results
2. Effects of second-generation H1-antihistamine drugs on angiogenesis in in vivo chick chorioallantoic membrane model
- Author
-
Nilay Duman, Reşat Duman, and Ayhan Vurmaz
- Subjects
angiogenesis ,Second-generation H1-antihistamines ,desloratadine ,rupatadine ,Receptor Antagonist ,General Medicine ,in vivo chick chorioallantoic membrane model ,cetirizine ,Toxicology ,Platelet-Activating-Factor ,Tumor-Cells ,Cancer - Abstract
BackgroundLiterature on the effects of second-generation H1-antihistamines on angiogenesis is limited.ObjectivesTo investigate the effects of cetirizine, desloratadine, and rupatadine (second-generation H1-antihistamines commonly used in dermatology clinics) on angiogenesis in an in vivo chick chorioallantoic membrane (CAM) model.MethodsThe study was approved by the local ethics committee on animal experimentation. Forty fertilized specific pathogen free eggs were incubated and kept under appropriate temperature and humidity control. Drug solutions were prepared in identical concentrations by dissolving powders in phosphate-buffered saline (PBS). On the third day of the incubation, a small window was opened on the CAM and 0.1 mL desloratadine (1.5 mu g/0.1 mL) in the first group, 0.1 mL cetirizine (1.5 mu g/0.1 mL) in the second group, 0.1 mL rupatadine in the third group (1.5 mu g/0.1 mL), and PBS (0.1 mL) in the fourth group were administered by injection. On the eighth day of incubation, the vascular structures of the CAMs were macroscopically examined and standard digital photographs were taken. The digital images were analyzed and data including mean vessel density, thickness, and number were compared between groups. p < 0.05 was considered statistically significant.ResultsVessel densities were similar in the desloratadine, cetirizine, and control groups, whereas they were significantly less in the rupatadine group (p = 0.01). Furthermore, the rupatadine group had significantly lower vessel thickness and number compared with the other groups (p < 0.05 for both).ConclusionsRupatadine showed anti-angiogenic effects in the chick CAM model, compared with desloratadine and cetirizine. The anti-angiogenic effect of rupatadine could be due to its platelet-activating factor (PAF) receptor inhibition. Thus, rupatadine could be a treatment agent in pathological processes in which angiogenesis is responsible. Further studies with larger series are needed to clarify this potential., Afyon Kocatepe University Scientific Research Foundation; [17.KARIYER.172], Afyon Kocatepe University Scientific Research Foundation (17.KARIYER.172) provided financial support for the conduct of the research.
- Published
- 2022
- Full Text
- View/download PDF
3. Targeting senescence as an anticancer therapy
- Author
-
Laura Bousset and Jesús Gil
- Subjects
Aging ,oncogene-induced senescence (OIS) ,Cancer Research ,TUMOR-CELLS ,SECRETORY PHENOTYPE ,Antineoplastic Agents ,chemotherapy ,Cellular senescence ,Neoplasms ,ONCOGENE-INDUCED SENESCENCE ,Genetics ,Humans ,TERMINAL PROLIFERATION ARREST ,1112 Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,radiotherapy ,Science & Technology ,INDUCED PREMATURE SENESCENCE ,BREAST-CANCER CELLS ,therapy-induced senescence (TIS) ,General Medicine ,DNA-DAMAGE ,Oncology ,senolytics ,therapy-induced senescence ,Molecular Medicine ,ACCELERATED SENESCENCE ,Life Sciences & Biomedicine ,GROWTH ARREST - Abstract
Cellular senescence is a stress response elicited by different molecular insults. Senescence results in cell cycle exit and is characterised by multiple phenotypic changes such as the production of a bioactive secretome. Senescent cells accumulate during ageing and are present in cancerous and fibrotic lesions. Drugs that selectively kill senescent cells (senolytics) have shown great promise for the treatment of age-related diseases. Senescence plays paradoxical roles in cancer. Induction of senescence limits cancer progression and contributes to therapy success, but lingering senescent cells fuel progression, recurrence, and metastasis. In this review, we describe the intricate relation between senescence and cancer. Moreover, we enumerate how current anti-cancer therapies induce senescence in tumour cells and how senolytic agents could be deployed to complement anticancer therapies. "One-two punch" therapies aim to first induce senescence in the tumour followed by senolytic treatment to target newly exposed vulnerabilities in senescent tumour cells. "One-two punch" represents an emerging and promising new strategy in cancer treatment. Future challenges of "one -two punch" approaches include how to best monitor senescence in cancer patients to effectively survey their efficacy.
- Published
- 2022
- Full Text
- View/download PDF
4. Applications of Magnetic Resonance in Model Systems: Cancer Therapeutics
- Author
-
Evelhoch, Jeffrey L, Gillies, Robert J, Karczmar, Gregory S, Koutcher, Jason A, Maxwell, Ross J, Nalcioglu, Orhan, Raghunand, Natarajan, Ronen, Sabrina M, Ross, Brian D, and Swartz, Harold M
- Subjects
nuclear magnetic resonance ,neoplasms ,pathophysiology ,metabolism ,therapy ,nuclear magnetic resonance ,neoplasms ,pathophysiology ,metabolism ,therapyweighted h-1-nmr spectroscopy ,carbogen-induced changes ,cells in-vitro ,thymidine kinase ,human breast ,tumor-cells ,murine tumor ,brain-tumor ,p-31 nmr ,capillary-permeability - Abstract
AbstractThe lack of information regarding the metabolism and pathophysiology of individual tumors limits, in part, both the development of new anti-cancer therapies and the optimal implementation of currently available treatments. Magnetic resonance [MR, including magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and electron paramagnetic resonance (EPR)] provides a powerful tool to assess many aspects of tumor metabolism and pathophysiology. Moreover, since this information can be obtained non-destructively, pre-clinical results from cellular or animal models are often easily translated into the clinic. This review presents selected examples of how MR has been used to identify metabolic changes associated with apoptosis, detect therapeutic response prior to a change in tumor volume, optimize the combination of metabolic inhibitors with chemotherapy and/or radiation, characterize and exploit the influence of tumor pH on the effectiveness of chemotherapy, characterize tumor reoxygenation and the effects of modifiers of tumor oxygenation in individual tumors, image transgene expression and assess the efficacy of gene therapy. These examples provide an overview of several of the areas in which cellular and animal model studies using MR have contributed to our understanding of the effects of treatment on tumor metabolism and pathophysiology and the importance of tumor metabolism and pathophysiology as determinants of therapeutic response.
- Published
- 2000
5. Association of PD-1 and PDL-1 gene polymorphisms with colorectal cancer risk and prognosis
- Author
-
Mehtap Cevik, Esat Namal, Ulkuhan Iner-Koksal, Nur Dinc-Sener, Atila Karaalp, Cavlan Ciftci, Belgin Susleyici, and Cevik M., Namal E., Iner-Koksal U., Dinc-Sener N., KARAALP A., Ciftci C., SÜSLEYİCİ B.
- Subjects
Cancer Research ,Aging ,Genotype ,rs36084323 ,CELL LUNG-CANCER ,TUMOR-CELLS ,Clinical Biochemistry ,rs2282055 ,Programmed Cell Death 1 Receptor ,Life Sciences (LIFE) ,Molecular Biology and Genetics ,Immune check point ,CHILDREN ,SUSCEPTIBILITY ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Biochemistry ,PD-1/PD-L1 ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,B7-H1 Antigen ,PATHWAY ,Structural Biology ,BİYOKİMYA VE MOLEKÜLER BİYOLOJİ ,Yaşam Bilimleri ,Drug Discovery ,PD-1 ,Genetics ,BREAST-CANCER ,Humans ,PD1 GENE ,Genetic Predisposition to Disease ,Cytogenetic ,Molecular Biology ,Moleküler Biyoloji ve Genetik ,INDUCED EXPRESSION ,rs822336 ,Temel Bilimler ,PDL-1 ,Life Sciences ,General Medicine ,Colorectal cancer ,IMMUNE ESCAPE ,MOLECULAR BIOLOGY & GENETICS ,Yaşam Bilimleri (LIFE) ,Case-Control Studies ,Natural Sciences ,Colorectal Neoplasms ,BIOCHEMISTRY & MOLECULAR BIOLOGY ,Sitogenetik - Abstract
Programmed Cell Death-1 (PD-1) together with Programmed Death Ligand 1 (PDL-1) have crucial roles in anti-tumor immune response, cancer susceptibility and prognosis. Since PD-1 and PDL-1 have been considered as important genetic risk factors in cancer development and their functions can be affected by polymorphic sites, we investigated the effects of PD-1 rs2227981, rs2227982, rs36084323 and PDL-1 rs2282055, rs822336 gene polymorphisms on colorectal cancer (CRC) risk and prognosis in Turkish subjects.Our study group consisted of 5-FU or Capacitabine prescribed CRC diagnosed patients and healthy controls. Genotype analyses of PD1 and PDL-1 polymorphisms were performed with Agena MassARRAY platform. rs36084323 CT genotype frequency was found to be higher in controls compared to cases (p 0.001). rs36084323 CT genotype was highly associated with reduced CRC risk compared to CC genotype (OR 0.068, 95% CI 0.022-0.211, p 0.001). In adjusted analysis, rs2282055 GG genotype was found to be associated with reduced CRC risk (OR 0.271, 95% CI 0.078-0.940, p = 0.040). rs2282055 TT genotype was found to be related to longer progression-free (Bonferroni corrected Log rank p = 0.013) and overall survival (Bonferroni corrected Log rank p = 0.009) to that of GG genotypes. Patients with rs822336 GC+CC genotypes showed longer overall survival times compared to GG (Log rank p = 0.044).According to our results, PD-1 rs822336 G C polymorphism might be useful in predicting CRC prognosis. PDL-1 rs2282055 T G polymorphism might be useful in predicting both CRC risk and prognosis. Further studies should be conducted in larger and different populations to clear the roles of PD-1 and PDL-1 polymorphisms in CRC risk and prognosis.
- Published
- 2022
- Full Text
- View/download PDF
6. Effect of whey protein derivatives on cell viability, cell migration and cell cycle phases in MCF-7 cells
- Author
-
AKSOY, F. Tutku, YILMAZ, Ayse Mine, BICIM, Gokhan, YALCIN, A. Suha, Aksoy, Fatma Tutku, and Aksoy F. T., YILMAZ GÖLER A. M., Bicim G., Yalcin A. S.
- Subjects
Whey proteins ,Oleic acid ,Cell survival ,Apoptosis ,Cell cycle ,Cell Survival ,TUMOR-CELLS ,Temel Tıp Bilimleri ,Medicine (miscellaneous) ,OLIVE OIL ,Assessment and Diagnosis ,Sağlık Bilimleri ,Temel Bilgi ve Beceriler ,Genel Tıp ,Fundamental Medical Sciences ,Pathophysiology ,Clinical Medicine (MED) ,TIP, GENEL & DAHİLİ ,Health Sciences ,Internal Medicine ,Klinik Tıp (MED) ,LETHAL ,Aile Sağlığı ,MEDICINE, GENERAL & INTERNAL ,Dahiliye ,Patofizyoloji ,Klinik Tıp ,Fundamentals and Skills ,Cell Cycle ,HUMAN ALPHA-LACTALBUMIN ,CYTOTOXIC COMPLEXES ,General Medicine ,OLEIC-ACID ,CLINICAL MEDICINE ,CANCER ,Değerlendirme ve Teşhis ,Tıp ,Whey Proteins ,General Health Professions ,Medicine ,BOVINE ,Tıp (çeşitli) ,Family Practice ,HAMLET ,Genel Sağlık Meslekleri ,Oleic Acid - Abstract
Objective: This study aimed to obtain protein derivatives after treatment of whey proteins with hazelnut oil and olive oil and determined their effects on MCF-7 cells. Materials and Methods: Whey proteins obtained from 6% whey powder were treated with hazelnut oil (HO) and olive oil (OO) at a protein to lipid ratio of 1:10 at 60 ̊C for 120 minutes. The protein derivatives formed with whey protein and HO or OO were applied to MCF-7 cancer cells and healthy fibroblasts. The effects of protein derivatives on cell viability, apoptosis, reactive oxygen species (ROS) production, wound healing, cell cycle phase distribution and cell cycle related proteins Akt and p21(Waf1/Cip1) expressions were investigated. Results: Cell viability decreased significantly after 24 h of incubation with WP:OO. The percentage of apoptotic or necrotic cells varied between 5-10% and no statistically significant effect was observed. There was no statistically significant difference in ROS production and colony formation between controls and WP:HO or WP:OO groups. Treatment of cells with WP:OO for 24 h significantly decreased cell migration compared to the control group. G2/M phase was significantly suppressed in WP:OO group compared to the control group. WP:OO also increased the expression of p21(Waf1/Cip1) significantly when compared with the control group. Conclusion: Our results showed that whey protein derivatives applied to MCF-7 cells are cytotoxic and may be useful in breast cancer treatment.
- Published
- 2023
7. Peptide-conjugated nanoparticles for targeted photodynamic therapy
- Subjects
targeting ,VEGF(165) BINDING ,RECEPTOR ,photosensitizer ,nanoparticle ,TUMOR-CELLS ,PLATFORMS ,CANCER ,peptide ,COMBINATION THERAPY ,photodynamic therapy ,SILICA NANOPARTICLES ,NEUROPILIN-1 ,INTRACELLULAR DELIVERY - Abstract
Cancer is the second leading cause of death worldwide after cardiovascular disease. Depending on the type and the location of the tumor, several cancer treatments are implemented. Among these, the three most conventional therapies are surgery, radiotherapy and chemotherapy. However, there are other therapeutic approaches such as photodynamic therapy (PDT). PDT relies on the combined action of light, a photoactivable molecule called photosensitizer (PS) and molecular oxygen. Most of the PSs used for clinical applications are not cancer-cell specific. One of the solutions to overcome this problem is the use of nanoparticles (NPs) to induce a passive targeting. It is also possible to graft a vector onto the NPs to specifically target membrane receptors overexpressed in the tumor cells or neovessels surrounding the tumor. In this review, we focus on the NPs loaded with PSs and coupled to peptides for targeted PDT. We described nanosystems that targeted Neuropilin-1 (NRP-1), alpha(v)beta(3) integrins, nucleolin membrane receptor, epidermal growth factor (EGF) receptor, protein-glutamine-gamma-glutamyltransferase (TGM2), p32, transferrin, PD-1, and mitochondrial membrane. The use of a cell absorbing-peptide is also described.
- Published
- 2021
- Full Text
- View/download PDF
8. Does the Choice of Anaesthesia Affect Cancer? A Molecular Crosstalk between Theory and Practice
- Author
-
Wiebrecht Debel, Ali Ramadhan, Caroline Vanpeteghem, Ramses G. Forsyth, Pathology, Supporting clinical sciences, Artificial Intelligence supported Modelling in clinical Sciences, and Experimental Pathology
- Subjects
CIRCULATING ,DOWN-REGULATION ,Cancer Research ,anatomy ,HEPATOCELLULAR-CARCINOMA CELLS ,TUMOR-CELLS ,TOTAL ,LONG-TERM SURVIVAL ,anaesthesia ,cell lines ,Pathology and Forensic Medicine ,Anaesthesia ,PROPOFOL SUPPRESSES PROLIFERATION ,Anesthesiology and Pain Medicine ,LUNG ADENOCARCINOMA ,Oncology ,Medicine and Health Sciences ,FUNCTION IN-VITRO ,outcome ,BREAST-CANCER ,OPIOID RECEPTOR EXPRESSION ,carcinogenesis ,INTRAVENOUS ANESTHESIA - Abstract
Simple Summary In recent years, there has been an increasing scientific interest in the interaction between anaesthesia and cancer development. Retrospective studies show that the choice of anaesthetics perioperatively may influence cancer outcome and cancer recurrence; however, these studies show contradictory results. Reviewing the recent and relevant literature for the biological effects of anaesthetics on cancer cells in comparison to the clinical effects, it was found that sevoflurane, propofol, opioids and lidocaine are likely to display direct biological effects on cancer cells. However, significant effects are only found in studies with exposure to high concentrations of anaesthetics for longer than practical durations, therefore incomparable to their clinical use. In recent years, there has been an increasing scientific interest in the interaction between anaesthesia and cancer development. Retrospective studies show that the choice of anaesthetics may influence cancer outcome and cancer recurrence; however, these studies show contradictory results. Recently, some large randomized clinical trials have been completed, yet they show no significant effect of anaesthetics on cancer outcomes. In this scoping review, we compiled a body of in vivo and in vitro studies with the goal of evaluating the biological effects of anaesthetics on cancer cells in comparison to clinical effects as described in recent studies. It was found that sevoflurane, propofol, opioids and lidocaine are likely to display direct biological effects on cancer cells; however, significant effects are only found in studies with exposure to high concentrations of anaesthetics and/or during longer exposure times. When compared to clinical data, these differences in exposure and dose-effect relation, as well as tissue selectivity, population selection and unclear anaesthetic dosing protocols might explain the lack of outcome.
