23 results on '"Nastały P"'
Search Results
2. PIP4K2B is mechanoresponsive and controls heterochromatin-driven nuclear softening through UHRF1
- Author
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Alessandro Poli, Fabrizio A. Pennacchio, Andrea Ghisleni, Mariagrazia di Gennaro, Margaux Lecacheur, Paulina Nastały, Michele Crestani, Francesca M. Pramotton, Fabio Iannelli, Galina Beznusenko, Alexander A. Mironov, Valeria Panzetta, Sabato Fusco, Bhavwanti Sheth, Dimos Poulikakos, Aldo Ferrari, Nils Gauthier, Paolo A. Netti, Nullin Divecha, and Paolo Maiuri
- Subjects
Science - Abstract
PIP4Ks are phosphoinositide kinases often dysregulated in cancer. Here Poli and colleagues find that PIP4K2B is downregulated on soft substrates, and its depletion leads to altered nuclear mechanical properties and defects in cell spreading and motility.
- Published
- 2023
- Full Text
- View/download PDF
3. EGFR as a stable marker of prostate cancer dissemination to bones
- Author
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Nastały, Paulina, Stoupiec, Sara, Popęda, Marta, Smentoch, Julia, Schlomm, Thorsten, Morrissey, Colm, Żaczek, Anna Joanna, Beyer, Burkhard, Tennstedt, Pierre, Graefen, Markus, Eltze, Elke, Maiuri, Paolo, Semjonow, Axel, Pantel, Klaus, Brandt, Burkhard, and Bednarz-Knoll, Natalia
- Published
- 2020
- Full Text
- View/download PDF
4. Role of the nuclear membrane protein Emerin in front-rear polarity of the nucleus
- Author
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Paulina Nastały, Divya Purushothaman, Stefano Marchesi, Alessandro Poli, Tobias Lendenmann, Gururaj Rao Kidiyoor, Galina V. Beznoussenko, Stefania Lavore, Orso Maria Romano, Dimos Poulikakos, Marco Cosentino Lagomarsino, Alexander A. Mironov, Aldo Ferrari, and Paolo Maiuri
- Subjects
Science - Abstract
During cell migration, cells are polarized with distinct front vs. rear regions but whether and how polarity is transmitted to the nucleus is unclear. Here the authors show that frontally-biased endoplasmic reticulum and the nuclear membrane protein Emerin contribute to front-rear nuclear cell polarity.
- Published
- 2020
- Full Text
- View/download PDF
5. Tailoring Cellular Function: The Contribution of the Nucleus in Mechanotransduction
- Author
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Fabrizio A. Pennacchio, Paulina Nastały, Alessandro Poli, and Paolo Maiuri
- Subjects
mechanosensing ,nuclear envelope ,LINC complex ,cell nucleus ,mechanotransduction ,Biotechnology ,TP248.13-248.65 - Abstract
Cells sense a variety of different mechanochemical stimuli and promptly react to such signals by reshaping their morphology and adapting their structural organization and tensional state. Cell reactions to mechanical stimuli arising from the local microenvironment, mechanotransduction, play a crucial role in many cellular functions in both physiological and pathological conditions. To decipher this complex process, several studies have been undertaken to develop engineered materials and devices as tools to properly control cell mechanical state and evaluate cellular responses. Recent reports highlight how the nucleus serves as an important mechanosensor organelle and governs cell mechanoresponse. In this review, we will introduce the basic mechanisms linking cytoskeleton organization to the nucleus and how this reacts to mechanical properties of the cell microenvironment. We will also discuss how perturbations of nucleus–cytoskeleton connections, affecting mechanotransduction, influence health and disease. Moreover, we will present some of the main technological tools used to characterize and perturb the nuclear mechanical state.
