Abstract LB-279: N-cadherin promotes castration-resistant prostate cancer progression by enhancing stem cell properties of prostate cancer cells

Abstract

Abstract New generation of anti-androgen treatments such as enzalutamide and abiraterone are improving survival of men with advanced and metastatic prostate cancers, but resistance to these inevitably arises. The molecular mechanisms governing the emergence of treatment resistance in castration resistant prostate cancer (CRPC) patients are not well understood. Recent experience suggests that tumor regeneration from castration-resistant stem-like cells induce resistance to hormonal therapy. Therefore, elucidating novel targets essential for driving stem-like activity is critical to prevent and defeat CRPC. It has been shown that normal and cancer stem cells exploit normal development process of epithelial-mesenchymal transition (EMT) to survive and metastasize, and that EMT confer stem cell properties to more differentiated cancer cell progeny in breast and other cancers. However, it is unclear if EMT is linked with stem cells in normal and malignant prostate. We previously showed that N-cadherin, a marker of EMT, promotes CRPC progression and that there was a correlation between N-cadherin expression and the expression of stem cell associated markers. This leads to hypothesis that N-cadherin may promote CRPC by enhancing tumorige esis/tumor initiating properties of cancer cells in a castrate environment. N-cadherin may confer tumor initiating or stem-like properties to prostate cancer cells perhaps uniquely or specific to in a castrate environment. Here, we verified that EMT is linked to stem cells in both normal prostate and CRPC. We further demonstrate that N-cadherin is involved in increased stem cell properties in normal mouse and human prostates from clinical samples in an androgen-deprived environment. Castration elevates the expression of N-cadherin and stem cell marker Trop2, accompanied with enhanced stem cell properties of luminal population in normal mouse prostates. N-cadherin upregulates stem cell properties in prostate cancer cells in the absence of androgen and CRPC tumors. N-cadherin-positive cells from CRPC tumors behave as stem cells. Overexpression of N-cadherin enhances ALDH activity in a panel of prostate cancer cell lines. Our findings reveal an important role of N-cadherin in prostate cancer and stem cells, and provide useful information of EMT-related biomarkers for preventing and developing efficient therapeutics to combat the treatment resistance to next-generation AR antagonists. Citation Format: Shu Lin, Tanya Stonyanova, Evelyn Kono, Jaclyn Matsuura, Naoko Kobayashi, Joyce Yamashiro, Dai Hong, Owen N. Witte, Andrew S. Goldstein, Robert E. Reiter. N-cadherin promotes castration-resistant prostate cancer progression by enhancing stem cell properties of prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-279.