- Published
- 2022
9. Metastasis-suppressor NME1 controls the invasive switch of breast cancer by regulating MT1-MMP surface clearance
- Author
-
Laetitia Fuhrmann, Ivan Bièche, Marie Irondelle, Fabien Reyal, Anne Houdusse, Olena Pylypenko, Stephen J. Weiss, Olivier De Wever, Mathieu Boissan, Anne Vincent-Salomon, Catalina Lodillinsky, Claire Calmel, Ana María Eiján, Philippe Chavrier, Hélène Bonsang-Kitzis, Marie-Lise Lacombe, Sophie Vacher, Xiao Yan Li, Universidad de Buenos Aires [Buenos Aires] (UBA), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Institut Curie [Paris], Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Michigan [Ann Arbor], University of Michigan System, Centre de Recherche Saint-Antoine (CR Saint-Antoine), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Ghent University Hospital, Service de biochimie et hormonologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Neurobiologie des Canaux Ioniques, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de chirurgie, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie [CRSA], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Pylypenko, Olena, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de la Méditerranée - Aix-Marseille 2, Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP]
- Subjects
0301 basic medicine ,Cancer Research ,TUMOR-CELLS ,[SDV]Life Sciences [q-bio] ,Endocytic cycle ,PROGRESSION ,Matrix metalloproteinase ,Extracellular matrix ,Dynamin II ,Mice ,Breast cancer ,0302 clinical medicine ,Membrane fission ,Cell Movement ,Medicine and Health Sciences ,Neoplasm Metastasis ,skin and connective tissue diseases ,Middle Aged ,NM23 Nucleoside Diphosphate Kinases ,Endocytosis ,Extracellular Matrix ,[SDV] Life Sciences [q-bio] ,CARCINOMA IN-SITU ,030220 oncology & carcinogenesis ,Female ,TRANSITION ,DYNAMIN ,MIGRATION ,Mice, Nude ,Breast Neoplasms ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Article ,Cell Line ,03 medical and health sciences ,Matrix Metalloproteinase 14 ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Genetics ,medicine ,Animals ,Humans ,TRAFFICKING ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Metastasis suppressor ,Molecular Biology ,Neoplasm Staging ,Carcinoma in situ ,MICROINVASION ,Ductal carcinoma ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Cancer research - Abstract
Membrane Type 1 Matrix Metalloprotease (MT1-MMP) contributes to the invasive progression of breast cancers by degrading extracellular matrix tissues. Nucleoside diphosphate kinase, NME1/NM23-H1, has been identified as a metastasis suppressor; however, its contribution to local invasion in breast cancer is not known. Here, we report that NME1 is up-regulated in ductal carcinoma in situ (DCIS) as compared to normal breast epithelial tissues. NME1 levels drop in microinvasive and invasive components of breast tumor cells relative to synchronous DCIS foci. We find a strong anti-correlation between NME1 and plasma membrane MT1-MMP levels in the invasive components of breast tumors, particularly in aggressive histological grade III and triple-negative breast cancers. Knockout of NME1 accelerates the invasive transition of breast tumors in the intraductal xenograft model. At the mechanistic level, we find that MT1-MMP, NME1 and dynamin-2, a GTPase known to require GTP production by NME1 for its membrane fission activity in the endocytic pathway, interact in clathrin-coated vesicles at the plasma membrane. Loss of NME1 function increases MT1-MMP surface levels by inhibiting endocytic clearance. As a consequence, the ECM degradation and invasive potentials of breast cancer cells are enhanced. This study identifies the down-modulation of NME1 as a potent driver of the in situ-to invasive transition during breast cancer progression.
- Published
- 2021
- Full Text
- View/download PDF
10. Senescence as a therapeutically relevant response to CDK4/6 inhibitors
- Author
-
Jesús Gil and Verena Wagner
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Cell cycle checkpoint ,TUMOR-CELLS ,Cell ,0302 clinical medicine ,Ribociclib ,Tumor Microenvironment ,Genetics & Heredity ,biology ,Retinoblastoma ,Kinase ,CELLULAR SENESCENCE ,PROLIFERATION ,STROMAL SENESCENCE ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,GROWTH ,Female ,biological phenomena, cell phenomena, and immunity ,Life Sciences & Biomedicine ,Senescence ,Biochemistry & Molecular Biology ,DEPENDENT KINASE 4/6 ,CDK4 ,CDK6 ,Palbociclib ,Article ,CDK4/6 inhibitors ,03 medical and health sciences ,LUNG-CANCER ,Genetics ,medicine ,Humans ,BREAST-CANCER ,1112 Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,neoplasms ,Molecular Biology ,PI3K/AKT/mTOR pathway ,P53 ,Science & Technology ,Cyclin-Dependent Kinase 4 ,1103 Clinical Sciences ,Cyclin-Dependent Kinase 6 ,Cell Biology ,medicine.disease ,Abemaciclib ,030104 developmental biology ,Apoptosis ,biology.protein ,Cancer research ,Cyclin-dependent kinase 6 - Abstract
Cyclin-dependent kinases 4 and 6 (CDK4/6) phosphorylate and inhibit retinoblastoma (RB) family proteins. Hyperphosphorylated RB releases E2F transcription factors, activating a transcriptional program that initiates S phase. Due to the critical role that this pathway has in regulating cell cycle progression, inhibiting CDK4/6 is an attractive therapeutic strategy. Indeed, CDK4/6 inhibitors in combination with antiestrogens produce a significant benefit in patients with ER+/HER2− breast cancer. Clinical trials are currently investigating if the use of CDK4/6 inhibitors alone or in combination can be extended to other cancer types. Inhibition of CDK4/6 can result in different cell fates such as quiescence, senescence, or apoptosis. Senescence is a stress response that can be induced by stimuli that include oncogenic activation, chemotherapy, irradiation, and targeted therapies such as CDK4/6 inhibitors. Senescent cells undergo a stable cell cycle arrest and produce a bioactive secretome that remodels their microenvironment and engages the immune system. In this review, we analyze the therapeutic relevance of senescence induction by CDK4/6 inhibitors. We also discuss how different therapies, including checkpoint inhibitors and drugs targeting MEK or PI3K, can be used in combination with CDK4/6 inhibitors to reinforce or exploit senescence. Recently, a lot of effort has been put into identifying compounds that selectively kill senescent cells (termed senolytics). Thus, sequential treatment with senolytics might be an additional strategy to potentiate the antitumor effects of CDK4/6 inhibitors.
- Published
- 2020
- Full Text
- View/download PDF
11. Harnessing natural killer cells for the treatment of ovarian cancer
- Subjects
BLOOD ,Ovarian cancer ,NK-CELL ,TUMOR-CELLS ,SURVIVAL ,LYMPHOMA ,Natural killer cells ,INTRAPERITONEAL CHEMOTHERAPY ,CYTOTOXICITY ,Immunotherapy ,ACUTE MYELOID-LEUKEMIA ,THERAPY - Abstract
Introduction. Adoptive cellular immunotherapy could be an interesting new treatment option for ovarian carcinoma (OC), as research has demonstrated that OC is an immunogenic disease. In particular, natural killer (NK) cells have attracted attention due to their ability to kill tumor cells without prior sensitization. The therapeutic value of allogeneic NK cells has been first observed in hematological cancers and is increasingly being explored in solid tumors.Methods. To substantiate the rationale for NK cell therapy in OC we performed a literature search in the Pubmed database and in the international trial register clinicaltrials.gov with attention for the effect of OC on NK cell function, the effect of current treatment on NK cell biology and the evidence on the therapeutic value of NK cell therapy against OC.Results. In six clinical trials only 31 OC patients have been reported that received NK cell adoptive transfer. The majority of patients reached stable disease after NK cell therapy, with a mild pattern of side effects. In patients who received repeated infusions, more complete responses are described. All reported studies investigated the intravenous infusion of NK cells. Whereas the studies that are currently recruiting, investigate intraperitoneal infusion of allogeneic NK cells.Conclusion. In this review the pre-clinical evidence and current trials on NK cell immunotherapy in OC patients are summarized. Furthermore, challenges that have to be overcome for NK cell adoptive therapy to have a significant impact on disease outcome are discussed. (C) 2020 The Authors. Published by Elsevier Inc.
- Published
- 2020
- Full Text
- View/download PDF
12. Immunotherapy of Equine Sarcoids—From Early Approaches to Innovative Vaccines
- Author
-
Jindra, Christoph, Brandt, Sabine, and Hainisch, Edmund K.
- Subjects
Pharmacology ,Infectious Diseases ,Drug Discovery ,Immunology ,Bovine Papillomavirus Type-1 ,Virus-Like Particles ,Regulatory T-Cell ,Leukocyte Antigens ,Tumor-Cells ,Human Interleukin-2 ,Immune-Response ,Gene-Expression ,Dna ,Protein ,Pharmacology (medical) - Abstract
Horses and other equid species are frequently affected by bovine papillomavirus type 1 and/or 2 (BPV1, BPV2)-induced skin tumors termed sarcoids. Although sarcoids do not metastasize, they constitute a serious health problem due to their BPV1/2-mediated resistance to treatment and propensity to recrudesce in a more severe, multiple form following accidental or iatrogenic trauma. This review provides an overview on BPV1/2 infection and associated immune escape in the equid host and presents early and recent immunotherapeutic approaches in sarcoid management.
- Published
- 2023
- Full Text
- View/download PDF
13. Intraoperative cell salvage in oncological surgery: a narrative review
- Author
-
Windal, P-J, Rex, S, and Van Den Eynde, R
- Subjects
RADICAL RETROPUBIC PROSTATECTOMY ,AUTOTRANSFUSION ,Science & Technology ,TUMOR-CELLS ,operative blood salvage ,GASTRIC-CANCER PATIENTS ,blood transfusion ,autologous ,LIVER-TRANSPLANTATION ,AUTOLOGOUS BLOOD-TRANSFUSION ,TERM OUTCOMES ,Anesthesiology ,Neoplasms ,HEPATOCELLULAR-CARCINOMA ,BIOCHEMICAL RECURRENCE ,CURATIVE RESECTION ,Life Sciences & Biomedicine - Abstract
ispartof: ACTA ANAESTHESIOLOGICA BELGICA vol:72 pages:191-201 status: published
- Published
- 2021
14. Resistance Mechanisms Influencing Oncolytic Virotherapy, a Systematic Analysis
- Subjects
therapeutic resistance ,PANCREATIC-CANCER CELLS ,TUMOR-CELLS ,INHIBITOR ,VIRAL THERAPY ,resistance mechanisms ,VESICULAR STOMATITIS-VIRUS ,GENE ,VACCINIA VIRUS ,ADENOVIRUS ,I INTERFERON RESPONSE ,NEUTRALIZATION ,cancer cells ,oncolytic virotherapy ,stromal cells - Abstract
Resistance to therapy is a frequently observed phenomenon in the treatment of cancer, and as with other cancer therapeutics, therapies based on oncolytic viruses also face the challenges of resistance, such as humoral and cellular antiviral responses, and tumor-associated interferon-mediated resistance. In order to identify additional mechanisms of resistance that may contribute to therapeutic failure, we developed a systematic search strategy for studies published in PubMed. We analyzed 6143 articles on oncolytic virotherapy and found that approximately 8% of these articles use resistance terms in the abstract and/or title. Of these 439 articles, 87 were original research. Most of the findings reported pertain to resistance mediated by tumor-cell-dependent interferon signaling. Yet, mechanisms such as epigenetic modifications, hypoxia-mediated inhibition, APOBEC-mediated resistance, virus entry barriers, and spatiotemporal restriction to viral spread, although not frequently assessed, were demonstrated to play a major role in resistance. Similarly, our results suggest that the stromal compartment consisting of, but not limited to, myeloid cells, fibroblasts, and epithelial cells requires more study in relation to therapy resistance using oncolytic viruses. Thus, our findings emphasize the need to assess the stromal compartment and to identify novel mechanisms that play an important role in conferring resistance to oncolytic virotherapy.
- Published
- 2021
15. Aberrant Expression of and Cell Death Induction by Engagement of the MHC-II Chaperone CD74 in Anaplastic Large Cell Lymphoma (ALCL)
- Author
-
Stephan Kreher, Lukas Kenner, Kathrin D Wurster, Olaf Merkel, Nikolai Schleussner, Arjan Diepstra, Reiner Siebert, Bernd Gillissen, Ioannis Anagnostopoulos, Mariantonia Costanza, Selina Glaser, Björn Lamprecht, Arturo Molina, Karl Köchert, Harald Stein, Korinna Jöhrens, Michael Hummel, Martin Janz, Stephan Mathas, and Stem Cell Aging Leukemia and Lymphoma (SALL)
- Subjects
Cancer Research ,C-Met ,CD74 ,TUMOR-CELLS ,Major histocompatibility complex ,SURFACE EXPRESSION ,ALK translocation ,Article ,T cell lymphoma ,T-Zell-Lymphom ,ACTIVATION ,PATHWAY ,invariant chain ,chemistry.chemical_compound ,immune system diseases ,hemic and lymphatic diseases ,PERIPHERAL T-CELL ,medicine ,Anaplastic lymphoma kinase ,T-cell lymphoma ,Cytotoxic T cell ,ddc:610 ,INVARIANT CHAIN CD74 ,MHC-II ,Anaplastic large-cell lymphoma ,Invariante Kette ,RC254-282 ,Crizotinib ,MIF ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Lymphoma ,Oncology ,chemistry ,Cancer research ,SURVIVAL ,C-MET ,HODGKIN ,DDC 610 / Medicine & health ,medicine.drug - Abstract
In 50–60% of cases, systemic anaplastic large cell lymphoma (ALCL) is characterized by the t(2, 5)(p23, q35) or one of its variants, considered to be causative for anaplastic lymphoma kinase (ALK)-positive (ALK+) ALCL. Key pathogenic events in ALK-negative (ALK−) ALCL are less well defined. We have previously shown that deregulation of oncogenic genes surrounding the chromosomal breakpoints on 2p and 5q is a unifying feature of both ALK+ and ALK− ALCL and predisposes for occurrence of t(2, 5). Here, we report that the invariant chain of the MHC-II complex CD74 or li, which is encoded on 5q32, can act as signaling molecule, and whose expression in lymphoid cells is usually restricted to B cells, is aberrantly expressed in T cell-derived ALCL. Accordingly, ALCL shows an altered DNA methylation pattern of the CD74 locus compared to benign T cells. Functionally, CD74 ligation induces cell death of ALCL cells. Furthermore, CD74 engagement enhances the cytotoxic effects of conventional chemotherapeutics in ALCL cell lines, as well as the action of the ALK-inhibitor crizotinib in ALK+ ALCL or of CD95 death-receptor signaling in ALK− ALCL. Additionally, a subset of ALCL cases expresses the proto-oncogene MET, which can form signaling complexes together with CD74. Finally, we demonstrate that the CD74-targeting antibody-drug conjugate STRO-001 efficiently and specifically kills CD74-positive ALCL cell lines in vitro. Taken together, these findings enabled us to demonstrate aberrant CD74-expression in ALCL cells, which might serve as tool for the development of new treatment strategies for this lymphoma entity.
- Published
- 2021
16. Cytotoxic T cells are able to efficiently eliminate cancer cells by additive cytotoxicity
- Author
-
Weigelin, Bettina, den Boer, Annemieke Th, Wagena, Esther, Broen, Kelly, Dolstra, Harry, de Boer, Rob J., Figdor, Carl G., Textor, Johannes, Friedl, Peter, Sub Theoretical Biology, Theoretical Biology and Bioinformatics, Interne Geneeskunde, RS: FHML non-thematic output, Sub Theoretical Biology, and Theoretical Biology and Bioinformatics
- Subjects
Cytotoxicity, Immunologic ,Male ,Chemistry(all) ,IMPACT ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,TUMOR-CELLS ,General Physics and Astronomy ,Apoptosis ,Biochemistry ,Cytotoxic T cell ,Cytotoxicity ,Melanoma ,IN-VIVO ,Multidisciplinary ,Cell Death ,Chemistry ,INDUCTION ,PERFORIN ,Cell killing ,INFILTRATION ,MCF-7 Cells ,Imaging the immune system ,Tumour immunology ,Female ,DNA damage ,Science ,Cytotoxic T cells ,Physics and Astronomy(all) ,Article ,General Biochemistry, Genetics and Molecular Biology ,Immune system ,All institutes and research themes of the Radboud University Medical Center ,Cell Line, Tumor ,Animals ,Humans ,GRANZYME-B ,DNA-DAMAGE ACCUMULATION ,REPAIR ,Biochemistry, Genetics and Molecular Biology(all) ,Immunological surveillance ,General Chemistry ,Mice, Inbred C57BL ,Kinetics ,CTL ,Cancer cell ,PLASMA-MEMBRANE ,Cancer research ,CD8 ,Genetics and Molecular Biology(all) ,DNA Damage ,T-Lymphocytes, Cytotoxic - Abstract
Lethal hit delivery by cytotoxic T lymphocytes (CTL) towards B lymphoma cells occurs as a binary, “yes/no” process. In non-hematologic solid tumors, however, CTL often fail to kill target cells during 1:1 conjugation. Here we describe a mechanism of “additive cytotoxicity” by which time-dependent integration of sublethal damage events, delivered by multiple CTL transiting between individual tumor cells, mediates effective elimination. Reversible sublethal damage includes perforin-dependent membrane pore formation, nuclear envelope rupture and DNA damage. Statistical modeling reveals that 3 serial hits delivered with decay intervals below 50 min discriminate between tumor cell death or survival after recovery. In live melanoma lesions in vivo, sublethal multi-hit delivery is most effective in interstitial tissue where high CTL densities and swarming support frequent serial CTL-tumor cell encounters. This identifies CTL-mediated cytotoxicity by multi-hit delivery as an incremental and tunable process, whereby accelerating damage magnitude and frequency may improve immune efficacy., Cytotoxic CD8+ T lymphocytes (CTL) often fail to kill tumour cells in one-to-one interactions. Here the authors show that these sublethal interactions from multiple CTL can add up over time and achieve tumour cell killing by additive cytotoxicity.