- Published
- 2021
- Full Text
- View/download PDF
6. Low Tumor-to-Stroma Ratio Reflects Protective Role of Stroma against Prostate Cancer Progression
- Author
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Paulina Nastały, Julia Smentoch, Marta Popęda, Emanuele Martini, Paolo Maiuri, Anna J. Żaczek, Marek Sowa, Marcin Matuszewski, Jolanta Szade, Leszek Kalinowski, Magdalena Niemira, Burkhard Brandt, Elke Eltze, Axel Semjonow, and Natalia Bednarz-Knoll
- Subjects
prostate cancer ,tumor-to-stroma ratio ,biochemical recurrence ,tumor progression ,digital pathology ,Medicine - Abstract
Tumor-to-stroma ratio (TSR) is a prognostic factor that expresses the relative amounts of tumor and intratumoral stroma. In this study, its clinical and molecular relevance was evaluated in prostate cancer (PCa). The feasibility of automated quantification was tested in digital scans of tissue microarrays containing 128 primary tumors from 72 PCa patients stained immunohistochemically for epithelial cell adhesion molecule (EpCAM), followed by validation in a cohort of 310 primary tumors from 209 PCa patients. In order to investigate the gene expression differences between tumors with low and high TSR, we applied multigene expression analysis (nCounter® PanCancer Progression Panel, NanoString) of 42 tissue samples. TSR scores were categorized into low (p = 0.04 and p = 0.01 for the pilot and validation cohort, respectively). Additionally, in the multivariate analysis of the validation cohort, TSR predicted BR independent of other factors, i.e., pT, pN, and age (p = 0.04, HR 2.75, 95%CI 1.07–7.03). Our data revealed that tumors categorized into low and high TSR score show differential expression of various genes; the genes upregulated in tumors with low TSR score were mostly associated with extracellular matrix and cell adhesion regulation. Taken together, this study shows that high stroma content can play a protective role in PCa. Automatic EpCAM-based quantification of TSR might improve prognostication in personalized medicine for PCa.
- Published
- 2021
- Full Text
- View/download PDF
7. Role of the nuclear membrane protein Emerin in front-rear polarity of the nucleus
- Author
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Nastały, Paulina, Purushothaman, Divya, Marchesi, Stefano, Poli, Alessandro, Lendenmann, Tobias, Kidiyoor, Gururaj Rao, Beznoussenko, Galina V., Lavore, Stefania, Romano, Orso Maria, Poulikakos, Dimos, Lagomarsino, Marco Cosentino, Mironov, Alexander A., Ferrari, Aldo, and Maiuri, Paolo
- Published
- 2020
- Full Text
- View/download PDF
8. Dissecting EGFR-AR interplay in prostate cancer progression
- Author
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Nastały, P., primary, Popęda, M., additional, Smentoch, J., additional, Dzianach, W., additional, Żaczek, A., additional, Eltze, E., additional, Semjonow, A., additional, Sowa, M., additional, Miszewski, K., additional, Matuszewski, M., additional, and Bednarz-Knoll, N., additional
- Published
- 2022
- Full Text
- View/download PDF
9. O12 - Dissecting EGFR-AR interplay in prostate cancer progression
- Author
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Nastały, P., Popęda, M., Smentoch, J., Dzianach, W., Żaczek, A., Eltze, E., Semjonow, A., Sowa, M., Miszewski, K., Matuszewski, M., and Bednarz-Knoll, N.
- Published
- 2022
- Full Text
- View/download PDF
10. ALDH1-positive intratumoral stromal cells indicate differentiated epithelial-like phenotype and good prognosis in prostate cancer.
- Author
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Nastały, Paulina, Filipska, Martyna, Morrissey, Colm, Eltze, Elke, Semjonow, Axel, Brandt, Burkhard, Pantel, Klaus, and Bednarz-Knoll, Natalia
- Abstract
Aldehyde dehydrogenase 1 (ALDH1) characterizes tumor-initiating cells in solid tumors; however, little is known about its expression in intratumoral stromal cells. Herein, we aimed to dissect its potential dual relevance in prostate cancer (PCa). ALDH1 expression was evaluated immunohistochemically in tumor and stromal cells in primary PCa and metastases. It was correlated to clinico-pathologic parameters, patients' outcome, and selected proteins (CK5/6, CK14, CK8/18, CK19, EpCAM, Ki-67, E-cadherin, N-cadherin, and vimentin). ALDH1 protein was detected in tumor and stromal cells in 16% and 67% of 348 primary PCa, respectively. Tumor cell ALDH1 expression was associated with advanced T stage (P = 0.009), higher Gleason score (P = 0.016), shorter time to biochemical recurrence (TBR P = 0.010) and CK14 expression (P = 0.023). Stromal cell ALDH1 expression correlated to lower T stage (P = 0.008) and Gleason score (P = 0.016), N0 stage (P = 0.017), and longer TBR (P = 0.017). It occurred to be an independent predictor of good prognosis in the subgroup of d'Amico high-risk patients (multivariate analysis, P = 0.050). ALDH1-positive stromal cells were found in tumors characterized frequently by CK8/18 (P = 0.033) or EpCAM expression (P < 0.001) and rarely by epithelial-mesenchymal transition defined as CK8/18(-)vimentin(+) phenotype (P = 0.003). ALDH1-positive tumor and stromal cells were detected in 33% and 41% of hormone naive lymph node metastases (n = 63), 52% and 24% of castration resistant bone metastases, as well as 89% and 28% of castration resistant visceral metastases (n = 21), respectively. We have determined that contrary to tumor cell ALDH1, the presence of stromal ALDH1 is associated with epithelial phenotype of primary PCa, improved clinical outcome, and is less frequent in PCa metastases. