Interleukin-17 promotes development of castration-resistant prostate cancer potentially through creating an immunotolerant and pro-angiogenic tumor microenvironment

Abstract

Background Interleukin-17 (IL-17) has been demonstrated to promote formation and growth of hormone-naïve prostate adenocarcinoma in mice. IL-17's role in development of castration-resistant prostate cancer is unknown. In the present study, we investigated IL-17's role in castration-resistant prostate cancer in a mouse model. Methods IL-17 receptor C (IL-17RC) deficient mice were interbred with Pten conditional mutant mice to produce RC+ mice that maintained IL-17RC expression and RC- mice that were IL-17RC deficient. Male RC+ and RC- mice were Pten-null and were castrated at 16 weeks of age when invasive prostate cancer had already formed. At 30 weeks of age, all male mice were analyzed for the prostate phenotypes. Results RC- mice displayed prostates that were smaller than RC+ mice. Approximately 23% of prostatic glands in RC - mice, in contrast to 65% of prostatic glands in RC+ mice, developed invasive adenocarcinomas. Compared to castrate RC+ mice, castrate RC- mouse prostate had lower rates of cellular proliferation and higher rates of apoptosis as well as lower levels of MMP7, YBX1, MTA1, and UBE2C proteins. In addition, castrate RC- mouse prostate had less angiogenesis, which was associated with decreased levels of COX-2 and VEGF. Moreover, castrate RC- mouse prostate had fewer inflammatory cells including lymphocytes, myeloid-derived suppressor cells, and macrophages. ConclusionS Taken together, our findings suggest that IL-17 promotes development of invasive prostate adenocarcinomas under castrate conditions, potentially through creating an immunotolerant and pro-angiogenic tumor microenvironment. © 2014 Wiley Periodicals, Inc.