- Published
- 2021
17. Peptide-conjugated nanoparticles for targeted photodynamic therapy
- Author
-
Batoul Dhaini, Tayssir Hamieh, Joël Daouk, Amina Ben-Mihoub, Samir Acherar, Bibigul Kenzhebayeva, Hervé Schohn, Céline Frochot, Francis Baros, Mickaël Gries, Noémie Thomas, Laboratoire Réactions et Génie des Procédés (LRGP), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Laboratoire de Chimie Physique Macromoléculaire (LCPM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Centre de Recherche en Automatique de Nancy (CRAN), Laboratoire de Matériaux, Catalyse, Environnement et Méthodes Analytiques (MCEMA), and Université Libanaise
- Subjects
VEGF(165) BINDING ,photosensitizer ,TUMOR-CELLS ,medicine.medical_treatment ,QC1-999 ,Integrin ,Cell ,Photodynamic therapy ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,02 engineering and technology ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,03 medical and health sciences ,Cell surface receptor ,Epidermal growth factor ,medicine ,cancer ,Photosensitizer ,Electrical and Electronic Engineering ,Receptor ,SILICA NANOPARTICLES ,NEUROPILIN-1 ,INTRACELLULAR DELIVERY ,targeting ,030304 developmental biology ,0303 health sciences ,RECEPTOR ,biology ,Chemistry ,Physics ,nanoparticle ,PLATFORMS ,021001 nanoscience & nanotechnology ,Atomic and Molecular Physics, and Optics ,peptide ,3. Good health ,Electronic, Optical and Magnetic Materials ,COMBINATION THERAPY ,medicine.anatomical_structure ,photodynamic therapy ,Cancer research ,biology.protein ,0210 nano-technology ,Nucleolin ,Biotechnology - Abstract
Cancer is the second leading cause of death worldwide after cardiovascular disease. Depending on the type and the location of the tumor, several cancer treatments are implemented. Among these, the three most conventional therapies are surgery, radiotherapy and chemotherapy. However, there are other therapeutic approaches such as photodynamic therapy (PDT). PDT relies on the combined action of light, a photoactivable molecule called photosensitizer (PS) and molecular oxygen. Most of the PSs used for clinical applications are not cancer-cell specific. One of the solutions to overcome this problem is the use of nanoparticles (NPs) to induce a passive targeting. It is also possible to graft a vector onto the NPs to specifically target membrane receptors overexpressed in the tumor cells or neovessels surrounding the tumor. In this review, we focus on the NPs loaded with PSs and coupled to peptides for targeted PDT. We described nanosystems that targeted Neuropilin-1 (NRP-1), αvβ3 integrins, nucleolin membrane receptor, epidermal growth factor (EGF) receptor, protein-glutamine-gamma-glutamyltransferase (TGM2), p32, transferrin, PD-1, and mitochondrial membrane. The use of a cell absorbing-peptide is also described.
- Published
- 2021
- Full Text
- View/download PDF
18. CD47 Expression Defines Efficacy of Rituximab with CHOP in Non–Germinal Center B-cell (Non-GCB) Diffuse Large B-cell Lymphoma Patients (DLBCL), but Not in GCB DLBCL
- Author
-
Marcel Nijland, Renee Bouwstra, Janneke Willemien de Boer, Yuan He, Edwin Bremer, Christine Eulenburg, Ewa Cendrowicz, Emanuele Ammatuna, Rudolf S N Fehrmann, Gerwin Huls, Hilde A. M. Kooistra, Tom van Meerten, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Life Course Epidemiology (LCE), Stem Cell Aging Leukemia and Lymphoma (SALL), and Targeted Gynaecologic Oncology (TARGON)
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Vincristine ,MONOCLONAL-ANTIBODY ,Cyclophosphamide ,TUMOR-CELLS ,medicine.medical_treatment ,Immunology ,MULTICENTER ,CD47 Antigen ,CHOP ,PHAGOCYTOSIS ,MECHANISMS ,03 medical and health sciences ,0302 clinical medicine ,POOR-PROGNOSIS ,immune system diseases ,Cell Line, Tumor ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,MACROPHAGES ,Chemotherapy ,business.industry ,Germinal center ,Middle Aged ,CHEMOTHERAPY ,Germinal Center ,Prognosis ,OPEN-LABEL ,medicine.disease ,Lymphoma ,030104 developmental biology ,Doxorubicin ,030220 oncology & carcinogenesis ,Prednisone ,Rituximab ,Lymphoma, Large B-Cell, Diffuse ,OVEREXPRESSION ,business ,Diffuse large B-cell lymphoma ,medicine.drug - Abstract
Addition of rituximab (R) to “CHOP” (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy improved outcome for diffuse large B-cell lymphoma (DLBCL) patients. Approximately 40% of patients who receive R-CHOP still succumb to disease due to intrinsic resistance or relapse. A potential negative regulator of DLBCL treatment outcome is the CD47 “don't eat me” immune checkpoint. To delineate the impact of CD47, we used a clinically and molecularly well-annotated cohort of 939 DLBCL patients, comprising both germinal center B-cell (GCB) and non-GCB DLBCL subtypes, treated with either CHOP or R-CHOP. High (above median) CD47 mRNA expression correlated with a detrimental effect on overall survival (OS) when DLBCL patients received R-CHOP therapy (P = 0.001), but not CHOP therapy (P = 0.645). Accordingly, patients with low CD47 expression benefited most from the addition of rituximab to CHOP [HR, 0.32; confidence interval (CI), 0.21–0.50; P < 0.001]. This negative impact of high CD47 expression on OS after R-CHOP treatment was only evident in cancers of non-GCB origin (HR, 2.09; CI, 1.26–3.47; P = 0.004) and not in the GCB subtype (HR, 1.16; CI, 0.68–1.99; P = 0.58). This differential impact of CD47 in non-GCB and GCB was confirmed in vitro, as macrophage-mediated phagocytosis stimulated by rituximab was augmented by CD47-blocking antibody only in non-GCB cell lines. Thus, high expression of CD47 mRNA limited the benefit of addition of rituximab to CHOP in non-GCB patients, and CD47-blockade only augmented rituximab-mediated phagocytosis in non-GCB cell lines. Patients with non-GCB DLBCL may benefit from CD47-targeted therapy in addition to rituximab.
- Published
- 2019
- Full Text
- View/download PDF
19. Gemcitabine, vinorelbine and cyclooxygenase inhibitors in the treatment of glioblastoma. Ultrastructural analyses in C6 glioma in vitro
- Author
-
Meric A. Altinoz, Ilhan Elmaci, Ayhan Bilir, Aysel Ozpinar, Promovendi MHN, Psychiatrie & Neuropsychologie, and RS: MHeNs - R2 - Mental Health
- Subjects
0301 basic medicine ,Radiosensitizer ,medicine.drug_class ,Autophagic Cell Death ,TUMOR-CELLS ,ENDOPLASMIC-RETICULUM ,PROTEIN ,Vinorelbine ,Deoxycytidine ,Vinca alkaloid ,Cyclooxygenase inhibitors ,03 medical and health sciences ,0302 clinical medicine ,Glioma ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,RIBONUCLEOTIDE REDUCTASE ,Mitotic catastrophe ,biology ,INDUCTION ,Autophagy ,ARCUATE NUCLEUS ,DIMETHYL-SULFOXIDE ,BREAST-CANCER CELLS ,Cell Biology ,General Medicine ,C6 glioma ,medicine.disease ,Gemcitabine ,APOPTOSIS ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,LIPID DROPLETS ,Cyclooxygenase ,Glioblastoma ,Developmental Biology ,medicine.drug - Abstract
Objectives: To define ultrastructural features accompanying to antitumor effects of gemcitabine, vinorelbine and cyclooxygenase inhibitors in C6 glioma cells in vitro. Vinorelbine is a semisynthetic vinca alkaloid and recent studies showed its antitumor activity in pediatric optic and pontine gliomas. Vinorelbine infusion induces a severe tumor site-pain in systemic cancers, but it is unknown whether algesia and inflammation contribute to its antitumor effects. Gemcitabine is a nucleoside-chemotherapeutic which was recently shown to act as a radiosensitizer in high-grade glioma. Some studies showed synergism of anti-inflammatory cyclooxygenase-inhibitors with microtubule inhibitors and gemcitabine. DMSO is a solvent and blocks both cylooxygenase and ribonucleotide reductase, another target of gemcitabine. Rofecoxib is withdrawn from the market, yet we used it for investigational purposes, since it blocks cylooxygenase-2 1000-times more potently than cylooxygenase-1 and is also a selective inhibitor of crinophagy.Methods: Plating efficacy, 3D-spheroid S-phase analysis with BrdU labelling and transmission electron micro-scopical analyses were performed.Results: Vinorelbine induced frequent mitotic slippage/apoptosis and autophagy. Despite both DMSO and rofecoxib induced autophagy alone and in synergy, they reduced mitotic catastrophe and autophagy triggered by vinorelbine, which was also reflected by reduced inhibition of spheroid S-phase. Gemcitabine induced karyolysis and margination of coarse chromatin towards the nuclear membrane, abundant autophagy, gutta adipis formation and decrease in mitochondria, which were enhanced by DMSO and rofecoxib.Conclusions: Detailed ultrastructural analysis of the effects of chemotherapeutic drugs may provide a broader insight about their actions and pave to develop better strategies in treatment of glioblastoma.
- Published
- 2019
- Full Text
- View/download PDF
20. MNK1/Nodal signaling promotes invasive progression of breast ductal carcinoma in situ
- Author
-
Henry Yu, Samuel E. J. Preston, Moulay A. Alaoui-Jamali, Christophe Goncalves, Fan Huang, Krikor Bijian, Zahra Talat, Yao Zhan, Maud Marques, Dany Plourde, Sara Al Habyan, Jessica N. Nichol, Wilson H. Miller, William Yang, Vivian Z. Li, Jose Torres, Jie Su, Michael Witcher, Guihua Zhang, Lynne-Marie Postovit, Fariba Behbod, Qianyu Guo, Muriel Brackstone, Luke McCaffrey, Mark Basik, Hanne Lefrère, Nadia V. Giannakopoulos, Sonia V. del Rincón, Frédéric Amant, CCA - Cancer biology and immunology, and Obstetrics and Gynaecology
- Subjects
0301 basic medicine ,Cancer Research ,TUMOR-CELLS ,MNK1 ,Nodal signaling ,CELL-MIGRATION ,Metastasis ,Mice ,0302 clinical medicine ,skin and connective tissue diseases ,N-TERMINI ,EIF4E PHOSPHORYLATION ,Carcinoma, Ductal, Breast ,Intracellular Signaling Peptides and Proteins ,CANCER ,Oncology ,030220 oncology & carcinogenesis ,Disease Progression ,Heterografts ,Female ,Life Sciences & Biomedicine ,STEM-CELLS ,Signal Transduction ,Nodal Protein ,C-TERMINI ,Mice, Nude ,Breast Neoplasms ,Protein Serine-Threonine Kinases ,Article ,03 medical and health sciences ,Breast cancer ,Cancer stem cell ,Cell Line, Tumor ,KINASE ,Carcinoma ,medicine ,Animals ,Humans ,neoplasms ,Cell Proliferation ,Science & Technology ,business.industry ,Cell growth ,Ductal carcinoma ,medicine.disease ,body regions ,030104 developmental biology ,METASTASIS ,Cancer research ,Breast Carcinoma In Situ ,CRISPR-Cas Systems ,business ,NODAL - Abstract
The mechanisms by which breast cancers progress from relatively indolent ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) are not well understood. However, this process is critical to the acquisition of metastatic potential. MAPK-interacting serine/threonine-protein kinase 1 (MNK1) signaling can promote cell invasion. NODAL, a morphogen essential for embryogenic patterning, is often reexpressed in breast cancer. Here we describe a MNK1/NODAL signaling axis that promotes DCIS progression to IDC. We generated MNK1 knockout (KO) or constitutively active MNK1 (caMNK1)-expressing human MCF-10A–derived DCIS cell lines, which were orthotopically injected into the mammary glands of mice. Loss of MNK1 repressed NODAL expression, inhibited DCIS to IDC conversion, and decreased tumor relapse and metastasis. Conversely, caMNK1 induced NODAL expression and promoted IDC. The MNK1/NODAL axis promoted cancer stem cell properties and invasion in vitro. The MNK1/2 inhibitor SEL201 blocked DCIS progression to invasive disease in vivo. In clinical samples, IDC and DCIS with microinvasion expressed higher levels of phospho-MNK1 and NODAL versus low-grade (invasion-free) DCIS. Cumulatively, our data support further development of MNK1 inhibitors as therapeutics for preventing invasive disease. Significance: These findings provide new mechanistic insight into progression of ductal carcinoma and support clinical application of MNK1 inhibitors to delay progression of indolent ductal carcinoma in situ to invasive ductal carcinoma.
- Published
- 2019
- Full Text
- View/download PDF
21. A melt-electrowritten filter for capture and culture of circulating colon cancer cells
- Author
-
Mathias Lindh Jørgensen, Zhongyang Zhang, Karen-Lise Garm Spindler, Jesper Just, Marcin Nadzieja, Mille Sikkersoq, Menglin Chen, Christoph Müller, and Yingchun Su
- Subjects
Colorectal cancer ,TUMOR-CELLS ,Biomedical Engineering ,Bioengineering ,Metastasis ,Flow cytometry ,COLORECTAL-CANCER ,Biomaterials ,Circulating tumor cell ,Full Length Article ,Biopsy ,medicine ,Melt electrospinning writing ,EX-VIVO CULTURE ,CTCS ,Molecular Biology ,lcsh:QH301-705.5 ,Whole blood ,On-site culture ,lcsh:R5-920 ,medicine.diagnostic_test ,business.industry ,Circulating tumor cells ,Bioconjugation ,Cancer ,Cell Biology ,EXPANSION ,medicine.disease ,FIBROCYTES ,Polycaprolactone ,lcsh:Biology (General) ,Cancer cell ,Cancer research ,business ,lcsh:Medicine (General) ,Biotechnology - Abstract
Metastasis is the major cause of death in cancer patients accounting for about 90% of the mortality. The detection and analysis of the hallmark of metastasis, circulating tumor cells (CTCs), have significant impact in cancer biology and clinical practice. However, the scarcity of CTCs in blood, particularly in that of colorectal cancer patients, is a serious bottleneck in the development of CTC-based precision medicine. Herein, the melt electrowriting (MEW) technology was used for reproductive fabrication of a biocompatible antibody-presenting polycaprolactone filter with tailored porous structure. It is demonstrated, for the first time, that such filter can be used not only to catch cancer cells spiked in whole blood but also to culture the cancer cells directly on site. Specifically, HT29 colon cancer cells can be captured with an efficiency of 85%, and when spiked into 4 mL of whole blood, 47% were captured on one Ø12mm filter. Furthermore, repeated capture and culture experiments have shown that as few as 20 HT29 colon cancer cells spiked into 4 mL of whole blood can be captured on the filter and within 2 weeks be expanded on site to become tumor bodies that are visible to the untrained eye. This filter allows for downstream analysis, such as flow cytometry, immunocytochemistry, Western blotting, and rt-qPCR. This technology represents a simple and cost-effective platform that potentially enables fast and efficient culture of rare CTCs from patients’ blood. This provides non-invasive alternatives for solid biopsy tumor materials for treatment screening, with great potential to realize precision medicine for cancer treatment., Graphical abstract Image 1
- Published
- 2020
- Full Text
- View/download PDF
22. A functional genetic screen defines the AKT-induced senescence signaling network
- Author
-
Jian Kang, Ross D. Hannan, Amee J George, Anna S Trigos, Lassi Paavolainen, Elaine Sanij, Katherine M. Hannan, Shaun Blake, Keefe T. Chan, Jeannine Diesch, Richard B. Pearson, Kaylene J. Simpson, Haoran Zhu, Piyush B. Madhamshettiwar, Peter Horvath, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, and University of Helsinki
- Subjects
0301 basic medicine ,Senescence ,TUMOR-CELLS ,mTORC1 ,Mechanistic Target of Rapamycin Complex 1 ,PI3K ,Article ,Cell Line ,Transcriptome ,ACTIVATION ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,ONCOGENE-INDUCED SENESCENCE ,Humans ,Tumour-suppressor proteins ,Molecular Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,biology ,CELLULAR SENESCENCE ,Cell Biology ,Oncogenes ,PATHWAY ALTERATIONS ,IN-VITRO ,Neurofibromin 1 ,CANCER ,3. Good health ,Cell biology ,030104 developmental biology ,NF1 ,030220 oncology & carcinogenesis ,biology.protein ,GROWTH ,1182 Biochemistry, cell and molecular biology ,RNA Interference ,Signal transduction ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,Genetic screen - Abstract
Exquisite regulation of PI3K/AKT/mTORC1 signaling is essential for homeostatic control of cell growth, proliferation, and survival. Aberrant activation of this signaling network is an early driver of many sporadic human cancers. Paradoxically, sustained hyperactivation of the PI3K/AKT/mTORC1 pathway in nontransformed cells results in cellular senescence, which is a tumor-suppressive mechanism that must be overcome to promote malignant transformation. While oncogene-induced senescence (OIS) driven by excessive RAS/ERK signaling has been well studied, little is known about the mechanisms underpinning the AKT-induced senescence (AIS) response. Here, we utilize a combination of transcriptome and metabolic profiling to identify key signatures required to maintain AIS. We also employ a whole protein-coding genome RNAi screen for AIS escape, validating a subset of novel mediators and demonstrating their preferential specificity for AIS as compared with OIS. As proof of concept of the potential to exploit the AIS network, we show that neurofibromin 1 (NF1) is upregulated during AIS and its ability to suppress RAS/ERK signaling facilitates AIS maintenance. Furthermore, depletion of NF1 enhances transformation of p53-mutant epithelial cells expressing activated AKT, while its overexpression blocks transformation by inducing a senescent-like phenotype. Together, our findings reveal novel mechanistic insights into the control of AIS and identify putative senescence regulators that can potentially be targeted, with implications for new therapeutic options to treat PI3K/AKT/mTORC1-driven cancers.