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
11. Preparing Map of Chromosome Territory Distribution Frequency
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Paolo Maiuri, Paulina Nastały, Nastały, P, and Maiuri, P
- Subjects
0303 health sciences ,education.field_of_study ,Quantitative imaging ,medicine.diagnostic_test ,Computer science ,Nuclear organization ,Population ,Chromosome ,03 medical and health sciences ,0302 clinical medicine ,Evolutionary biology ,Chromosome Territory ,medicine ,Interphase ,education ,030217 neurology & neurosurgery ,Distribution (differential geometry) ,030304 developmental biology ,Fluorescence in situ hybridization - Abstract
The chromosomes in mammalian interphase nuclei are organized into domains called chromosome territories that play a major role in nuclear organization. Here we propose a methodology that combines the use of micro-patterning of adhesive molecules to impose single-cell geometry, with visualization of chromosome territories. This allows obtaining a representative statistical map of the absolute positions of chromosome territories relative to the geometry imposed to the cell population by combining the signal from each cell.
- Published
- 2021
12. EGFR as a stable marker of prostate cancer dissemination to bones
- Author
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Natalia Bednarz-Knoll, Thorsten Schlomm, Burkhard Beyer, Axel Semjonow, Julia Smentoch, Markus Graefen, Sara Stoupiec, Paulina Nastały, Paolo Maiuri, Anna J. Żaczek, Colm Morrissey, Marta Popęda, Klaus Pantel, Elke Eltze, Pierre Tennstedt, Burkhard Brandt, Nastały, P, Stoupiec, S, Popęda, M, Smentoch, J, Schlomm, T, Morrissey, C, Żaczek, A J, Beyer, B, Tennstedt, P, Graefen, M, Eltze, E, Maiuri, P, Semjonow, A, Pantel, K, Brandt, B, and Bednarz-Knoll, N
- Subjects
Male ,Cancer Research ,Epithelial-Mesenchymal Transition ,Bone Neoplasms ,Disease ,Localised disease ,Article ,Collagen Type I ,Metastasis ,Flow cytometry ,Tumour biomarkers ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Text mining ,Cell Movement ,Biomarkers, Tumor ,medicine ,Humans ,Vimentin ,Epithelial–mesenchymal transition ,medicine.diagnostic_test ,business.industry ,Prostatic Neoplasms ,Flow Cytometry ,Neoplastic Cells, Circulating ,medicine.disease ,Immunohistochemistry ,Phenotype ,Collagen Type I, alpha 1 Chain ,ErbB Receptors ,Prostatic Neoplasms, Castration-Resistant ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Feasibility Studies ,business - Abstract
Background Prostate cancer (PCa) is among the most commonly diagnosed malignancies in men. Although 5-year survival in patients with localised disease reaches nearly 100%, metastatic disease still remains incurable. Therefore, there is a need for markers indicating metastatic dissemination. Methods EGFR overexpression (EGFRover) was tracked in 1039 primary tumours, circulating tumour cells from 39 d’Amico high-risk patients and metastatic samples from 21 castration-resistant PCa cases. EGFR status was compared to clinical parameters and multiple molecular factors were assessed using immunohistochemistry and gene ontology analysis. The functional aspect of EGFR was evaluated by plating PC-3 cells on soft and rigid matrices. Results EGFRover was found in 14% of primary tumours, where it was associated with shorter metastasis-free survival and was an independent indicator of worse overall survival. EGFRover correlated with a pro-migratory and pro-metastatic phenotype of tumour cells as well as rich collagen fibre content. All circulating tumour cells (detected in 13% of cases) were positive for EGFR, independent of their EMT-related phenotype. EGFRover was more prevalent in castration-resistant bone metastases (29% of patients) and supported growth of human PCa cells on rigid matrices mimicking bone stiffness. Conclusions EGFRover is a stable, EMT-independent marker of PCa disseminating to rigid organs, preferentially bones.
- Published
- 2020
13. Emerin mislocalization during chromatin bridge resolution can drive prostate cancer cell invasiveness in a collagen-rich microenvironment.
