Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer
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- Mercedes Marín-Aguilera
- Authors' Affiliations: 1Laboratory of Translational Oncology and Medical Oncology Department; 2Bioinformatics Platform Department, Centro de Investigación Biomédica en Red—Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; 3Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 4Laboratory and Department of Urology, Hospital Clínic, Barcelona; 5Department of Pathology, Hospital Clínic, Universitat de Barcelona; 6Althia; 7Tumor Bank, Hospital Clínic—IDIBAPS Biobank, Barcelona; 8Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and 9Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain
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- Jordi Codony-Servat
- Authors' Affiliations: 1Laboratory of Translational Oncology and Medical Oncology Department; 2Bioinformatics Platform Department, Centro de Investigación Biomédica en Red—Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; 3Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 4Laboratory and Department of Urology, Hospital Clínic, Barcelona; 5Department of Pathology, Hospital Clínic, Universitat de Barcelona; 6Althia; 7Tumor Bank, Hospital Clínic—IDIBAPS Biobank, Barcelona; 8Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and 9Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain
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- Òscar Reig
- Authors' Affiliations: 1Laboratory of Translational Oncology and Medical Oncology Department; 2Bioinformatics Platform Department, Centro de Investigación Biomédica en Red—Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; 3Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 4Laboratory and Department of Urology, Hospital Clínic, Barcelona; 5Department of Pathology, Hospital Clínic, Universitat de Barcelona; 6Althia; 7Tumor Bank, Hospital Clínic—IDIBAPS Biobank, Barcelona; 8Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and 9Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain
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- Juan José Lozano
- Authors' Affiliations: 1Laboratory of Translational Oncology and Medical Oncology Department; 2Bioinformatics Platform Department, Centro de Investigación Biomédica en Red—Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; 3Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 4Laboratory and Department of Urology, Hospital Clínic, Barcelona; 5Department of Pathology, Hospital Clínic, Universitat de Barcelona; 6Althia; 7Tumor Bank, Hospital Clínic—IDIBAPS Biobank, Barcelona; 8Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and 9Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain
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- Pedro Luis Fernández
- Authors' Affiliations: 1Laboratory of Translational Oncology and Medical Oncology Department; 2Bioinformatics Platform Department, Centro de Investigación Biomédica en Red—Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; 3Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 4Laboratory and Department of Urology, Hospital Clínic, Barcelona; 5Department of Pathology, Hospital Clínic, Universitat de Barcelona; 6Althia; 7Tumor Bank, Hospital Clínic—IDIBAPS Biobank, Barcelona; 8Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and 9Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain
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- María Verónica Pereira
- Authors' Affiliations: 1Laboratory of Translational Oncology and Medical Oncology Department; 2Bioinformatics Platform Department, Centro de Investigación Biomédica en Red—Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; 3Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 4Laboratory and Department of Urology, Hospital Clínic, Barcelona; 5Department of Pathology, Hospital Clínic, Universitat de Barcelona; 6Althia; 7Tumor Bank, Hospital Clínic—IDIBAPS Biobank, Barcelona; 8Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and 9Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain
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- Natalia Jiménez
- Authors' Affiliations: 1Laboratory of Translational Oncology and Medical Oncology Department; 2Bioinformatics Platform Department, Centro de Investigación Biomédica en Red—Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; 3Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 4Laboratory and Department of Urology, Hospital Clínic, Barcelona; 5Department of Pathology, Hospital Clínic, Universitat de Barcelona; 6Althia; 7Tumor Bank, Hospital Clínic—IDIBAPS Biobank, Barcelona; 8Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and 9Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain
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- Michael Donovan
- Authors' Affiliations: 1Laboratory of Translational Oncology and Medical Oncology Department; 2Bioinformatics Platform Department, Centro de Investigación Biomédica en Red—Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; 3Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 4Laboratory and Department of Urology, Hospital Clínic, Barcelona; 5Department of Pathology, Hospital Clínic, Universitat de Barcelona; 6Althia; 7Tumor Bank, Hospital Clínic—IDIBAPS Biobank, Barcelona; 8Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and 9Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain
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- Pere Puig
- Authors' Affiliations: 1Laboratory of Translational Oncology and Medical Oncology Department; 2Bioinformatics Platform Department, Centro de Investigación Biomédica en Red—Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; 3Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 4Laboratory and Department of Urology, Hospital Clínic, Barcelona; 5Department of Pathology, Hospital Clínic, Universitat de Barcelona; 6Althia; 7Tumor Bank, Hospital Clínic—IDIBAPS Biobank, Barcelona; 8Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and 9Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain
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- Lourdes Mengual
- Authors' Affiliations: 1Laboratory of Translational Oncology and Medical Oncology Department; 2Bioinformatics Platform Department, Centro de Investigación Biomédica en Red—Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; 3Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 4Laboratory and Department of Urology, Hospital Clínic, Barcelona; 5Department of Pathology, Hospital Clínic, Universitat de Barcelona; 6Althia; 7Tumor Bank, Hospital Clínic—IDIBAPS Biobank, Barcelona; 8Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and 9Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain
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- Raquel Bermudo
- Authors' Affiliations: 1Laboratory of Translational Oncology and Medical Oncology Department; 2Bioinformatics Platform Department, Centro de Investigación Biomédica en Red—Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; 3Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 4Laboratory and Department of Urology, Hospital Clínic, Barcelona; 5Department of Pathology, Hospital Clínic, Universitat de Barcelona; 6Althia; 7Tumor Bank, Hospital Clínic—IDIBAPS Biobank, Barcelona; 8Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and 9Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain
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- Albert Font
- Authors' Affiliations: 1Laboratory of Translational Oncology and Medical Oncology Department; 2Bioinformatics Platform Department, Centro de Investigación Biomédica en Red—Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; 3Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 4Laboratory and Department of Urology, Hospital Clínic, Barcelona; 5Department of Pathology, Hospital Clínic, Universitat de Barcelona; 6Althia; 7Tumor Bank, Hospital Clínic—IDIBAPS Biobank, Barcelona; 8Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and 9Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain
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- Enrique Gallardo
- Authors' Affiliations: 1Laboratory of Translational Oncology and Medical Oncology Department; 2Bioinformatics Platform Department, Centro de Investigación Biomédica en Red—Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; 3Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 4Laboratory and Department of Urology, Hospital Clínic, Barcelona; 5Department of Pathology, Hospital Clínic, Universitat de Barcelona; 6Althia; 7Tumor Bank, Hospital Clínic—IDIBAPS Biobank, Barcelona; 8Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and 9Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain
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- María José Ribal
- Authors' Affiliations: 1Laboratory of Translational Oncology and Medical Oncology Department; 2Bioinformatics Platform Department, Centro de Investigación Biomédica en Red—Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; 3Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 4Laboratory and Department of Urology, Hospital Clínic, Barcelona; 5Department of Pathology, Hospital Clínic, Universitat de Barcelona; 6Althia; 7Tumor Bank, Hospital Clínic—IDIBAPS Biobank, Barcelona; 8Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and 9Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain
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- Antonio Alcaraz
- Authors' Affiliations: 1Laboratory of Translational Oncology and Medical Oncology Department; 2Bioinformatics Platform Department, Centro de Investigación Biomédica en Red—Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; 3Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 4Laboratory and Department of Urology, Hospital Clínic, Barcelona; 5Department of Pathology, Hospital Clínic, Universitat de Barcelona; 6Althia; 7Tumor Bank, Hospital Clínic—IDIBAPS Biobank, Barcelona; 8Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and 9Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain
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- Pere Gascón
- Authors' Affiliations: 1Laboratory of Translational Oncology and Medical Oncology Department; 2Bioinformatics Platform Department, Centro de Investigación Biomédica en Red—Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; 3Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 4Laboratory and Department of Urology, Hospital Clínic, Barcelona; 5Department of Pathology, Hospital Clínic, Universitat de Barcelona; 6Althia; 7Tumor Bank, Hospital Clínic—IDIBAPS Biobank, Barcelona; 8Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and 9Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain
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- Begoña Mellado
- Authors' Affiliations: 1Laboratory of Translational Oncology and Medical Oncology Department; 2Bioinformatics Platform Department, Centro de Investigación Biomédica en Red—Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; 3Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 4Laboratory and Department of Urology, Hospital Clínic, Barcelona; 5Department of Pathology, Hospital Clínic, Universitat de Barcelona; 6Althia; 7Tumor Bank, Hospital Clínic—IDIBAPS Biobank, Barcelona; 8Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and 9Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain
抄録
<jats:title>Abstract</jats:title> <jats:p>Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer participating in a phase II neoadjuvant docetaxel and androgen deprivation trial to identify mediators of resistance. Transcriptional level of 93 genes from a docetaxel-resistant prostate cancer cell lines microarray study was analyzed by TaqMan low-density arrays in tumors from patients with high-risk localized prostate cancer (36 surgically treated, 28 with neoadjuvant docetaxel + androgen deprivation). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and RELA were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and docetaxel-resistant castration-resistant prostate cancer cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after docetaxel exposure. Reversion of EMT phenotype was investigated as a docetaxel resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P < 0.05), including genes related to androgen receptor, NF-κB transcription factor, and EMT. Increased expression of EMT markers correlated with radiologic relapse. Docetaxel-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted docetaxel resistance and reduced CD44 expression in DU-145R and PC-3R. Before docetaxel exposure, a selected CD44+ subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44+ subpopulations were found in tumor cell lines and primary tumors; this correlated with aggressive clinical behavior. This study identifies genes potentially related to chemotherapy resistance and supports evidence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer. Mol Cancer Ther; 13(5); 1270–84. ©2014 AACR.</jats:p>
収録刊行物
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- Molecular Cancer Therapeutics
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Molecular Cancer Therapeutics 13 (5), 1270-1284, 2014-05-01
American Association for Cancer Research (AACR)