- Published
- 2020
23. Advanced technological tools to study multidrug resistance in cancer
- Author
-
Yehuda G. Assaraf, Luca Andrei, Mónica Suárez Korsnes, Radka Vaclavikova, Ignacio Ochoa Garrido, Tijana Stanković, Sandor Kasas, and Milica Pešić
- Subjects
0301 basic medicine ,Genome instability ,Cancer Research ,Cell Culture Techniques ,Drug resistance ,Microscopy, Atomic Force ,stem-cells ,Transcriptome ,Atomic force microscopy ,drug-resistance ,0302 clinical medicine ,Neoplasms ,Tumor Microenvironment ,Medicine ,Pharmacology (medical) ,cancer multidrug resistance ,microfluidic devices ,Cancer multidrug resistance ,atomic force microscopy ,single live-cell tracking ,High-Throughput Nucleotide Sequencing ,personalized medicine ,tumor-cells ,circular rnas ,Drug Resistance, Multiple ,3. Good health ,Infectious Diseases ,Oncology ,030220 oncology & carcinogenesis ,extracellular vesicles ,Biotechnology ,Microfluidic devices ,Computational biology ,03 medical and health sciences ,Animals ,Humans ,atomic-force microscopy ,Epigenetics ,breast-cancer ,Pharmacology ,Tumor microenvironment ,3D cultures ,business.industry ,Cancer ,single-cell tracking ,medicine.disease ,Multiple drug resistance ,030104 developmental biology ,Biotechnology/methods ,Cell Culture Techniques/methods ,Drug Resistance, Multiple/genetics ,Drug Resistance, Neoplasm/genetics ,High-Throughput Nucleotide Sequencing/methods ,Microscopy, Atomic Force/methods ,Neoplasms/genetics ,Neoplasms/pathology ,Tumor Microenvironment/genetics ,Next-generation sequencing ,Single live-cell tracking ,a-chip platforms ,Drug Resistance, Neoplasm ,Cancer cell ,next-generation sequencing ,business ,3d cultures - Abstract
The complexity of cancer biology and its clinical manifestation are driven by genetic, epigenetic, transcriptomic, proteomic and metabolomic alterations, supported by genomic instability as well as by environmental conditions and lifestyle factors. Although novel therapeutic modalities are being introduced, efficacious cancer therapy is not achieved due to the frequent emergence of distinct mechanisms of multidrug resistance (MDR). Advanced technologies with the potential to identify and characterize cancer MDR could aid in selecting the most efficacious therapeutic regimens and prevent inappropriate treatments of cancer patients. Herein, we aim to present technological tools that will enhance our ability to surmount drug resistance in cancer in the upcoming decade. Some of these tools are already in practice such as next-generation sequencing. Identification of genes and different types of RNAs contributing to the MDR phenotype, as well as their molecular targets, are of paramount importance for the development of new therapeutic strategies aimed to enhance drug response in resistant tumors. Other techniques known for many decades are in the process of adaptation and improvement to study cancer cells’ characteristics and biological behavior including atomic force microscopy (AFM) and live-cell imaging. AFM can monitor in real-time single molecules or molecular complexes as well as structural alterations occurring in cancer cells induced upon treatment with various antitumor agents. Cell tracking methodologies and software tools recently progressed towards quantitative analysis of the spatio-temporal dynamics of heterogeneous cancer cell populations and enabled direct monitoring of cells and their descendants in 3D cultures. Besides, novel 3D systems with the advanced mimicking of the in vivo tumor microenvironment are applicable to study different cancer biology phenotypes, particularly drug-resistant and aggressive ones. They are also suitable for investigating new anticancer treatment modalities. The ultimate goal of using phenotype-driven 3D cultures for the investigation of patient biopsies as the most appropriate in vivo mimicking model, can be achieved in the near future.
- Published
- 2020
24. Harnessing natural killer cells for the treatment of ovarian cancer
- Author
-
Ruud L.M. Bekkers, Janneke S. Hoogstad-van Evert, Harry Dolstra, Leon F.A.G. Massuger, Nelleke Ottevanger, and Joop H. Jansen
- Subjects
0301 basic medicine ,Adoptive cell transfer ,BLOOD ,NK-CELL ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,medicine.medical_treatment ,TUMOR-CELLS ,Cell ,ACUTE MYELOID-LEUKEMIA ,THERAPY ,Cell therapy ,03 medical and health sciences ,0302 clinical medicine ,Ovarian cancer ,medicine ,LYMPHOMA ,Humans ,CYTOTOXICITY ,Sensitization ,Ovarian Neoplasms ,Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17] ,business.industry ,Obstetrics and Gynecology ,Immunotherapy ,medicine.disease ,Women's cancers Radboud Institute for Health Sciences [Radboudumc 17] ,Lymphoma ,Killer Cells, Natural ,Clinical trial ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,SURVIVAL ,Natural killer cells ,INTRAPERITONEAL CHEMOTHERAPY ,Female ,business - Abstract
Contains fulltext : 220786.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Adoptive cellular immunotherapy could be an interesting new treatment option for ovarian carcinoma (OC), as research has demonstrated that OC is an immunogenic disease. In particular, natural killer (NK) cells have attracted attention due to their ability to kill tumor cells without prior sensitization. The therapeutic value of allogeneic NK cells has been first observed in hematological cancers and is increasingly being explored in solid tumors. METHODS: To substantiate the rationale for NK cell therapy in OC we performed a literature search in the Pubmed database and in the international trial register clinicaltrials.gov with attention for the effect of OC on NK cell function, the effect of current treatment on NK cell biology and the evidence on the therapeutic value of NK cell therapy against OC. RESULTS: In six clinical trials only 31 OC patients have been reported that received NK cell adoptive transfer. The majority of patients reached stable disease after NK cell therapy, with a mild pattern of side effects. In patients who received repeated infusions, more complete responses are described. All reported studies investigated the intravenous infusion of NK cells. Whereas the studies that are currently recruiting, investigate intraperitoneal infusion of allogeneic NK cells. CONCLUSION: In this review the pre-clinical evidence and current trials on NK cell immunotherapy in OC patients are summarized. Furthermore, challenges that have to be overcome for NK cell adoptive therapy to have a significant impact on disease outcome are discussed. 01 juni 2020
- Published
- 2020
25. Multivalent antibody-recruiting macromolecules : linking increased binding affinity with enhanced innate immune killing
- Author
-
Annemiek Uvyn and Bruno G. De Geest
- Subjects
medicine.drug_class ,Antibodies, Neoplasm ,Macromolecular Substances ,TUMOR-CELLS ,EPITOPE ,Monoclonal antibody ,Biochemistry ,THERAPY ,Epitope ,Article ,PHAGOCYTOSIS ,MOLECULES ,Immune system ,medicine ,Medicine and Health Sciences ,Humans ,antibodies ,cancer ,Cytotoxicity ,Molecular Biology ,innate immunity ,ANTICARBOHYDRATE ANTIBODIES ,polymers ,Antibody-dependent cell-mediated cytotoxicity ,Innate immune system ,biology ,Chemistry ,Organic Chemistry ,RECOGNITION ,GAL ANTIBODY ,Immunity, Innate ,Cell biology ,Cancer cell ,BACTERIA ,biology.protein ,Molecular Medicine ,glycans ,Antibody ,MONOCLONAL-ANTIBODIES - Abstract
Antibody-recruiting molecules (ARMs) are a novel class of immunotherapeutics. They are capable of introducing antibodies on disease-relevant targets such as cancer cells, bacterial cells or viruses. This can induce antibody-mediated immune responses such as antibody dependent cellular cytotoxicity (ADCC), complement dependent cytotoxicity (CDC) and antibody dependent phagocytosis (ADCP) which can lead to killing of the pathogen. In contrast to the classic ARMs, multivalent antibody-recruiting macromolecules could offer an advantage in view of increasing the efficiency of antibody recruitment and subsequent innate immune killing. Such compounds consist of multiple target binding termini (TBT) and/or antibody binding termini (ABT). Those multivalent interactions are able to convert low binding affinities into increased binding avidities. This review summarizes the current status on multivalent antibody-recruiting macromolecules and gives insight into possible benefits, still to overcome hurdles and future perspectives.
- Published
- 2020
26. Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress
- Author
-
Juliette Humeau, Allan Sauvat, Giulia Cerrato, Wei Xie, Friedemann Loos, Francesca Iannantuoni, Lucillia Bezu, Sarah Lévesque, Juliette Paillet, Jonathan Pol, Marion Leduc, Laurence Zitvogel, Hugues de Thé, Oliver Kepp, and Guido Kroemer
- Subjects
Medicine (General) ,TUMOR-CELLS ,DNA-BINDING ,ANTICANCER CHEMOTHERAPY ,translation ,Antineoplastic Agents ,Immunogenic Cell Death ,QH426-470 ,Article ,EWINGS-SARCOMA ,R5-920 ,Artificial Intelligence ,Neoplasms ,Chemical Biology ,immunogenic cell death ,Genetics ,Medicine and Health Sciences ,Humans ,dactinomycin ,eIF2α phosphorylation ,ATP SECRETION ,Cancer ,CALRETICULIN EXPOSURE ,MOLECULAR-MECHANISMS ,DEATH ,Computational Biology ,Biology and Life Sciences ,Articles ,CANCER ,eIF2 alpha phosphorylation ,Dactinomycin ,ACTINOMYCIN-D ,transcription - Abstract
Chemotherapy still constitutes the standard of care for the treatment of most neoplastic diseases. Certain chemotherapeutics from the oncological armamentarium are able to trigger pre‐mortem stress signals that lead to immunogenic cell death (ICD), thus inducing an antitumor immune response and mediating long‐term tumor growth reduction. Here, we used an established model, built on artificial intelligence to identify, among a library of 50,000 compounds, anticancer agents that, based on their molecular descriptors, were predicted to induce ICD. This algorithm led us to the identification of dactinomycin (DACT, best known as actinomycin D), a highly potent cytotoxicant and ICD inducer that mediates immune‐dependent anticancer effects in vivo. Since DACT is commonly used as an inhibitor of DNA to RNA transcription, we investigated whether other experimentally established or algorithm‐selected, clinically employed ICD inducers would share this characteristic. As a common leitmotif, a panel of pharmacological ICD stimulators inhibited transcription and secondarily translation. These results establish the inhibition of RNA synthesis as an initial event for ICD induction., Anticancer drugs that trigger immunogenic cell death (ICD) are particularly efficient because they mobilize the host immune system against malignant cells expressing tumor‐associated antigens. Dactinomycin is identified as an ICD inducer and showed to stimulate anticancer immune responses in vivo.
- Published
- 2020
27. Association between dopamine and somatostatin receptor expression and pharmacological response to somatostatin analogues in acromegaly
- Author
-
Raúl M. Luque, Mari C Vázquez-Borrego, Miguel A. Japón, Elena Dios, Alvaro Flores-Martínez, David A. Cano, Noelia Gros-Herguido, Justo P. Castaño, Eva Venegas-Moreno, Esther Rivero-Cortés, Alfonso Soto-Moreno, Ainara Madrazo-Atutxa, [Venegas-Moreno, Eva] Univ Seville, CSIC, Hosp Univ Virgen del Rocio, Unidad Gest Endocrinol Nutr,Inst Biomed Sevilla I, Seville, Spain, [Dios, Elena] Univ Seville, CSIC, Hosp Univ Virgen del Rocio, Unidad Gest Endocrinol Nutr,Inst Biomed Sevilla I, Seville, Spain, [Gros-Herguido, Noelia] Univ Seville, CSIC, Hosp Univ Virgen del Rocio, Unidad Gest Endocrinol Nutr,Inst Biomed Sevilla I, Seville, Spain, [Flores-Martinez, Alvaro] Univ Seville, CSIC, Hosp Univ Virgen del Rocio, Unidad Gest Endocrinol Nutr,Inst Biomed Sevilla I, Seville, Spain, [Madrazo-Atutxa, Ainara] Univ Seville, CSIC, Hosp Univ Virgen del Rocio, Unidad Gest Endocrinol Nutr,Inst Biomed Sevilla I, Seville, Spain, [Cano, David A.] Univ Seville, CSIC, Hosp Univ Virgen del Rocio, Unidad Gest Endocrinol Nutr,Inst Biomed Sevilla I, Seville, Spain, [Soto-Moreno, Alfonso] Univ Seville, CSIC, Hosp Univ Virgen del Rocio, Unidad Gest Endocrinol Nutr,Inst Biomed Sevilla I, Seville, Spain, [Vazquez-Borrego, Mari C.] Univ Cordoba, Agrifood Campus Int Excellence CeiA3, CIBER Physiopathol Obes & Nutr CIBERobn,Dept Cell, Maimonides Inst Biomed Res Cordoba IMIBIC,Rein So, Cordoba, Spain, [Rivero-Cortes, Esther] Univ Cordoba, Agrifood Campus Int Excellence CeiA3, CIBER Physiopathol Obes & Nutr CIBERobn,Dept Cell, Maimonides Inst Biomed Res Cordoba IMIBIC,Rein So, Cordoba, Spain, [Luque, Raul M.] Univ Cordoba, Agrifood Campus Int Excellence CeiA3, CIBER Physiopathol Obes & Nutr CIBERobn,Dept Cell, Maimonides Inst Biomed Res Cordoba IMIBIC,Rein So, Cordoba, Spain, [Castano, Justo P.] Univ Cordoba, Agrifood Campus Int Excellence CeiA3, CIBER Physiopathol Obes & Nutr CIBERobn,Dept Cell, Maimonides Inst Biomed Res Cordoba IMIBIC,Rein So, Cordoba, Spain, [Japon, Miguel A.] Univ Seville, CSIC, Hosp Univ Virgen del Rocio, Dept Pathol,Inst Biomed Sevilla IBIS, Seville, Spain, ISCIII-Subdireccion General de Evaluacion y Fomento de la Investigacion, Fondos FEDER, Novartis Oncology Spain, Junta de Andalucia, MINECO, CIBERobn (CIBER is an initiative of Instituto de Salud Carlos III, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain), Novartis Oncology, Andalusian and Spanish Societies of Endocrinology and Nutrition (SAEDYN), Andalusian and Spanish Societies of Endocrinology and Nutrition (SEEN), and 'Nicolas Monardes' programme of the Andalusian Ministry of Health
- Subjects
Male ,Octreotide-lar ,Gene Expression ,pituitary adenoma ,Receptors, Dopamine ,In-vitro ,0302 clinical medicine ,Subtype 2a ,dopamine receptor ,Protein Isoforms ,Somatostatin receptor 2 ,Pituitary-adenomas ,Somatostatin receptor 1 ,Receptors, Somatostatin ,Receptor ,Somatotroph adenomas ,somatostatin analogues ,Reverse Transcriptase Polymerase Chain Reaction ,Somatostatin receptor ,Middle Aged ,Immunohistochemistry ,somatostatin receptor ,Somatostatin ,Biochemical response ,Dopamine receptor ,030220 oncology & carcinogenesis ,Molecular Medicine ,Original Article ,Female ,Adenoma ,Adult ,medicine.medical_specialty ,Monoclonal-antibodies ,030209 endocrinology & metabolism ,03 medical and health sciences ,Pituitary adenoma ,Internal medicine ,Acromegaly ,medicine ,Humans ,Retrospective Studies ,Tumor-cells ,business.industry ,Original Articles ,Cell Biology ,medicine.disease ,Endocrinology ,acromegaly ,Clinical-response ,Growth Hormone-Secreting Pituitary Adenoma ,Aggressive features ,business - Abstract
Acromegaly is a hormonal disorder resulting from excessive growth hormone (GH) secretion frequently produced by pituitary adenomas and consequent increase in insulin‐like growth factor 1 (IGF‐I). Elevated GH and IGF‐I levels result in a wide range of somatic, cardiovascular, endocrine, metabolic and gastrointestinal morbidities. Somatostatin analogues (SSAs) form the basis of medical therapy for acromegaly and are currently used as first‐line treatment or as second‐line therapy in patients undergoing unsuccessful surgery. However, a considerable percentage of patients do not respond to SSAs treatment. Somatostatin receptors (SSTR1‐5) and dopamine receptors (DRD1‐5) subtypes play critical roles in the regulation of hormone secretion. These receptors are considered important pharmacological targets to inhibit hormone oversecretion. It has been proposed that decreased expression of SSTRs may be associated with poor response to SSAs. Here, we systematically examine SSTRs and DRDs expression in human somatotroph adenomas by quantitative PCR. We observed an association between the response to SSAs treatment and DRD4, DRD5, SSTR1 and SSTR2 expression. We also examined SSTR expression by immunohistochemistry and found that the immunohistochemical detection of SSTR2 in particular might be a good predictor of response to SSAs.