- Author
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Popęda M, Kowalski K, Wenta T, Beznoussenko GV, Rychłowski M, Mironov A, Lavagnino Z, Barozzi S, Richert J, Bertolio R, Myszczyński K, Szade J, Bieńkowski M, Miszewski K, Matuszewski M, Żaczek AJ, Braga L, Del Sal G, Bednarz-Knoll N, Maiuri P, and Nastały P
- Abstract
Micronuclei (MN) can form through many mechanisms, including the breakage of aberrant cytokinetic chromatin bridges. The frequent observation of MN in tumors suggests that they might not merely be passive elements but could instead play active roles in tumor progression. Here, we propose a mechanism through which the presence of micronuclei could induce specific phenotypic and functional changes in cells and increase the invasive potential of cancer cells. Through the integration of diverse in vitro imaging and molecular techniques supported by clinical samples from patients with prostate cancer (PCa) defined as high-risk by the D'Amico classification, we demonstrate that the resolution of chromosome bridges can result in the accumulation of Emerin and the formation of Emerin-rich MN. These structures are negative for Lamin A/C and positive for the Lamin-B receptor and Sec61β. MN can act as a protein sinks and result in the pauperization of Emerin from the nuclear envelope. The Emerin mislocalization phenotype is associated with a molecular signature that is correlated with a poor prognosis in PCa patients and is enriched in metastatic samples. Emerin mislocalization corresponds with increases in the migratory and invasive potential of tumor cells, especially in a collagen-rich microenvironment. Our study demonstrates that the mislocalization of Emerin to MN results in increased cell invasiveness, thereby worsening patient prognosis., (© 2024. The Author(s).)
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- 2024
- Full Text
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14. Cellular Polarity Transmission to the Nucleus.
- Author
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Nastały P and Maiuri P
- Subjects
- Nerve Tissue Proteins metabolism, Cell Nucleus, Cell Polarity, Nuclear Envelope metabolism, Microfilament Proteins metabolism
- Abstract
Polarity is an intrinsic and fundamental property of unicellular organisms and, as well, of single cells in multicellular ones. It can be defined as asymmetric cell organization that is self-reinforced and maintained by appropriate signaling. While cellular polarity is widely studied at the membrane and cytoplasmic level, if and how it is transmitted to the nucleus is still a matter of research and discussion. However, there is growing evidence of polarity transmission from the cell to the nucleus. In this chapter, we discuss recent reports on nuclear polarity and involvement of potential molecular players including emerin, nesprins, and nuclear F-actin which may play a significant role in establishment of this phenomenon., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)
- Published
- 2022
- Full Text
- View/download PDF
15. Low Tumor-to-Stroma Ratio Reflects Protective Role of Stroma against Prostate Cancer Progression.
- Author
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Nastały P, Smentoch J, Popęda M, Martini E, Maiuri P, Żaczek AJ, Sowa M, Matuszewski M, Szade J, Kalinowski L, Niemira M, Brandt B, Eltze E, Semjonow A, and Bednarz-Knoll N
- Abstract
Tumor-to-stroma ratio (TSR) is a prognostic factor that expresses the relative amounts of tumor and intratumoral stroma. In this study, its clinical and molecular relevance was evaluated in prostate cancer (PCa). The feasibility of automated quantification was tested in digital scans of tissue microarrays containing 128 primary tumors from 72 PCa patients stained immunohistochemically for epithelial cell adhesion molecule (EpCAM), followed by validation in a cohort of 310 primary tumors from 209 PCa patients. In order to investigate the gene expression differences between tumors with low and high TSR, we applied multigene expression analysis (nCounter
® PanCancer Progression Panel, NanoString) of 42 tissue samples. TSR scores were categorized into low (<1 TSR) and high (≥1 TSR). In the pilot cohort, 31 patients (43.1%) were categorized as low and 41 (56.9%) as high TSR score, whereas 48 (23.0%) patients from the validation cohort were classified as low TSR and 161 (77.0%) as high. In both cohorts, high TSR appeared to indicate the shorter time to biochemical recurrence in PCa patients (Log-rank test, p = 0.04 and p = 0.01 for the pilot and validation cohort, respectively). Additionally, in the multivariate analysis of the validation cohort, TSR predicted BR independent of other factors, i.e., pT, pN, and age ( p = 0.04, HR 2.75, 95%CI 1.07-7.03). Our data revealed that tumors categorized into low and high TSR score show differential expression of various genes; the genes upregulated in tumors with low TSR score were mostly associated with extracellular matrix and cell adhesion regulation. Taken together, this study shows that high stroma content can play a protective role in PCa. Automatic EpCAM-based quantification of TSR might improve prognostication in personalized medicine for PCa.- Published
