Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

被引：129

作者：

Marin-Aguilera, Mercedes ^{[1
,2
]}

Codony-Servat, Jordi ^{[1
,2
]}

Reig, Oscar ^{[1
,2
]}

Jose Lozano, Juan ^{[3
]}

Luis Fernandez, Pedro ^{[4
,6
]}

Veronica Pereira, Maria ^{[1
,2
]}

Jimenez, Natalia ^{[1
,2
]}

Donovan, Michael ^{[7
]}

Puig, Pere ^{[7
]}

Mengual, Lourdes ^{[5
]}

Bermudo, Raquel ^{[4
,8
]}

Font, Albert ^{[9
]}

Gallardo, Enrique ^{[10
]}

Jose Ribal, Maria ^{[5
]}

Alcaraz, Antonio ^{[4
,5
]}

Gascon, Pere ^{[1
,2
,4
]}

Mellado, Begona ^{[1
,2
,4
]}

机构：

[1] Hosp Clin Barcelona, Lab Translat Oncol, E-08036 Barcelona, Spain

[2] Hosp Clin Barcelona, Dept Med Oncol, E-08036 Barcelona, Spain

[3] Hosp Clin Barcelona, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Bioinformat Platform Dept, E-08036 Barcelona, Spain

[4] Inst Invest Biomed August Pi i Sunyer IDIBAPS, Barcelona, Spain

[5] Hosp Clin Barcelona, Lab & Dept Urol, E-08036 Barcelona, Spain

[6] Univ Barcelona, Hosp Clin Barcelona, Dept Pathol, Barcelona, Spain

[7] Althia, Barcelona, Spain

[8] Hosp Clin IDIBAPS Biobank, Tumor Bank, Barcelona, Spain

[9] Catalan Inst Oncol, Hosp Germans Trias i Pujol, Dept Med Oncol, Badalona, Spain

[10] Hosp Parc Tauli, Dept Med Oncol, Sabadell, Spain

来源：

MOLECULAR CANCER THERAPEUTICS | 2014年 / 13卷 / 05期

关键词：

FACTOR-KAPPA-B; ANDROGEN RECEPTOR; NEOADJUVANT DOCETAXEL; SIGNALING PATHWAYS; EXPRESSION; SUPPRESSION; INHIBITION; CELLS; CHEMORESISTANCE; IDENTIFICATION;

D O I：

10.1158/1535-7163.MCT-13-0775

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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-kappa B 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. (C) 2014 AACR.

引用

页码：1270 / 1284

页数：15

共 49 条

[11] Suppression of Acquired Docetaxel Resistance in Prostate Cancer through Depletion of Notch- and Hedgehog-Dependent Tumor-Initiating Cells [J].