- Published
- 2017
- Full Text
- View/download PDF
28. Oncogenic p95HER2/611CTF primes human breast epithelial cells for metabolic stress-induced down-regulation of FLIP and activation of TRAIL-R/Caspase-8-dependent apoptosis
- Author
-
Ana Cano-González, Rocío Mora-Molina, Rosario Yerbes, Carmen Palacios, Massimiliano Mazzone, Joaquín Arribas, Rosa Martín-Pérez, Abelardo López-Rivas, Red Temática de Investigación Cooperativa en Cáncer (España), Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, European Commission, and Junta de Andalucía
- Subjects
EXPRESSION ,0301 basic medicine ,TRAIL-R ,FLIP ,Angiogenesis ,TUMOR-CELLS ,p95HER2/611CTF ,TRAIL ,Inflammation ,Tumor initiation ,UP-REGULATION ,Caspase 8 ,PATHWAY ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Metabolic stress ,PI3K/AKT/mTOR pathway ,Science & Technology ,RECEPTOR ,P95HER2/611CTF ,Oncogene ,UNFOLDED-PROTEIN-RESPONSE ,MTOR ,business.industry ,DEATH ,Cell Biology ,CANCER ,GLUTAMINE ,030104 developmental biology ,Oncology ,Apoptosis ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Tumor necrosis factor alpha ,medicine.symptom ,business ,Life Sciences & Biomedicine ,Research Paper - Abstract
Oncogenic transformation triggers reprogramming of cell metabolism, as part of the tumorigenic process. However, metabolic reprogramming may also increase the sensitivity of transformed cells to microenvironmental stress, at the early stages of tumor development. Herein, we show that transformation of human breast epithelial cells by the p95HER2/611CTF oncogene markedly sensitizes these cells to metabolic stress induced by the simultaneous inhibition of glucose and glutamine metabolism. In p95HER2/611CTF-transformed cells, metabolic stress activates a TNF related apoptosis-inducing ligand (TRAIL)-R and caspase-8-dependent apoptotic process that requires prior down-regulation of cellular FLICE-like inhibitor protein (c-FLIP) levels. Importantly, sustained mTOR activation is involved in FLIP down-regulation and apoptosis induced by metabolic stress. In vivo experiments in immunodeficient mice demonstrate a requirement for caspase-8 in restraining primary tumor growth of xenografts with p95HER2/611CTF-transformed cells. Collectively, these data define a critical role of the extrinsic pathway of apoptosis in the control of tumor initiation by microenvironmental cues., This work was supported by grants from Ministerio de Economía y Competitividad (SAF2012-32824 and SAF2015-64383-P), Junta de Andalucía Excellence Program (BIO 778), CIBERONC ISCIII CB16/12/00421 and Red Temática de Investigación Cooperativa en Cáncer (RD12/0036/0026 to ALR and RD12/0036/0042 to JA) and the European Community through the regional development funding program (FEDER).
- Published
- 2017
- Full Text
- View/download PDF
29. Prognostic significance of peritoneal lavage cytology in staging gastric cancer: systematic review and meta-analysis
- Author
-
Sheraz R. Markar, George B. Hanna, Thanos Athanasiou, Sara Jamel, Amish Acharya, and George Malietzis
- Subjects
Male ,Oncology ,Cancer Research ,INFORMATION ,TUMOR-CELLS ,medicine.medical_treatment ,Review Article ,030230 surgery ,Cochrane Library ,Cancer staging ,NEOADJUVANT CHEMOTHERAPY ,0302 clinical medicine ,Cytology ,Peritoneal Lavage ,WASHING CYTOLOGY ,Neoadjuvant therapy ,POTENTIALLY CURATIVE RESECTION ,Peritoneal cytology ,Hazard ratio ,Gastroenterology ,General Medicine ,Middle Aged ,Prognosis ,030220 oncology & carcinogenesis ,Meta-analysis ,SURVIVAL ,Adenocarcinoma ,Female ,Life Sciences & Biomedicine ,medicine.medical_specialty ,CARCINOMA ,03 medical and health sciences ,Stomach Neoplasms ,Internal medicine ,medicine ,Humans ,Oncology & Carcinogenesis ,CLINICAL-SIGNIFICANCE ,Gastric cancer, stomach neoplasm ,Aged ,Neoplasm Staging ,Cancer prognosis ,Science & Technology ,GASTRECTOMY ,Gastroenterology & Hepatology ,business.industry ,Cancer ,medicine.disease ,Laparoscopy ,business - Abstract
Background Peritoneal cytology has been used as a part of the cancer staging of gastric cancer patients. The primary aim of this systematic review was to evaluate the value of peritoneal cytology as part of the staging of gastric cancer and survival prediction. The second aim was to establish if positive cytology may be modified by neoadjuvant therapy, to improve prognosis. Methods An electronic literature search was performed using Embase, Medline, Web of Science, and Cochrane library databases up to January 2016. The logarithm of the hazard ratio (HR) with 95% confidence intervals (CI) was used as the primary summary statistic. Comparative studies were used, and the outcome measure was survival in three groups: (1) positive versus negative cytology at staging laparoscopy immediately preceding surgery; (2) effect of neoadjuvant therapy on cytology and survival; and (3) positive cytology in the absence of macroscopic peritoneal disease was compared with obvious macroscopic peritoneal disease. Results Pooled analysis demonstrated that positive cytology was associated with significantly reduced overall survival (HR, 3.46; 95% CI, 2.77–4.31; P < 0.0001). Interestingly, negative cytology following neoadjuvant chemotherapy was associated with significantly improved overall survival (HR, 0.42; 95% CI, 0.31–0.57; P < 0.0001). The absence of macroscopic peritoneal disease with positive cytology was associated with significantly improved overall survival (HR, 0.64; 95% CI, 0.56–0.73; P < 0.0001). Conclusion This study suggests that patients with initial positive cytology may have a good prognosis following neoadjuvant treatment if the cytology results change to negative after treatment.
- Published
- 2017
- Full Text
- View/download PDF
30. Expression of toll-like receptors in non-endemic nasopharyngeal carcinoma
- Author
-
Caj Haglund, Heikki Minn, Jaana Hagström, Miia Ruuskanen, Tero Vahlberg, Ilmo Leivo, Heikki Irjala, HUS Abdominal Center, Department of Surgery, II kirurgian klinikka, University Management, University of Helsinki, Research Programs Unit, CAN-PRO - Translational Cancer Medicine Program, Medicum, Department of Pathology, and HUSLAB
- Subjects
Male ,0301 basic medicine ,Herpesvirus 4, Human ,Cancer Research ,TUMOR-CELLS ,Thyroid Gland ,Kaplan-Meier Estimate ,medicine.disease_cause ,0302 clinical medicine ,INFECTION ,TLR3 ,Child ,Head and neck cancer ,Papillomaviridae ,Finland ,Aged, 80 and over ,Toll-like receptor ,education.field_of_study ,Toll-Like Receptors ,Age Factors ,virus diseases ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3. Good health ,Survival Rate ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,RNA, Viral ,Immunohistochemistry ,Female ,SQUAMOUS-CELL CARCINOMA ,Research Article ,Adult ,Human papillomavirus ,Adolescent ,3122 Cancers ,Population ,lcsh:RC254-282 ,Young Adult ,03 medical and health sciences ,INFLAMMATION ,Nasopharyngeal carcinoma ,Genetics ,medicine ,Humans ,Epstein-Barr virus ,education ,POLYMORPHISMS ,Cyclin-Dependent Kinase Inhibitor p16 ,Aged ,business.industry ,Cancer ,Nasopharyngeal Neoplasms ,Human papillomavirus 6 ,medicine.disease ,Toll-Like Receptor 1 ,Epstein–Barr virus ,Toll-Like Receptor 2 ,Toll-Like Receptor 4 ,Toll-Like Receptor 5 ,TLR2 ,030104 developmental biology ,Toll-Like Receptor 7 ,Toll-Like Receptor 9 ,Cancer research ,Carcinogenesis ,business - Abstract
BackgroundNasopharyngeal carcinoma (NPC) is a malignant disease with an enigmatic etiology. NPC associates with Epstein-Barr virus (EBV) and human papillomaviruses (HPVs), while immunological factors also play a role in carcinogenesis. Toll-like receptors (TLRs) are pattern recognition receptors that participate in the immunological defence against pathogens, but their functions are also linked to cancer.MethodsIn our whole population-based study, we retrieved 150 Finnish NPC cases and studied their tumour samples for TLR1, TLR2, TLR4, TLR5, TLR7, and TLR9 expressions by immunohistochemistry, and for the presence of EBV and high-risk HPVs with EBV RNA and HPV E6/E7 mRNA in situ hybridizations. In addition, we analyzed the TLR expression patterns according to age, tumour histology, EBV/HPV status, and outcome.ResultsWe found that all TLRs studied were highly expressed in NPC. Viral status of the tumours varied, and 62% of them were EBV-positive, 14% HPV-positive, and 24% virus-negative. The tumours with strong TLR2(nucl) or TLR5 expression were mostly virus-negative or HPV-positive keratinizing squamous cell carcinomas, and the patients with these tumours were significantly older than those with mild or negative TLR2(nucl)/TLR5 expression. In Kaplan-Meier analysis, the patients with strong TLR5 expression had worse survival compared to the patients with negative or mild TLR5 expression, but the results were linked to other patient and tumour characteristics. In multivariable-adjusted Cox regression analysis, the patients with positive TLR7 tumour expression had better overall survival than those with no TLR7 expression. The 5-year overall survival rates according to TLR7 expression were 66% (mild), 52% (moderate or strong), and 22% (negative).ConclusionsTLRs are highly expressed in non-endemic NPC. Intensity of TLR2 and TLR5 expressions correlate with viral status, and TLR7 seems to be an independent prognostic factor of non-endemic NPC.
- Published
- 2019
- Full Text
- View/download PDF
31. HAS3-induced extracellular vesicles from melanoma cells stimulate IHH mediated c-Myc upregulation via the hedgehog signaling pathway in target cells
- Author
-
Petri I. Mäkinen, Maciej Lalowski, Sanna Pasonen-Seppänen, Pia Siljander, Ashik Jawahar Deen, Uma Thanigai Arasu, Kai Härkönen, Riikka Kärnä, Kirsi Rilla, Elisa Lázaro-Ibáñez, Sanna Oikari, Sami Heikkinen, Anna-Liisa Levonen, Department of Biochemistry and Developmental Biology, Faculty of Medicine, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Extracellular Vesicles, Divisions of Faculty of Pharmacy, Faculty of Pharmacy, Division of Pharmaceutical Biosciences, Molecular and Integrative Biosciences Research Programme, Drug Research Program, and Faculty of Biological and Environmental Sciences
- Subjects
IHH ,TUMOR-CELLS ,Cell ,Proliferation ,Hedgehog signaling ,SHEDDING LIGHT ,ACTIVATION ,0302 clinical medicine ,Hyaluronan synthase ,Melanoma ,Hyaluronan ,Cancer ,0303 health sciences ,biology ,Chemistry ,Extracellular vesicles ,PANCREATIC-CANCER ,Hedgehog signaling pathway ,Cell biology ,Up-Regulation ,TRANSCRIPTION FACTORS ,medicine.anatomical_structure ,Hyaluronan Receptors ,c-Myc ,030220 oncology & carcinogenesis ,Molecular Medicine ,Original Article ,Claspin ,O-GLCNACYLATION ,Signal Transduction ,Epithelial-Mesenchymal Transition ,Cell Line ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Humans ,Hedgehog Proteins ,CYCLE ,Molecular Biology ,030304 developmental biology ,Cell Proliferation ,EXOSOMES ,Pharmacology ,Cell growth ,CD44 ,Cell Biology ,Microvesicles ,Cancer cell ,biology.protein ,1182 Biochemistry, cell and molecular biology ,3111 Biomedicine ,Hyaluronan Synthases - Abstract
Intercellular communication is fundamental to the survival and maintenance of all multicellular systems, whereas dysregulation of communication pathways can drive cancer progression. Extracellular vesicles (EVs) are mediators of cell-to-cell communication that regulate a variety of cellular processes involved in tumor progression. Overexpression of a specific plasma membrane enzyme, hyaluronan synthase 3 (HAS3), is one of the factors that can induce EV shedding. HAS3, and particularly its product hyaluronan (HA), are carried by EVs and are known to be associated with the tumorigenic properties of cancer cells. To elucidate the specific effects of cancerous, HAS3-induced EVs on target cells, normal human keratinocytes and melanoma cells were treated with EVs derived from GFP-HAS3 expressing metastatic melanoma cells. We found that the HA receptor CD44 participated in the regulation of EV binding to target cells. Furthermore, GFP-HAS3-positive EVs induced HA secretion, proliferation and invasion of target cells. Our results suggest that HAS3-EVs contains increased quantities of IHH, which activates the target cell hedgehog signaling cascade and leads to the activation of c-Myc and regulation of claspin expression. This signaling of IHH in HAS3-EVs resulted in increased cell proliferation. Claspin immunostaining correlated with HA content in human cutaneous melanocytic lesions, supporting our in vitro findings and suggesting a reciprocal regulation between claspin expression and HA synthesis. This study shows for the first time that EVs originating from HAS3 overexpressing cells carry mitogenic signals that induce proliferation and epithelial-to-mesenchymal transition in target cells. The study also identifies a novel feedback regulation between the hedgehog signaling pathway and HA metabolism in melanoma, mediated by EVs carrying HA and IHH. Electronic supplementary material The online version of this article (10.1007/s00018-019-03399-5) contains supplementary material, which is available to authorized users.
- Published
- 2019
32. Broadening the Message
- Author
-
Ine Lentacker, Rein Verbeke, Jonas Janssens, Heleen Dewitte, Stefaan C. De Smedt, Serge Van Calenbergh, Karine Breckpot, Basic (bio-) Medical Sciences, Laboratory of Molecullar and Cellular Therapy, and Linguistics and Literary Studies
- Subjects
Lymphoma ,CANCER VACCINES ,T-Lymphocytes ,CLINICAL-APPLICATIONS ,TUMOR-CELLS ,Cell ,Melanoma, Experimental ,General Physics and Astronomy ,Kaplan-Meier Estimate ,02 engineering and technology ,Lymphocyte Activation ,IMMUNOGENICITY ,01 natural sciences ,ANERGY INDUCTION ,BETA-CATENIN ,Mice ,Nanoparticle ,checkpoint inhibition ,Medicine and Health Sciences ,Cytotoxic T cell ,General Materials Science ,alpha-galactosylceramide ,Melanoma ,Cancer ,Immunity, Cellular ,Chemistry ,nanoparticle ,General Engineering ,021001 nanoscience & nanotechnology ,Natural killer T cell ,Killer Cells, Natural ,medicine.anatomical_structure ,ACTIVATED NKT CELLS ,oncology ,Female ,modified nucleotides ,0210 nano-technology ,CD1D EXPRESSION ,Ovalbumin ,T cell ,Immunology ,Galactosylceramides ,Immunopotentiator ,010402 general chemistry ,Cancer Vaccines ,DENDRITIC CELLS ,Immune system ,Antigen ,Antigens, Neoplasm ,medicine ,Animals ,RNA, Messenger ,INKT CELLS ,Tumor microenvironment ,Biology and Life Sciences ,0104 chemical sciences ,immunothertapy ,mRNA vaccine ,Liposomes ,Cancer research ,Natural Killer T-Cells - Abstract
Messenger RNA encoding tumor antigens has the potential to evoke effective antitumor immunity. This study reports on a nanoparticle platform, named mRNA Galsomes, that successfully co-delivers nucleoside-modified antigen-encoding mRNA and the glycolipid antigen and immunopotentiator α-galactosylceramide (α-GC) to antigen-presenting cells after intravenous administration. By co-formulating low doses of α-GC, mRNA Galsomes induce a pluripotent innate and adaptive tumor-specific immune response in mice, with invariant natural killer T cells (iNKT) as a driving force. In comparison, mRNA Galsomes exhibit advantages over the state-of-the-art cancer vaccines using unmodified ovalbumin (OVA)-encoding mRNA, as we observed up to seven times more tumor-infiltrating antigen-specific cytotoxic T cells, combined with a strong iNKT cell and NK cell activation. In addition, the presence of suppressive myeloid cells (myeloid-derived suppressor cells and tumor-associated macrophages) in the tumor microenvironment was significantly lowered. Owing to these antitumor effects, OVA mRNA Galsomes significantly reduced tumor growth in established E.G7-OVA lymphoma, with a complete tumor rejection in 40% of the animals. Moreover, therapeutic vaccination with mRNA Galsomes enhanced the responsiveness to treatment with a PD-L1 checkpoint inhibitor in B16-OVA melanoma, as evidenced by a synergistic reduction of tumor outgrowth and a significantly prolonged median survival. Taken together, these data show that intravenously administered mRNA Galsomes can provide controllable, multifaceted, and effective antitumor immunity, especially when combined with checkpoint inhibition.