- 2021
- Full Text
- View/download PDF
16. Tailoring Cellular Function: The Contribution of the Nucleus in Mechanotransduction.
- Author
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Pennacchio FA, Nastały P, Poli A, and Maiuri P
- Abstract
Cells sense a variety of different mechanochemical stimuli and promptly react to such signals by reshaping their morphology and adapting their structural organization and tensional state. Cell reactions to mechanical stimuli arising from the local microenvironment, mechanotransduction, play a crucial role in many cellular functions in both physiological and pathological conditions. To decipher this complex process, several studies have been undertaken to develop engineered materials and devices as tools to properly control cell mechanical state and evaluate cellular responses. Recent reports highlight how the nucleus serves as an important mechanosensor organelle and governs cell mechanoresponse. In this review, we will introduce the basic mechanisms linking cytoskeleton organization to the nucleus and how this reacts to mechanical properties of the cell microenvironment. We will also discuss how perturbations of nucleus-cytoskeleton connections, affecting mechanotransduction, influence health and disease. Moreover, we will present some of the main technological tools used to characterize and perturb the nuclear mechanical state., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pennacchio, Nastały, Poli and Maiuri.)
- Published
- 2021
- Full Text
- View/download PDF
17. Detection of Circulating Tumor Cells (CTCs) in Patients with Testicular Germ Cell Tumors.
- Author
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Nastały P, Honecker F, Pantel K, and Riethdorf S
- Subjects
- Cell Line, Tumor, Cell Separation methods, Cells, Cultured, Fluorescent Antibody Technique, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Liquid Biopsy, Male, Molecular Diagnostic Techniques, Neoplastic Cells, Circulating metabolism, Prognosis, Biomarkers, Tumor, Neoplasms, Germ Cell and Embryonal diagnosis, Neoplasms, Germ Cell and Embryonal etiology, Neoplastic Cells, Circulating pathology, Testicular Neoplasms diagnosis, Testicular Neoplasms etiology
- Abstract
While the majority of patients with advanced testicular germ cell tumors (GCT) achieve complete responses after chemotherapy and if indicated after postchemotherapy resection of residual lesions, about 20% of patients have incomplete responses or show relapses. Moreover, toxicity of chemotherapy is high, and severe adverse chronic effects have been described. Therefore, there is an urgent need for biomarkers that could help to improve tumor staging, and support decision-making, ideally including monitoring of therapy response and prediction of relapse. Besides the well-established serum markers lactate dehydrogenase, α-fetoprotein, and β-subunit of human chorionic gonadotropin, during recent years new noninvasive liquid biopsy markers have been investigated in GCT, including cell-free nucleic acids like microRNAs, and circulating tumor cells (CTCs).Prognostic relevance has been demonstrated for circulating tumor cells (CTCs) in patients with different cancers. However, little is known in GCT patients. Histologically, GCT are a very heterogeneous group of tumors comprising pure seminomas (consisting of cells that remember primordial germ cells) and nonseminomas, which are either undifferentiated (embryonal carcinoma) or differentiated, exhibiting different degrees of embryonic (teratoma) or extraembryonic (yolk sac tumor and choriocarcinoma) differentiation. This heterogeneity hampers capture and detection of CTCs deriving from those tumors using a single method or a single antibody. To date, label-independent capture methods that enrich tumor cells according to the density of GCT cells, which is similar to that of mononuclear cells, have been successfully applied. Since testicular GCT might also express epithelial proteins, methods based on enrichment of CTCs using epithelial markers are promising to detect CTCs in certain subgroups of patients with GCTs as well.Here, we describe and discuss a combination of methods to capture and detect GCT cells with epithelial and germ cell characteristics in blood.
- Published
- 2021
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18. Preparing Map of Chromosome Territory Distribution Frequency.
- Author
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Nastały P and Maiuri P
- Subjects
- Animals, Cell Nucleus genetics, Cell Nucleus metabolism, Chromosomes genetics, Fluorescent Antibody Technique, Humans, In Situ Hybridization, Fluorescence, Chromosomes metabolism, Microscopy, Confocal methods
- Abstract
The chromosomes in mammalian interphase nuclei are organized into domains called chromosome territories that play a major role in nuclear organization. Here we propose a methodology that combines the use of micro-patterning of adhesive molecules to impose single-cell geometry, with visualization of chromosome territories. This allows obtaining a representative statistical map of the absolute positions of chromosome territories relative to the geometry imposed to the cell population by combining the signal from each cell.
