374 ANDROGEN DEPRIVATION UP REGULATES EXPRESSION OF STEM CELL AND NEUROENDOCRINE MARKERS IN PROSTATE CANCER CELLS IN VITRO AND IN VIVO

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research III1 Apr 2010374 ANDROGEN DEPRIVATION UP REGULATES EXPRESSION OF STEM CELL AND NEUROENDOCRINE MARKERS IN PROSTATE CANCER CELLS IN VITRO AND IN VIVO Markus Germann, Marco G. Cecchini, Antoinette Wetterwald, Urs E. Studer, and George N. Thalmann Markus GermannMarkus Germann More articles by this author , Marco G. CecchiniMarco G. Cecchini More articles by this author , Antoinette WetterwaldAntoinette Wetterwald More articles by this author , Urs E. StuderUrs E. Studer More articles by this author , and George N. ThalmannGeorge N. Thalmann More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.442AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To evaluate changes in expression of genes related to tumor progression and the cancer stem cell concept in response to androgen deprivation (AD) in different in vitro and in vivo models of castration resistant prostate cancer. METHODS LNCaP, LNCaP-Bic, C4-2 and C4-2B4 cell lines were used for in vitro experiments. Gene specific mRNA expression was measured by RT-PCR and compared to the parental LNCaP cells. Tumors of the androgen dependent CaP xenograft model BM18 show an almost complete regression after castration of tumor bearing mice. Tumor growth can be reinitiated even months after castration by re-administration of testosterone. After tumor regression only very small clusters of residual epithelial cells can be observed. To investigate the nature of these cells, BM18 tumors were harvested before castration (intact), 14 days after castration (regressed) or 3 days after testosterone readministration to regressed tumors and tested gene specific mRNA expression. RESULTS Overall AD induced expression of proliferation and anti-apoptotic genes as well as the putative stem/progenitor cell markers á2-integrin, Oct4, Nanog, Nestin and Sca1 in all LNCaP derived cell lines in vitro. In vivo, compared to intact BM18 tumors, regressed tumors show a significant higher expression of Bcl2 together with a 10-20 fold higher expression of the self-renewal markers Oct4, Sox2 and Nanog. Regressed tumors express low PSA mRNA levels but maintain high expression of markers of luminal cell differentiation (AR, CK18 and PSP94). Furthermore, regressed tumors show a 40-1000 fold increased expression of markers of neuroendocrine differentiation (Chromogranin A, Synaptophysin, Enolase 2 and Nestin). Interestingly, 3 days after testosterone readministration, relapsed tumors show at least partial reversal of these alterations in gene expression. These results were confirmed in the cell lines in vitro. CONCLUSIONS AD up regulates stem/progenitor and neuroendocrine cell markers, as well as markers of proliferative potential, self-renewal and inhibition of apoptosis in LNCaP cells in vitro and in BM18 tumors in vivo suggesting the outgrowth of a more malignant phenotype with stem cell properties by AD leading to castration resistance. Bern, Switzerland© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e148 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Markus Germann More articles by this author Marco G. Cecchini More articles by this author Antoinette Wetterwald More articles by this author Urs E. Studer More articles by this author George N. Thalmann More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...