- Published
- 2019
33. JUNB, DUSP2, SGK1, SOCS1 and CREBBP are frequently mutated in T-cell/histiocyte-rich large B-cell lymphoma
- Author
-
Christian Steidl, Maurilio Ponzoni, Ralf Küppers, Julia Bein, Vladimir Benes, Martin-Leo Hansmann, Bianca Schuhmacher, Tobias Rausch, Martine Vornanen, Sylvia Hartmann, Randy D. Gascoyne, Thomas Tousseyn, Lorenz Thurner, Schuhmacher, B., Bein, J., Rausch, T., Benes, V., Tousseyn, T., Vornanen, M., Ponzoni, M., Thurner, L., Gascoyne, R., Steidl, C., Kuppers, R., Hansmann, M. -L., Hartmann, S., Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, and Tampere University
- Subjects
Male ,Mutation rate ,Somatic cell ,IMPACT ,TUMOR-CELLS ,T-Lymphocytes ,Medizin ,Aggressive lymphoma ,ACTIVATION ,0302 clinical medicine ,Mutation Rate ,immune system diseases ,hemic and lymphatic diseases ,AID ,Aged, 80 and over ,Hematology ,Middle Aged ,SHOWS ,Protein-Serine-Threonine Kinases ,CREB-Binding Protein ,PREDOMINANT HODGKIN LYMPHOMA ,Female ,Lymphoma, Large B-Cell, Diffuse ,Life Sciences & Biomedicine ,EXPRESSION ,Adult ,GENES ,JUNB ,Biolääketieteet - Biomedicine ,Non-Hodgkin Lymphoma ,Somatic hypermutation ,Biology ,Article ,Immediate-Early Proteins ,03 medical and health sciences ,Young Adult ,Suppressor of Cytokine Signaling 1 Protein ,medicine ,Biomarkers, Tumor ,Humans ,Aged ,Tumor microenvironment ,Science & Technology ,MUTATIONS ,Dual Specificity Phosphatase 2 ,Histiocytes ,medicine.disease ,Lymphoma ,ABERRANT SOMATIC HYPERMUTATION ,Mutation ,Cancer research ,T-Cell/Histiocyte-Rich Large B-Cell Lymphoma ,030215 immunology ,Transcription Factors - Abstract
T-cell/histiocyte-rich large B-cell lymphoma is a rare aggressive lymphoma showing histopathological overlap with nodular lymphocyte-predominant Hodgkin lymphoma. Despite differences in tumor microenvironment and clinical behavior, the tumor cells of both entities show remarkable similarities, suggesting that both lymphomas might represent a spectrum of the same disease. To address this issue, we investigated whether these entities share mutations. Ultra-deep targeted resequencing of six typical and 11 histopathological variants of nodular lymphocyte-predominant Hodgkin lymphoma, and nine cases of T-cell/histiocyte-rich large B-cell lymphoma revealed that genes recurrently mutated in nodular lymphocyte-predominant Hodgkin lymphoma are affected by mutations at similar frequencies in T-cell/histiocyte-rich large B-cell lymphoma. The most recurrently mutated genes were JUNB, DUSP2, SGK1, SOCS1 and CREBBP, which harbored mutations more frequently in T-cell/histiocyte-rich large B-cell lymphoma and the histopathological variants of nodular lymphocyte-predominant Hodgkin lymphoma than in its typical form. Mutations in JUNB, DUSP2, SGK1 and SOCS1 were highly enriched for somatic hypermutation hotspot sites, suggesting an important role of aberrant somatic hypermutation in the generation of these somatic mutations and thus in the pathogenesis of both lymphoma entities. Mutations in JUNB are generally rarely observed in malignant lymphomas and thus are relatively specific for nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma at such high frequencies (5/17 and 5/9 cases with JUNB mutations, respectively). Taken together, the findings of the present study further support a close relationship between T-cell/histiocyte-rich large B-cell lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma by showing that they share highly recurrent genetic lesions. ispartof: HAEMATOLOGICA vol:104 issue:2 pages:330-337 ispartof: location:Italy status: published
- Published
- 2019
34. A novel 3D nanofibre scaffold conserves the plasticity of glioblastoma stem cell invasion by regulating galectin-3 and integrin-β1 expression
- Author
-
Hassan Boukhaddaoui, Ali Saleh, Jean-Philippe Hugnot, Luc Bauchet, Hugues Duffau, Igor Lima Maldonado, Norbert Bakalara, Zahra Hassani, Emilie Marhuenda, Jan de Weille, David Cornu, Sophie Guelfi, Christine Fabre, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Européen des membranes (IEM), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM), and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
DYNAMICS ,Galectin 3 ,TUMOR-CELLS ,Acrylic Resins ,Nanofibers ,lcsh:Medicine ,Corpus Callosum ,Extracellular matrix ,Mice ,0302 clinical medicine ,Laminin ,Cell Movement ,BINDING ,10. No inequality ,lcsh:Science ,Oligonucleotide Array Sequence Analysis ,0303 health sciences ,Multidisciplinary ,biology ,Tissue Scaffolds ,Chemistry ,Brain Neoplasms ,Integrin beta1 ,Cell migration ,Blood Proteins ,CANCER ,Cell biology ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Basal lamina ,Stem cell ,MIGRATION ,Galectins ,EGFR ,Kruppel-Like Transcription Factors ,Mice, Nude ,Article ,Focal adhesion ,03 medical and health sciences ,medicine ,Cell Adhesion ,Animals ,Humans ,[CHIM]Chemical Sciences ,Neoplasm Invasiveness ,Cell adhesion ,030304 developmental biology ,Mesenchymal stem cell ,lcsh:R ,CNS cancer ,biology.protein ,lcsh:Q ,Glioblastoma - Abstract
Glioblastoma Multiforme (GBM) invasiveness renders complete surgical resection impossible and highly invasive Glioblastoma Initiating Cells (GICs) are responsible for tumour recurrence. Their dissemination occurs along pre-existing fibrillary brain structures comprising the aligned myelinated fibres of the corpus callosum (CC) and the laminin (LN)-rich basal lamina of blood vessels. The extracellular matrix (ECM) of these environments regulates GIC migration, but the underlying mechanisms remain largely unknown. In order to recapitulate the composition and the topographic properties of the cerebral ECM in the migration of GICs, we have set up a new aligned polyacrylonitrile (PAN)-derived nanofiber (NF) scaffold. This system is suitable for drug screening as well as discrimination of the migration potential of different glioblastoma stem cells. Functionalisation with LN increases the spatial anisotropy of migration and modulates its mode from collective to single cell migration. Mechanistically, equally similar to what has been observed for mesenchymal migration of GBM in vivo, is the upregulation of galectin-3 and integrin-β1 in Gli4 cells migrating on our NF scaffold. Downregulation of Calpain-2 in GICs migrating in vivo along the CC and in vitro on LN-coated NF underlines a difference in the turnover of focal adhesion (FA) molecules between single-cell and collective types of migration.
- Published
- 2019
- Full Text
- View/download PDF
35. Functional Analysis of the Adrenomedullin Pathway in Malignant Pleural Mesothelioma
- Author
-
Zohra Benyahia, Mylène Cayol, L'Houcine Ouafik, Pierre-Marie Martin, Nadège Dussault, Christine Delfino, Fabrice Barlesi, Laurent Greillier, Asma Tounsi, Stéphane Garcia, Kamel Mabrouk, Caroline Berenguer-Daizé, Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Service d'oncologie multidisciplinaire innovations thérapeutiques [Hôpital Nord - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM), Laboratoire de Transfert d'Oncologie Biologique [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Oncologie multidisciplinaire et innovations thérapeutiques [Hôpital Nord - APHM], Aix Marseille Université (AMU)- Hôpital Nord [CHU - APHM]-Assistance Publique - Hôpitaux de Marseille (APHM), and Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Mesothelioma ,0301 basic medicine ,MAPK/ERK pathway ,Lung Neoplasms ,Neoangiogenesis- and lymphangiogenesis-associated tumors ,Angiogenesis ,Receptor Activity-Modifying Protein 2 ,Proto-Oncogene Mas ,Receptor Activity-Modifying Protein 3 ,Immunoenzyme Techniques ,Mice ,Adrenomedullin ,angiogenesis ,0302 clinical medicine ,Invasion ,Cell Movement ,pancreatic-cancer ,Tumor Cells, Cultured ,Receptor ,Neovascularization, Pathologic ,Reverse Transcriptase Polymerase Chain Reaction ,glioblastoma cell-lines ,Calcitonin Receptor-Like Protein ,apoptosis ,tumor-cells ,Flow Cytometry ,3. Good health ,Lymphangiogenesis ,Gene Expression Regulation, Neoplastic ,lymphangiogenesis ,Oncology ,030220 oncology & carcinogenesis ,vivo ,Pulmonary and Respiratory Medicine ,Pleural Neoplasms ,Blotting, Western ,Mice, Nude ,receptor-like receptor ,in-vitro ,Biology ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,Biomarkers, Tumor ,Animals ,Humans ,[CHIM]Chemical Sciences ,RNA, Messenger ,Receptors, Adrenomedullin ,Protein kinase A ,Tumor growth ,Cell Proliferation ,Messenger RNA ,Cell growth ,Mesothelioma, Malignant ,Xenograft Model Antitumor Assays ,030104 developmental biology ,RAMP2 ,Cancer research ,endothelial growth-factor - Abstract
International audience; Introduction: Malignant pleural mesothelioma (MPM) grows aggressively within the thoracic cavity and has a very low cure rate, thus highlighting the need for identification of new therapeutic targets. Adrenomedullin (AM) is a multifunctional peptide that is highly expressed in several tumors and plays an important role in angiogenesis and tumor growth after binding to its receptors, calcitonin receptor-like receptor/receptor activity-modifying protein 2 (CLR/RAMP2) and calcitonin receptor-like receptor/receptor activity-modifying protein 3 (CLR/RAMP3). Methods: Real time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was used to assess the steady-state levels of AM, CLR, RAMP2 and RAMP3 messenger RNA (mRNA) transcripts in normal pleural tissue (n=5) and MPM (n=24). The expression of these candidates at protein level was revealed by immunohistochemistry. We also characterized the expression and regulation by hypoxia of AM system in MPM cell lines and MeT-5A cells. In vitro and in vivo studies were performed to determine the functional role of AM system in MPM. Results: In this study, real-time quantitative reverse transcriptase polymerase chain reaction showed twofold to 10 fold higher levels of AM messenger RNA in MPM tissue than in normal pleural tissue. The MPM cell lines H2452, H2052, and human mesothelioma cell line MSTO-211H showed a significant increase in expression of AM messenger RNA under hypoxic conditions. Our results also show that AM stimulates cell proliferation in vitro through the Raf1 protooncogene, serine/threonine kinase (CRAF)/Mitogen-activated protein kinase kinase 1 (MEIC)/Extracellular regulated MAPKinase (ERK) pathway. Furthermore, the proliferation, migration, and invasion of MPM cells were decreased after treatment with anti-AM (alpha AM) and anti-AM receptor antibodies, thus indicating that MPM cells are regulated by AM. The action of AM was specific and mediated by CLR/RAMP2 and CLR/RAMP3 receptors. In vivo, aAM and AM(22-52) antagonist therapies blocked angiogenesis and induced apoptosis in MSTO-211H xenografts, thereby resulting in tumor regression. Histologic examination of tumors treated with AM(22-52) and aAM antibody showed evidence of disruption of tumor vasculature with depletion of vascular endothelial cells and a significant decrease in lymphatic endothelial cells. Conclusions: Our findings highlight the importance of the AM pathway in growth of MPM and in neovascularization by supplying and amplifying signals that are essential for pathologic neoangiogenesis and lymphangiogenesis.
- Published
- 2016
- Full Text
- View/download PDF
36. Preoperative Biomarker Panel, Including Fibrinogen and FVIII, Improves Diagnostic Accuracy for Pancreatic Ductal Adenocarcinoma
- Author
-
Hanna Seppänen, Caj Haglund, Harri Mustonen, Riitta Lassila, Beata Przybyla, Nora Mattila, II kirurgian klinikka, Department of Surgery, Clinicum, University of Helsinki, HUS Abdominal Center, HUS Comprehensive Cancer Center, Department of Oncology, Translational Cancer Biology (TCB) Research Programme, Research Programs Unit, Hematologian yksikkö, Department of Clinical Chemistry and Hematology, Medicum, and HUSLAB
- Subjects
Male ,endocrine system diseases ,TUMOR-CELLS ,pancreatic cancer ,030204 cardiovascular system & hematology ,Fibrinogen ,D-DIMER LEVELS ,Gastroenterology ,0302 clinical medicine ,Stage (cooking) ,Aged, 80 and over ,RISK ,Area under the curve ,Hematology ,General Medicine ,Middle Aged ,3. Good health ,030220 oncology & carcinogenesis ,CA 19-9 ,SURVIVAL ,Biomarker (medicine) ,biomarker ,CA19-9 ,Female ,medicine.drug ,Carcinoma, Pancreatic Ductal ,Adult ,FVIII ,medicine.medical_specialty ,3122 Cancers ,COAGULATION ,CANCER-PATIENTS ,03 medical and health sciences ,Internal medicine ,Pancreatic cancer ,medicine ,Biomarkers, Tumor ,Humans ,Aged ,VENOUS THROMBOEMBOLISM ,Factor VIII ,Intraductal papillary mucinous neoplasm ,business.industry ,Cancer ,Original Articles ,medicine.disease ,THROMBOSIS ,CLINICAL-ASPECTS ,CA-19-9 ,fibrinogen ,3111 Biomedicine ,business - Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer often diagnosed late. Earlier detection is urgently needed. Pancreatic ductal adenocarcinoma is known to associate with increased coagulation activity. We studied whether preoperative coagulation biomarkers are useful in distinguishing PDAC from a benign tumor, intraductal papillary mucinous neoplasm (IPMN) in this observational study. We analyzed standard clinical and coagulation variables in patients operated during 2010 and 2015 at Helsinki University Hospital. Pancreatic ductal adenocarcinoma with preoperative coagulation variables available and no neoadjuvant treatment or other active cancer was observed in 80 patients (stage I-III in 67 and IV in 13) and IPMN in 18 patients. Fibrinogen, factor VIII (FVIII), carbohydrate antigen (CA) 19-9, albumin, alkaline phosphatase, and conjugated bilirubin were higher in both stages I to III and IV PDAC compared to IPMN ( P < .05). Factor VIII was highest in stage IV ( P < .05). Combining these variables in a panel increased sensitivity and specificity for PDAC. In receiver operating characteristic analysis, the area under the curve (95% confidence interval) was 0.95 (0.90-1.00) for the panel, compared to 0.80 (0.71-0.88) for CA 19-9 alone ( P < .01). In conclusion, PDAC was associated with increased fibrinogen and FVIII. Combining these coagulation biomarkers with CA 19-9, albumin, and alkaline phosphatase improves diagnostic accuracy.
- Published
- 2018
37. Working in 'NK Mode': Natural Killer Group 2 Member D and Natural Cytotoxicity Receptors in Stress-Surveillance by γδ T Cells
- Author
-
Jessica Strid, Bruno Silva-Santos, Repositório da Universidade de Lisboa, and Wellcome Trust
- Subjects
0301 basic medicine ,Cytotoxicity, Immunologic ,TUMOR-CELLS ,medicine.medical_treatment ,T-Lymphocytes ,Lymphocyte Activation ,TUBERCULOSIS INFECTION ,NKG2D ,Mice ,Immunology and Allergy ,Cytotoxicity ,Receptor ,natural killer group 2 member D ,CELIAC-DISEASE ,Receptors, Antigen, T-Cell, gamma-delta ,Transmembrane protein ,Cell biology ,Killer Cells, Natural ,medicine.anatomical_structure ,Natural cytotoxicity receptors ,NK Cell Lectin-Like Receptor Subfamily K ,SIGNALING PATHWAY ,Immunotherapy ,immunotherapy ,Signal transduction ,Life Sciences & Biomedicine ,natural cytotoxicity receptors ,lcsh:Immunologic diseases. Allergy ,T cell ,Mini Review ,BUTYROPHILIN 3A1 ,Immunology ,Biology ,γδ T cells ,MEDIATED LYSIS ,natural killer cell receptors ,Natural killer cell ,03 medical and health sciences ,medicine ,gamma delta T cells ,Animals ,Humans ,Science & Technology ,ACTIVATING RECEPTOR ,B30.2 DOMAIN ,Natural Cytotoxicity Triggering Receptor 3 ,Natural Cytotoxicity Triggering Receptor 2 ,RECOGNITION ,Natural killer group 2 member D ,Natural killer cell receptors ,030104 developmental biology ,lcsh:RC581-607 - Abstract
Copyright: © 2018 Silva-Santos and Strid. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms., Natural killer cell receptors (NKRs) are germline-encoded transmembrane proteins that regulate the activation and homeostasis of NK cells as well as other lymphocytes. For γδ T cells, NKRs play critical roles in discriminating stressed (transformed or infected) cells from their healthy counterparts, as proposed in the "lymphoid stress-surveillance" theory. Whereas the main physiologic role is seemingly fulfilled by natural killer group 2 member D, constitutively expressed by γδ T cells, enhancement of their therapeutic potential may rely on natural cytotoxicity receptors (NCRs), like NKp30 or NKp44, that can be induced selectively on human Vδ1+ T cells. Here, we review the contributions of NCRs, NKG2D, and their multiple ligands, to γδ T cell biology in mouse and human., We acknowledge funding from the Wellcome Trust (100999/Z/13/Z) and Cancer Research UK (C21010/A19788) (to JS) and Fundação para a Ciência e a Tecnologia (PTDC/DTP-PIC/4931/2014) (to BS-S). This publication was sponsored by LISBOA-01-0145-FEDER-007391, project cofunded by FEDER, through POR Lisboa 2020—Programa Operacional Regional de Lisboa, PORTUGAL 2020, and Fundação para a Ciência e a Tecnologia.