- Published
- 2021
- Full Text
- View/download PDF
19. Tumor-Associated Release of Prostatic Cells into the Blood after Transrectal Ultrasound-Guided Biopsy in Patients with Histologically Confirmed Prostate Cancer.
- Author
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Joosse SA, Beyer B, Gasch C, Nastały P, Kuske A, Isbarn H, Horst LJ, Hille C, Gorges TM, Cayrefourcq L, Alix-Panabières C, Tennstedt P, Riethdorf S, Schlomm T, and Pantel K
- Subjects
- Adult, Aged, Aged, 80 and over, Humans, Image-Guided Biopsy, Male, Middle Aged, Multivariate Analysis, Neoplastic Cells, Circulating metabolism, Odds Ratio, Progression-Free Survival, Proportional Hazards Models, Prostate-Specific Antigen blood, Prostatic Neoplasms metabolism, Prostatic Neoplasms mortality, Ultrasonography, Neoplastic Cells, Circulating chemistry, Prostatic Neoplasms pathology
- Abstract
Background: Transrectal ultrasound-guided prostate biopsy (TRUS) is a standard procedure for prostate cancer diagnosis. Because prostate cancer is a multifocal disease in many patients, multiple sampling (n ≥ 10) is required, which may bear the risk of systemic spread of cancer cells., Design: Using the standardized CellSearch® system that allows for the detection of single epithelial cell adhesion molecule-positive circulating tumor cells (CTCs) in blood, we investigated whether prostate biopsy is associated with release of prostatic tumor cells into the circulation. Peripheral blood was obtained before and within 30 min after performing prostate biopsy from 115 men with increased serum prostate-specific antigen., Results: The number of CTCs significantly increased after biopsy in men with histologically confirmed prostate cancer (odds ratio, 7.8; 95% CI, 4.8-12.8), whereas no biopsy-related changes could be detected in men without confirmed prostate cancer. Multivariable analysis showed that biopsy-related increase of CTCs was significantly correlated with a worse progression-free survival (hazard ratio, 12.4; 95% CI, 3.2-48.6) within the median follow-up of 41 months., Conclusions: Prostate biopsies may lead to a tumor-associated release of CTCs into the blood circulation. Larger confirmatory trials with longer follow-up periods are required before any change in clinical practice can be recommended., (© 2019 American Association for Clinical Chemistry.)
- Published
- 2020
- Full Text
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20. Somatic aberrations of BRCA1 gene are associated with ALDH1, EGFR, and tumor progression in prostate cancer.
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Omari A, Nastały P, Stoupiec S, Bałabas A, Dąbrowska M, Bielińska B, Huss S, Pantel K, Semjonow A, Eltze E, Brandt B, and Bednarz-Knoll N
- Subjects
- Aged, Aged, 80 and over, Aldehyde Dehydrogenase 1 Family, BRCA1 Protein genetics, Disease Progression, ErbB Receptors biosynthesis, ErbB Receptors genetics, ErbB Receptors metabolism, Humans, Immunohistochemistry, Isoenzymes biosynthesis, Isoenzymes genetics, Male, Middle Aged, Prostatic Neoplasms metabolism, Retinal Dehydrogenase biosynthesis, Retinal Dehydrogenase genetics, Genes, BRCA1, Germ-Line Mutation, Isoenzymes metabolism, Prostatic Neoplasms genetics, Retinal Dehydrogenase metabolism
- Abstract
BRCA1 is a pivotal tumor suppressor. Its dysfunction is known to play a role in different tumors. Among others, BRCA1 germline mutations account for higher risk and more aggressive course of prostate cancer (PCa). In addition, somatic BRCA1 gene loss was demonstrated to be a signature of PCa dissemination to lymph nodes and peripheral blood, and indicate worse clinical outcome. In order to substantiate the data for BRCA1 gene loss in PCa and reveal its phenotypical background, BRCA1 gene status was assessed in a large cohort of PCa patients and compared to different molecular factors. BRCA1 gene dosage was assessed in 2398 tumor samples from 1,199 PCa patients using fluorescent in situ hybridization. It was compared to clinico-pathological parameters, patients' outcome as well as selected proteins (Ki-67, apoptosis marker, cytokeratins, vimentin, E- and N-cadherin, ALDH1 and EGFR) examined immunohistochemically. BRCA1 losses were found in 10%, whereas gains appeared in 7% of 603 informative PCa patients. BRCA1 losses correlated to higher T stage (p = 0.027), Gleason score (p = 0.039), shorter time to biochemical recurrence in patients with Gleason score > 7 independently of other factors (multivariate analysis, p = 0.005) as well as expression of proteins regulating stemness and epithelial-mesenchymal transition, that is, ALDH1 (p = 0.021) and EGFR (p = 0.011), respectively. BRCA1 gains correlated to shorter time to metastasis (p = 0.012) and expression of ALDH1 (p = 0.014). These results support the assumption that BRCA1 gene losses contribute to a progressive and stem cell-like phenotype of PCa. Furthermore, they reveal that also BRCA1 gain conceivably representing loss-of-function might mark more invasive tumors., (© 2018 UICC.)
