Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer
Menée sur des cellules tumorales issues de prélèvements sur des patients atteints d'un cancer de la prostate et inclus dans un essai clinique, cette étude met en évidence une surexpression de divers gènes impliqués dans la transition épithélio-mésenchymateuse en association avec l'apparition d'une résistance au docétaxel
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 (PC) participating in a phase-II neoadjuvant docetaxel (D) and androgen deprivation (AD) trial to identify mediators of resistance. Transcriptional level of 93 genes from a D-resistant PC cell lines microarray study was analyzed by Taqman low-density arrays in tumors from patients with high-risk localized PC (36 surgically treated, 28 with neoadjuvant D+AD). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and P65 were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and D-resistant CRPC cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after D-exposure. Reversion of EMT phenotype was investigated as a D-resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P<0.05), including genes related to androgen receptor, NFKB transcription factor, and EMT. Increased EMT markers expression correlated with radiological relapse. D-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted D-resistance and reduced CD44 expression in DU-145R and PC-3R. Before D-exposure, a selected CD44+ subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic D-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 PC.
http://mct.aacrjournals.org/content/early/2014/03/21/1535-7163.MCT-13-0775.abstract