- Published
- 2018
- Full Text
- View/download PDF
38. Epigenetic markers in circulating cell-free DNA as prognostic markers for survival of castration-resistant prostate cancer patients
- Author
-
Peter F.A. Mulders, Wim Van Criekinge, Rianne J. Hendriks, Jack A. Schalken, Inge M. van Oort, Hendrik Van de Voorde, Frank Smit, Johan Vandersmissen, and Siebren Dijkstra
- Subjects
0301 basic medicine ,Oncology ,Male ,TUMOR-CELLS ,PLUS PREDNISONE ,urologic and male genital diseases ,CPG ISLAND HYPERMETHYLATION ,Circulating Tumor DNA ,Epigenesis, Genetic ,Prostate cancer ,chemistry.chemical_compound ,DOUBLE-BLIND ,0302 clinical medicine ,Prostate ,Medicine and Health Sciences ,Prospective Studies ,Prospective cohort study ,cell‐free DNA ,prostate ,PLASMA ,Abiraterone acetate ,SERUM DNA ,Middle Aged ,CHEMOTHERAPY ,prostate cancer ,Prognosis ,ABIRATERONE ACETATE ,hypermethylation ,Prostatic Neoplasms, Castration-Resistant ,medicine.anatomical_structure ,Cell-free fetal DNA ,030220 oncology & carcinogenesis ,Original Article ,Cell-Free Nucleic Acids ,Adult ,medicine.medical_specialty ,CLINICAL-RELEVANCE ,Urology ,Adenomatous Polyposis Coli Protein ,cell-free DNA ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Internal medicine ,Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15] ,medicine ,Humans ,cancer ,Clinical significance ,GSTP1 ,Survival analysis ,Aged ,PLACEBO-CONTROLLED PHASE-3 ,epigenetics ,business.industry ,Cancer ,Biology and Life Sciences ,Original Articles ,DNA Methylation ,medicine.disease ,APC ,030104 developmental biology ,chemistry ,Glutathione S-Transferase pi ,business - Abstract
Background : Noninvasive biomarkers to guide personalized treatment for castration‐resistant prostate cancer (CRPC) are needed. In this study, we analyzed hypermethylation patterns of two genes (GSTP1 and APC) in plasma cell‐free DNA (cfDNA) of CRPC patients. The aim of this study was to analyze the cfDNA concentrations and levels of the epigenetic markers and to assess the value of these biomarkers for prognosis. Methods : In this prospective study, patients were included before starting new treatment after developing CRPC. The blood samples were collected prior to start of the treatment and at three time points thereafter. cfDNA was extracted from 1.5 mL of plasma and before performing a methylation‐specific PCR, bisulfate modification was carried out. Results : The median levels of cfDNA, GSTP1, and APC copies in the baseline samples of CRPC patients (n = 47) were higher than in controls (n = 30). In the survival analysis, the group with baseline marker levels below median had significant less PCa‐related deaths (P‐values
- Published
- 2018
39. A haploid genetic screen identifies the G1/S regulatory machinery as a determinant of Wee1 inhibitor sensitivity
- Author
-
Marcel A. T. M. van Vugt, Xavier Bisteau, Felipe Yu Matsushita, Vincent A. Blomen, Philipp Kaldis, Fabian Degener, Anne Margriet Heijink, Floris Foijer, Stem Cell Aging Leukemia and Lymphoma (SALL), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
- Subjects
CANCER-THERAPY ,CDK1 ,CDC25 PROTEIN ,TUMOR-CELLS ,AZD-1775 ,Cell Cycle Proteins ,Haploidy ,Gene mutation ,MITOTIC CATASTROPHE ,S Phase ,Insertional mutagenesis ,checkpoint ,CELL-CYCLE REGULATION ,KINASE ,Humans ,PHOSPHORYLATION ,Mitosis ,DNA-DAMAGING AGENTS ,polyploidy ,Cyclin-dependent kinase 1 ,Multidisciplinary ,biology ,G1 Phase ,Nuclear Proteins ,Protein-Tyrosine Kinases ,Biological Sciences ,Cell cycle ,Wee1 ,MK-1775 ,Cancer cell ,Cancer research ,biology.protein ,cell cycle ,Genetic screen - Abstract
The Wee1 cell cycle checkpoint kinase prevents premature mitotic entry by inhibiting cyclin-dependent kinases. Chemical inhibitors of Wee1 are currently being tested clinically as targeted anticancer drugs. Wee1 inhibition is thought to be preferentially cytotoxic in p53-defective cancer cells. However, TP53 mutant cancers do not respond consistently to Wee1 inhibitor treatment, indicating the existence of genetic determinants of Wee1 inhibitor sensitivity other than TP53 status. To optimally facilitate patient selection for Wee1 inhibition and uncover potential resistance mechanisms, identification of these currently unknown genes is necessary. The aim of this study was therefore to identify gene mutations that determine Wee1 inhibitor sensitivity. We performed a genome-wide unbiased functional genetic screen in TP53 mutant near-haploid KBM-7 cells using gene-trap insertional mutagenesis. Insertion site mapping of cells that survived long-term Wee1 inhibition revealed enrichment of G(1)/S regulatory genes, including SKP2, CUL1, and CDK2. Stable depletion of SKP2, CUL1, or CDK2 or chemical Cdk2 inhibition rescued the gamma-H2AX induction and abrogation of G2 phase as induced by Wee1 inhibition in breast and ovarian cancer cell lines. Remarkably, live cell imaging showed that depletion of SKP2, CUL1, or CDK2 did not rescue the Wee1 inhibition-induced karyokinesis and cytokinesis defects. These data indicate that the activity of the DNA replication machinery, beyond TP53 mutation status, determines Wee1 inhibitor sensitivity, and could serve as a selection criterion for Wee1-inhibitor eligible patients. Conversely, loss of the identified S-phase genes could serve as a mechanism of acquired resistance, which goes along with development of severe genomic instability.
- Published
- 2015
40. Green synthesis, characterization and anticancer activity of luminescent gold nanoparticles capped with apo-α-lactalbumin
- Author
-
Deepthi S. Yarramala, Sejal Doshi, and Chebrolu P. Rao
- Subjects
Lactalbumin ,Silver ,biology ,Stereochemistry ,Chemistry ,General Chemical Engineering ,Metal Nanoparticles ,Shape ,Nanoparticle ,Apoptosis ,Conversion ,General Chemistry ,biology.organism_classification ,Tumor-Cells ,HeLa ,Biomedicine ,Sensitivity ,Size ,Colloidal gold ,Cancer cell ,Biophysics ,Fluorescence microscope ,Viability assay ,Cytotoxicity ,Inhibition - Abstract
A green synthesis was developed in order to prepare protein coated gold nanoparticles using a metal free, alpha-helical protein, i.e., apo-alpha-LA, that acts as both the reducing as well as stabilizing agent to result in Au-0 nanoparticles from Au3+ which are luminescent and hence can be used for biological imaging, including of cells. The nanoparticles, apo-alpha-LA-AuNPs, thus synthesized were characterized by multiple techniques, such as, analytical, spectral, microscopy and light scattering, in order to support the presence of NPs in terms of their size and shape, involvement of Au-0 and the protein encapsulation and its structural changes upon coating. The 10-16 nm sized apo-alpha-LA-AuNPs were shown to be non-toxic to healthy cells as studied using normal mouse fibroblast cells (L929). Having found that these NPs are biocompatible and possess structurally altered apo-alpha-LA protein, the luminescent apo-alpha-LA-AuNPs were demonstrated to have cytotoxicity towards cancer cells as studied by cell viability tests as well as fluorescence microscopy. While these NPs kill similar to 75% of MCF-7 cells, at the same concentration these are capable of killing only similar to 30% of HeLa cells, thus exhibiting cell dependency. The present study clearly demonstrates the advantage of the luminescent apo-alpha-LA-AuNPs in their attack of cancer cells in general and selective killing of breast cancer cells in particular. Thus coating AuNPs with the protein apo-alpha-LA enhanced their anticancer activity several fold.
- Published
- 2015
- Full Text
- View/download PDF
41. Selective formation of discrete versus polymeric copper organophosphates: DNA cleavage and cytotoxic activity
- Author
-
Ramaswamy Murugavel, Aijaz A. Dar, Raihana Maqbool, Gulzar A. Bhat, and Mahboob Ul Hussain
- Subjects
Spectrometry, Mass, Electrospray Ionization ,Stereochemistry ,Molecular Conformation ,chemistry.chemical_element ,Antineoplastic Agents ,010402 general chemistry ,Ligands ,Crystallography, X-Ray ,01 natural sciences ,Tumor-Cells ,Inorganic Chemistry ,chemistry.chemical_compound ,Crystal-Structures ,Coordination Complexes ,Cell Line, Tumor ,Polymer chemistry ,Molecule ,Animals ,Humans ,1,10-Phenanthroline ,DNA Cleavage ,Cytotoxicity ,Terpyridine ,Cell Proliferation ,Microscopy, Confocal ,010405 organic chemistry ,Chemistry ,2,2'/6',2''-Terpyridines ,Serum Albumin, Bovine ,DNA ,Phosphate ,Copper ,In vitro ,Organophosphates ,0104 chemical sciences ,Cell culture ,Yield (chemistry) ,Anticancer Agents ,Cattle ,Metal-Complexes ,Cisplatin ,Cancer-Therapy ,Plasmids - Abstract
Copper phosphate metalloligands [Cu(X-dipp)(Pyterpy)](2) [X = H (1), Br (2)], exemplifying expanded 4,4'-bipyridine type molecules, have been synthesized by reacting 4'-(4-pyridyl)-2,2': 6', 2''-terpyridine (Pyterpy) and para substituted 2,6-diisopropylphenyl phosphate (X-dippH(2)) with copper acetate. The pendant N, N-ends of dimeric copper phosphates 1 and 2 have been forced to engage in further coordination by limiting the concentration of Pyterpy in the reaction mixture to yield rare Pyterpy bridged corner-shared polymeric copper phosphates [Cu-2(X-dippH)(X-dipp)(Pyterpy)(H2O)](n) [X = Cl (3), Br (4), I (5)]. The formation of 1-5 is supported by spectroscopic and analytical data. The solid state structures of these compounds have further been confirmed by single-crystal X-ray diffraction studies. Soluble dimeric complexes 1 and 2 have been assessed for their in vitro anti-tumour properties against human breast and colorectal cancer cell lines. The DNA cleavage, protein cleaving and cytotoxicity assays revealed that these compounds are effective in cleaving DNA, while the activity of 1 as an anti-tumor agent is better than 2.
- Published
- 2017
42. Role of Charge and Hydrophobicity in Liprotide Formation: A Molecular Dynamics Study with Experimental Constraints
- Author
-
Pim W. J. M. Frederix, Jan Skov Pedersen, Jannik Nedergaard Pedersen, Siewert J. Marrink, Daniel E. Otzen, and Molecular Dynamics
- Subjects
0301 basic medicine ,TUMOR-CELLS ,Calorimetry ,Molecular Dynamics Simulation ,01 natural sciences ,Biochemistry ,Protein–protein interaction ,Hydrophobic effect ,03 medical and health sciences ,Molecular dynamics ,X-Ray Diffraction ,0103 physical sciences ,Scattering, Small Angle ,Journal Article ,Molecular Biology ,MOLTEN GLOBULE ,010304 chemical physics ,biology ,FATTY-ACID ,Chemistry ,Small-angle X-ray scattering ,Organic Chemistry ,HUMAN ALPHA-LACTALBUMIN ,Isothermal titration calorimetry ,OLEIC-ACID ,Molten globule ,X-RAY-SCATTERING ,PROTEIN INTERACTIONS ,Crystallography ,030104 developmental biology ,Alpha-lactalbumin ,biology.protein ,FORCE-FIELD ,Lactalbumin ,Molecular Medicine ,COMPLEXES ,Lipid core ,HAMLET ,Hydrophobic and Hydrophilic Interactions ,Oleic Acid - Abstract
Bovine α-lactalbumin (aLA) and oleate (OA) form a complex that has been intensively studied for its tumoricidal activity. Small-angle X-ray scattering (SAXS) has revealed that this complex consists of a lipid core surrounded by partially unfolded protein. We call this type of complex a liprotide. Little is known of the molecular interactions between OA and aLA, and no technique has so far provided any high-resolution structure of a liprotide. Here we have used coarse-grained (CG) molecular dynamics (MD) simulations, isothermal titration calorimetry (ITC) and SAXS to investigate the interactions between aLA and OA during the process of liprotide formation. With ITC we found that the strongest enthalpic interactions occurred at a molar ratio of 12.0±1.4:1 OA/aLA. Liprotides formed between OA and aLA at several OA/aLA ratios in silico were stable both in CG and in all-atom simulations. From the simulated structures we calculated SAXS spectra that show good agreement with experimentally measured patterns of matching liprotides. The simulations showed that aLA assumes a molten globular (MG) state, exposing several hydrophobic patches involved in interactions with OA. Initial binding of aLA to OA occurs in an area of aLA in which a high amount of positive charge is located, and only later do hydrophobic interactions become important. The results reveal how unfolding of aLA to expose hydrophobic residues is important for complex formation between aLA and OA. Our findings suggest a general mechanism for liprotide formation and might explain the ability of a large number of proteins to form liprotides with OA.
- Published
- 2017
- Full Text
- View/download PDF
43. CXCR4 Ligands
- Author
-
Ken Herrmann, Hans-Juergen Wester, Constantin Lapa, Annemiek M E Walenkamp, and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
- Subjects
0301 basic medicine ,Receptors, CXCR4 ,Chemokine receptor CCR5 ,medicine.medical_treatment ,TUMOR-CELLS ,Medizin ,CHEMOKINE RECEPTOR CXCR4 ,ACUTE MYELOID-LEUKEMIA ,ANTI-PD-L1 ANTIBODY ,PHASE-2 TRIAL ,Pharmacology ,Ligands ,CXCR4 ,Targeted therapy ,03 medical and health sciences ,Chemokine receptor ,0302 clinical medicine ,Neoplasms ,MULTIPLE-MYELOMA ,Medicine ,Animals ,Humans ,tumor microenvironment ,endoradiotherapy ,Radiology, Nuclear Medicine and imaging ,Molecular Targeted Therapy ,Tumor microenvironment ,biology ,business.industry ,RAPID MOBILIZATION ,Cancer ,medicine.disease ,CXCR4-DIRECTED ENDORADIOTHERAPY ,Chemokine CXCL12 ,4 EXPRESSION ,030104 developmental biology ,MYOCARDIAL-INFARCTION ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,biology.protein ,immunotherapy ,Stem cell ,business - Abstract
The G protein-coupled protein receptor C-X-C chemokine receptor 4 (CXCR4) is an attractive target for cancer diagnosis and treatment, as it is overexpressed in many solid and hematologic cancers. Binding of its ligand, C-X-C chemokine ligand 12 (CXCL12), results in receptor internalization and activation of several signal transduction pathways, such as phosphoinositide 3-kinase/protein kinase B, which are critical in cell proliferation, angiogenesis, development of metastasis, and survival. Also, the CXCR4-CXCL12 axis is involved in the interaction between hematopoietic stem cells (as well as hematologic and solid tumor cells) and their protective microenvironment. This interaction can be disrupted by CXCR4 antagonists. This concept is being used clinically to harvest hematopoietic stem or progenitor cells from bone marrow and to sensitize cancer cells to conventional chemotherapy and radiotherapy, and the potential to overcome tumor microenvironment-driven immunosuppression is being explored. This review focuses on new strategies for improvement of cancer treatment by targeting of the CXCR4-CXCL12 interaction. Because of its critical role in cancer, many peptidic and nonpeptidic ligands with different modes of antagonistic activity against the CXCR4-CXCL12 axis have been developed, with some of them reaching clinical trials. Molecular imaging with recently developed radiolabeled CXCR4 ligands could facilitate the selection of patients who might benefit from directed targeted therapy, including CXCR4-directed endoradiotherapy.