- Published
- 2019
- Full Text
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21. ALDH1-positive intratumoral stromal cells indicate differentiated epithelial-like phenotype and good prognosis in prostate cancer.
- Author
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Nastały P, Filipska M, Morrissey C, Eltze E, Semjonow A, Brandt B, Pantel K, and Bednarz-Knoll N
- Subjects
- Aldehyde Dehydrogenase 1 Family, Cells, Cultured, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Isoenzymes genetics, Male, Middle Aged, Prognosis, Prostatic Neoplasms diagnosis, Prostatic Neoplasms pathology, Retinal Dehydrogenase genetics, Isoenzymes metabolism, Prostatic Neoplasms enzymology, Retinal Dehydrogenase metabolism, Stromal Cells metabolism
- Abstract
Aldehyde dehydrogenase 1 (ALDH1) characterizes tumor-initiating cells in solid tumors; however, little is known about its expression in intratumoral stromal cells. Herein, we aimed to dissect its potential dual relevance in prostate cancer (PCa). ALDH1 expression was evaluated immunohistochemically in tumor and stromal cells in primary PCa and metastases. It was correlated to clinico-pathologic parameters, patients' outcome, and selected proteins (CK5/6, CK14, CK8/18, CK19, EpCAM, Ki-67, E-cadherin, N-cadherin, and vimentin). ALDH1 protein was detected in tumor and stromal cells in 16% and 67% of 348 primary PCa, respectively. Tumor cell ALDH1 expression was associated with advanced T stage (P = 0.009), higher Gleason score (P = 0.016), shorter time to biochemical recurrence (TBR P = 0.010) and CK14 expression (P = 0.023). Stromal cell ALDH1 expression correlated to lower T stage (P = 0.008) and Gleason score (P = 0.016), N0 stage (P = 0.017), and longer TBR (P = 0.017). It occurred to be an independent predictor of good prognosis in the subgroup of d'Amico high-risk patients (multivariate analysis, P = 0.050). ALDH1-positive stromal cells were found in tumors characterized frequently by CK8/18 (P = 0.033) or EpCAM expression (P < 0.001) and rarely by epithelial-mesenchymal transition defined as CK8/18(-)vimentin(+) phenotype (P = 0.003). ALDH1-positive tumor and stromal cells were detected in 33% and 41% of hormone naive lymph node metastases (n = 63), 52% and 24% of castration resistant bone metastases, as well as 89% and 28% of castration resistant visceral metastases (n = 21), respectively. We have determined that contrary to tumor cell ALDH1, the presence of stromal ALDH1 is associated with epithelial phenotype of primary PCa, improved clinical outcome, and is less frequent in PCa metastases., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
22. Stromal expression of ALDH1 in human breast carcinomas indicates reduced tumor progression.
- Author
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Bednarz-Knoll N, Nastały P, Żaczek A, Stoupiec MG, Riethdorf S, Wikman H, Müller V, Skokowski J, Szade J, Sejda A, Wełnicka-Jaśkiewicz M, and Pantel K
- Subjects
- Aged, Aldehyde Dehydrogenase 1 Family, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Breast Neoplasms surgery, Carcinoma surgery, Cohort Studies, Disease Progression, Disease-Free Survival, Female, Germany, HLA-DR Antigens metabolism, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Lymphatic Metastasis, Middle Aged, Multivariate Analysis, Neoplasm Metastasis, Neoplastic Stem Cells cytology, Poland, Stromal Cells cytology, Tissue Array Analysis, Tretinoin chemistry, Breast Neoplasms metabolism, Carcinoma metabolism, Gene Expression Regulation, Neoplastic, Isoenzymes metabolism, Retinal Dehydrogenase metabolism
- Abstract
Interactions between cancer cells and microenvironment are emerging issue in tumor progression. Aldehyde dehydrogenase 1 (ALDH1) is a recognized cancer stem cell marker but little is known about its role in intratumoral stroma. Therefore, we focused on ALDH1 expression in tumor-associated stroma of breast carcinomas (BrCa). Stromal and tumoral ALDH1 expression was evaluated immunohistochemically in BrCa and their lymph node metastases (LNMs), and related to clinico-pathological characteristics, patients' outcome, presence of CD68, HLADR, retinoic acid (RA) in stroma, and selected proteins in tumor cells. ALDH1(+) stromal cells were detected in 53% of 374 BrCa and 61% of 102 LNMs. ALDH1(+) stroma in primary tumor correlated to longer disease-free (p = 0.030), metastasis-free (p = 0.024), and overall survival (p = 0.043) having an independent prognostic impact on DFS (multivariate analysis, p = 0.047). It was associated with concomitant presence of HLA-DR(+) stromal cells and RA in tumor cells (both p < 0.001), and inversely associated with vimentin expression in tumor cells (p = 0.036). ALDH1(+) stroma in LNMs correlated inversely to presence of disseminated tumor cells in patients' bone marrow (p = 0.014) and was independent prognosticator of shorter DFS and MFS (multivariate analysis, p = 0.004 and p = 0.002, respectively). In conclusion, ALDH1 expression in tumor-associated stromal cells indicates reduced BrCa progression, possibly via RA secretion.
- Published
- 2015
- Full Text
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23. Circulating tumor cells in patients with testicular germ cell tumors.
- Author
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Nastały P, Ruf C, Becker P, Bednarz-Knoll N, Stoupiec M, Kavsur R, Isbarn H, Matthies C, Wagner W, Höppner D, Fisch M, Bokemeyer C, Ahyai S, Honecker F, Riethdorf S, and Pantel K
- Subjects
- Adolescent, Adult, Aged, Cell Line, Tumor, Chromosomes, Human, Pair 12, Humans, Male, Middle Aged, Neoplasms, Germ Cell and Embryonal genetics, Prognosis, Testicular Neoplasms genetics, Trisomy pathology, Young Adult, Neoplasms, Germ Cell and Embryonal pathology, Neoplastic Cells, Circulating pathology, Testicular Neoplasms pathology
- Abstract
Purpose: Germ cell tumors (GCTs) represent the most frequent malignancies among young men, but little is known about circulating tumor cells (CTCs) in these tumors. Considering their heterogeneity, CTCs were investigated using two independent assays targeting germ cell tumor and epithelial cell-specific markers, and results were correlated with disease stage, histology, and serum tumor markers., Experimental Design: CTCs were enriched from peripheral blood (n = 143 patients) and testicular vein blood (TVB, n = 19 patients) using Ficoll density gradient centrifugation. For CTC detection, a combination of germ cell tumor (anti-SALL4, anti-OCT3/4) and epithelial cell-specific (anti-keratin, anti-EpCAM) antibodies was used. In parallel, 122 corresponding peripheral blood samples were analyzed using the CellSearch system., Results: In total, CTCs were detected in 25 of 143 (17.5%) peripheral blood samples, whereas only 11.5% of patients were CTC-positive when considering exclusively the CellSearch assay. The presence of CTCs in peripheral blood correlated with clinical stage (P < 0.001) with 41% of CTC positivity in patients with metastasized tumors and 100% in patients with relapsed and chemotherapy-refractory disease. Histologically, CTC-positive patients suffered more frequently from nonseminomatous primary tumors (P < 0.001), with higher percentage of yolk sac (P < 0.001) and teratoma (P = 0.004) components. Furthermore, CTC detection was associated with elevated serum levels of α-fetoprotein (AFP; P = 0.025), β-human chorionic gonadotropin (βHCG; P = 0.002), and lactate dehydrogenase (LDH; P = 0.002). Incidence and numbers of CTCs in TVB were much higher than in peripheral blood., Conclusions: The inclusion of germ cell tumor-specific markers improves CTC detection in GCTs. CTCs occur frequently in patients with more aggressive disease, and there is a gradient of CTCs with decreasing numbers from the tumor-draining vein to the periphery., (©2014 American Association for Cancer Research.)
- Published
- 2014
- Full Text
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