- Published
- 2017
- Full Text
- View/download PDF
44. EpCAM Expression in Lymph Node Metastases of Urothelial Cell Carcinoma of the Bladder: A Pilot Study
- Author
-
Igle J. de Jong, Christa A. M. van der Fels, Stefano Rosati, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Stem Cell Aging Leukemia and Lymphoma (SALL)
- Subjects
0301 basic medicine ,Male ,Pathology ,IMPACT ,TUMOR-CELLS ,medicine.medical_treatment ,Pilot Projects ,lcsh:Chemistry ,chemistry.chemical_compound ,0302 clinical medicine ,lcsh:QH301-705.5 ,Lymph node ,Spectroscopy ,Epithelial cell adhesion molecule ,General Medicine ,MUSCLE ,Middle Aged ,Epithelial Cell Adhesion Molecule ,Immunohistochemistry ,Computer Science Applications ,Dissection ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Lymphatic Metastasis ,SURVIVAL ,Female ,RADICAL CYSTECTOMY ,ADHESION MOLECULE EPCAM ,lymph node metastases ,Adult ,medicine.medical_specialty ,Urinary Bladder ,urothelial cell carcinoma ,immunohistochemistry ,EpCAM ,Catalysis ,Article ,Inorganic Chemistry ,Cystectomy ,03 medical and health sciences ,LUNG-CANCER ,Breast cancer ,medicine ,BREAST-CANCER ,Humans ,Physical and Theoretical Chemistry ,Lung cancer ,Molecular Biology ,Aged ,Retrospective Studies ,Carcinoma, Transitional Cell ,Bladder cancer ,business.industry ,Organic Chemistry ,medicine.disease ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,Urinary Bladder Neoplasms ,OVEREXPRESSION ,Lymph Nodes ,business ,TOMOGRAPHY/COMPUTED TOMOGRAPHY - Abstract
In this retrospective pilot study, the feasibility of the epithelial cell adhesion molecule (EpCAM) as an imaging target for lymph node (LN) metastatic disease of urothelial cell carcinoma (UCC) of the bladder was investigated. LN metastases and LNs without metastases of patients who underwent pelvic lymph node dissection because of muscle invasive bladder cancer (MIBC) were used. Primary tumors of the same patients were used from cystectomy specimen, transurethral resections, and biopsies. A pathologist, blinded to clinical data, scored EpCAM immunoreactivity. This method determines a total immunostaining score, which is the product of a proportion score and an intensity score. EpCAM expression was observed in 19/20 (95%) LNs with UCC metastases and in 11/12 (92%) of the primary tumors. EpCAM expression was absent in 14/14 (100%) LNs without metastases. Median EpCAM expression (TIS) in LN metastases was 5 (IQR 2.0-8.0) and in the primary tumors 6 (IQR 2.3-11.0). Based on the absence of staining in LNs without metastases, EpCAM show high tumor distinctiveness. EpCAM seems to be a feasible imaging target in LN metastases of UCC of the bladder. Pre- and perioperative visualization of these metastases will improve disease staging and improve the complete resection of LN metastases in MIBC.
- Published
- 2017
45. Engineering exosomes for cancer therapy
- Author
-
Roisin M. Dwyer and Katie E. Gilligan
- Subjects
0301 basic medicine ,antitumor response ,Review ,lipofection ,Drug Delivery Systems ,0302 clinical medicine ,Neoplasms ,induction ,Spectroscopy ,cell-derived exosomes ,Electroporation ,General Medicine ,tumor-cells ,Computer Science Applications ,030220 oncology & carcinogenesis ,Immunotherapy ,delivery ,Genetic Engineering ,extracellular vesicles ,viral ,electroporation ,Programmed cell death ,microrna ,growth ,Antineoplastic Agents ,exosomes ,Biology ,Exosome ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,Immune system ,microRNA ,medicine ,Animals ,Humans ,cancer ,Secretion ,Physical and Theoretical Chemistry ,micrornas ,Molecular Biology ,therapy ,Organic Chemistry ,Cancer ,medicine.disease ,Microvesicles ,030104 developmental biology ,Immunology ,Cancer research ,peptide-based vaccine - Abstract
There remains an urgent need for novel therapeutic strategies to treat metastatic cancer, which results in over 8 million deaths annually worldwide. Following secretion, exosomes are naturally taken up by cells, and capable of the stable transfer of drugs, therapeutic microRNAs and proteins. As knowledge of the biogenesis, release and uptake of exosomes continues to evolve, and thus also has interest in these extracellular vesicles as potential tumor-targeted vehicles for cancer therapy. The ability to engineer exosome content and migratory itinerary holds tremendous promise. Studies to date have employed viral and non-viral methods to engineer the parent cells to secrete modified exosomes, or alternatively, to directly manipulate exosome content following secretion. The majority of studies have demonstrated promising results, with decreased tumor cell invasion, migration and proliferation, along with enhanced immune response, cell death, and sensitivity to chemotherapy observed. The studies outlined in this review highlight the exciting potential for exosomes as therapeutic vehicles for cancer treatment. Successful implementation in the clinical setting will be dependent upon establishment of rigorous standards for exosome manipulation, isolation, and characterisation.
- Published
- 2017
46. The Cytotoxicity of the Ajoene Analogue BisPMB in WHCO1 Oesophageal Cancer Cells Is Mediated by CHOP/GADD153
- Author
-
Georgia Schäfer, Catherine H. Kaschula, Arieh A. Katz, Roger Hunter, Iryna Grafova, Andriy Grafov, Martin Nieger, Vuyolwethu Siyo, M. Iqbal Parker, and Department of Chemistry
- Subjects
0301 basic medicine ,Esophageal Neoplasms ,TUMOR-CELLS ,116 Chemical sciences ,Pharmaceutical Science ,CARCINOMA-CELLS ,CHOP ,Analytical Chemistry ,chemistry.chemical_compound ,garlic ,0302 clinical medicine ,ENDOPLASMIC-RETICULUM STRESS ,Drug Discovery ,HUMAN PROMYELOLEUKEMIC CELLS ,Disulfides ,Cytotoxicity ,Endoplasmic Reticulum Chaperone BiP ,CHOP/GADD153 ,cancer prevention ,Diallyl disulfide ,unfolded protein response ,ORGANOSULFUR COMPOUNDS ,Endoplasmic Reticulum Stress ,3. Good health ,Biochemistry ,Chemistry (miscellaneous) ,030220 oncology & carcinogenesis ,Sulfoxides ,Molecular Medicine ,DIALLYL DISULFIDE ,ER stress ,MITOCHONDRIAL PATHWAY ,Biology ,ER-STRESS ,Article ,Biological pathway ,lcsh:QD241-441 ,03 medical and health sciences ,DISULFIDE INDUCES APOPTOSIS ,lcsh:Organic chemistry ,Cell Line, Tumor ,Humans ,ajoene ,Ajoene ,Physical and Theoretical Chemistry ,Endoplasmic reticulum ,Organic Chemistry ,030104 developmental biology ,chemistry ,Cancer cell ,Unfolded protein response ,Cancer research ,Transcription Factor CHOP - Abstract
Garlic is a food and medicinal plant that has been used in folk medicine since ancient times for its beneficial health effects, which include protection against cancer. Crushed garlic cloves contain an array of small sulfur-rich compounds such as ajoene. Ajoene is able to interfere with biological processes and is cytotoxic to cancer cells in the low micromolar range. BisPMB is a synthetic ajoene analogue that has been shown in our laboratory to have superior cytotoxicity to ajoene. In the current study we have performed a DNA microarray analysis of bisPMB-treated WHCO1 oesophageal cancer cells to identify pathways and processes that are affected by bisPMB. The most significantly enriched biological pathways as assessed by gene ontology, KEGG and ingenuity pathway analysis were those involving protein processing in the endoplasmic reticulum (ER) and the unfolded protein response. In support of these pathways, bisPMB was found to inhibit global protein synthesis and lead to increased levels of ubiquitinated proteins. BisPMB also induced alternate splicing of the transcription factor XBP-1; increased the expression of the ER stress sensor GRP78 and induced expression of the ER stress marker CHOP/GADD153. CHOP expression was found to be central to the cytotoxicity of bisPMB as its silencing with siRNA rendered the cells resistant to bisPMB. The MAPK proteins, JNK and ERK1/2 were activated following bisPMB treatment. However JNK activation was not critical in the cytotoxicity of bisPMB, and ERK1/2 activation was found to play a pro-survival role. Overall the ajoene analogue bisPMB appears to induce cytotoxicity in WHCO1 cells by activating the unfolded protein response through CHOP/GADD153.
- Published
- 2017
47. Combining radiotherapy with immunotherapy
- Subjects
RESISTANT PROSTATE-CANCER ,COMPLETE RESPONSE ,CELL LUNG-CANCER ,TUMOR-CELLS ,RADIATION-THERAPY ,ANTITUMOR IMMUNITY ,MELANOMA ,REGULATORY T-CELLS ,PRECLINICAL RATIONALE ,LOCAL RADIOTHERAPY - Abstract
The advent of immunotherapy is currently revolutionizing the field of oncology, where different drugs are used to stimulate different steps in a failing cancer immune response chain. This review gives a basic overview of the immune response against cancer, as well as the historical and current evidence on the interaction of radiotherapy with the immune system and the different forms of immunotherapy. Furthermore the review elaborates on the many open questions on how to exploit this interaction to the full extent in clinical practice.
- Published
- 2017
48. The TAK1-NF-κB axis as therapeutic target for AML
- Author
-
Matthieu C.J. Bosman, Jan Jacob Schuringa, Annet Z. Brouwers-Vos, Hein Schepers, Jennifer Jaques, Wim J. Quax, Edo Vellenga, Stem Cell Aging Leukemia and Lymphoma (SALL), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Biopharmaceuticals, Discovery, Design and Delivery (BDDD), and Nanotechnology and Biophysics in Medicine (NANOBIOMED)
- Subjects
EXPRESSION ,Myeloid ,Stromal cell ,TUMOR-CELLS ,NF-KAPPA-B ,Sialic Acid Binding Ig-like Lectin 3 ,Immunology ,CD34 ,Apoptosis ,ACUTE MYELOID-LEUKEMIA ,Biochemistry ,Mice ,Cancer stem cell ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,Progenitor cell ,Protein Kinase Inhibitors ,Gene Expression Regulation, Leukemic ,Chemistry ,NF-kappa B ,STEM/PROGENITOR CELLS ,Myeloid leukemia ,Genetic Therapy ,Cell Biology ,Hematology ,MAP Kinase Kinase Kinases ,medicine.disease ,TAK1 INHIBITION ,BETA-ACTIVATED KINASE-1 ,SELF-RENEWAL ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Gene Knockdown Techniques ,SURVIVAL ,Cancer research ,Female ,Stem cell ,Transcriptome ,STEM-CELLS ,Signal Transduction - Abstract
Development and maintenance of leukemia can be partially attributed to alterations in (anti)-apoptotic gene expression. Genome-wide transcriptome analyses revealed that 89 apoptosis-associated genes were differentially expressed between patient acute myeloid leukemia (AML) CD34(+) cells and normal bone marrow (NBM) CD34(+) cells. Among these, transforming growth factor-β activated kinase 1 (TAK1) was strongly upregulated in AML CD34(+) cells. Genetic downmodulation or pharmacologic inhibition of TAK1 activity strongly impaired primary AML cell survival and cobblestone formation in stromal cocultures. TAK1 inhibition was mainly due to blockade of the nuclear factor κB (NF-κB) pathway, as TAK1 inhibition resulted in reduced levels of P-IκBα and p65 activity. Overexpression of a constitutive active variant of NF-κB partially rescued TAK1-depleted cells from apoptosis. Importantly, NBM CD34(+) cells were less sensitive to TAK1 inhibition compared with AML CD34(+) cells. Knockdown of TAK1 also severely impaired leukemia development in vivo and prolonged overall survival in a humanized xenograft mouse model. In conclusion, our results indicate that TAK1 is frequently overexpressed in AML CD34(+) cells, and that TAK1 inhibition efficiently targets leukemic stem/progenitor cells in an NF-κB-dependent manner.
- Published
- 2014
- Full Text
- View/download PDF
49. Upregulation of endogenous ICAM-1 reduces ovarian cancer cell growth in the absence of immune cells
- Subjects
EXPRESSION ,zinc finger ,epigenetics ,CARCINOMA ,TUMORIGENICITY ,TUMOR-CELLS ,INDUCTION ,cisplatin ,ARTIFICIAL TRANSCRIPTION FACTORS ,GENE-TRANSFER ,artificial transcription factor ,ANTITUMOR IMMUNITY ,BREAST-CANCER ,tumor suppressor gene ,INTERCELLULAR-ADHESION MOLECULE-1 - Abstract
Ovarian cancer is a difficult-to-treat cancer with a 5-year survival rate of only approximate to 45%, due to late diagnosis and therapy resistance. In need of new therapeutic approaches, induction of intercellular adhesion molecule (ICAM)-1 expression might be of interest, since the expression of ICAM-1 is lower in ovarian cancer cells compared with healthy ovarian cells and correlated with decreased tumorigenicity. Whereas ICAM-1 expression on tumor cells is of importance for attracting immune cells, ICAM-1 might also induce tumorigenicity and chemoresistance. In ovarian cancer, such a role of ICAM-1 is unclear. Here, we investigated whether ICAM-1 has a cell-biological role by bidirectional modulation of ICAM-1 expression using ICAM-targeting artificial transcription factors. For a panel of ovarian cancer cells, tumor growth and cisplatin sensitivity were evaluated. Induction of ICAM-1 expression (ranging from 3- to 228-fold on mRNA level and 1.7- to 108-fold on protein level) resulted in indications of decreased ovarian cancer cell growth and reduced cisplatin sensitivity. Repression ranged from 48 to 94% on mRNA level and 47 to 91% on protein level. This study shows that, next to its established immunogenic role, ICAM-1 affects cell biological behavior of ovarian cancer cells and, importantly, that reexpression by artificial transcription factors represents a powerful approach for functional validation of genes epigenetically silenced in cancer, such as ICAM-1.
- Published
- 2014
50. A novel small molecule RAD51 inactivator overcomes imatinib-resistance in chronic myeloid leukaemia
- Author
-
Heiko Konig, A. Richard Chamberlin, Wen-Hwa Lee, Chun-Mei Hu, Guideng Li, Phang Lang Chen, Erin M. Goldblatt, Xiao Long Qiu, Longen Zhou, Chi Fen Chen, Xiaoqin Lin, Ravi Bhatia, Guikai Wu, and Jiewen Zhu
- Subjects
Indoles ,Time Factors ,RAD51 ,Fusion Proteins, bcr-abl ,Apoptosis ,Mice, SCID ,Piperazines ,Mice ,Mice, Inbred NOD ,hemic and lymphatic diseases ,Tetrahydroisoquinolines ,Medicine and Health Sciences ,Homologous Recombination ,Cml ,CML ,Research Articles ,Cancer ,Radiation ,Life Sciences ,Synaptonemal Complexes ,Protein-Tyrosine Kinases ,Tumor Burden ,inhibitor ,Gene Expression Regulation, Neoplastic ,Molecular Docking Simulation ,Mammalian-Cells ,Benzamides ,Imatinib Mesylate ,Neoplastic Stem Cells ,Molecular Medicine ,Female ,RNA Interference ,biological phenomena, cell phenomena, and immunity ,Proteasome Inhibitors ,Bcr-Abl ,medicine.drug ,Proteasome Endopeptidase Complex ,Inhibitor ,small molecule ,Antineoplastic Agents ,Protein degradation ,Biology ,Transfection ,Tumor-Cells ,Cell Line, Tumor ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,cancer ,Animals ,Humans ,Progenitor cell ,Protein Kinase Inhibitors ,Cell Proliferation ,Binding Sites ,Dose-Response Relationship, Drug ,Cell growth ,Protein ,Imatinib ,Small Molecule Dna-Damage Response ,medicine.disease ,Brc Repeats ,enzymes and coenzymes (carbohydrates) ,Pyrimidines ,Drug Resistance, Neoplasm ,Cancer cell ,Mutation ,Rad51 ,Cancer research ,Rad51 Recombinase ,Protein Multimerization ,Protein Processing, Post-Translational ,Repair - Abstract
RAD51 recombinase activity plays a critical role for cancer cell proliferation and survival, and often contributes to drug-resistance. Abnormally elevated RAD51 function and hyperactive homologous recombination (HR) rates have been found in a panel of cancers, including breast cancer and chronic myeloid leukaemia (CML). Directly targeting RAD51 and attenuating the deregulated RAD51 activity has therefore been proposed as an alternative and supplementary strategy for cancer treatment. Here we show that a newly identified small molecule, IBR2, disrupts RAD51 multimerization, accelerates proteasome-mediated RAD51 protein degradation, reduces ionizing radiation-induced RAD51 foci formation, impairs HR, inhibits cancer cell growth and induces apoptosis. In a murine imatinib-resistant CML model bearing the T315I Bcr-abl mutation, IBR2, but not imatinib, significantly prolonged animal survival. Moreover, IBR2 effectively inhibits the proliferation of CD34(+) progenitor cells from CML patients resistant to known BCR-ABL inhibitors. Therefore, small molecule inhibitors of RAD51 may suggest a novel class of broad-spectrum therapeutics for difficult-to-treat cancers.
- Published
- 2013
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.