CXCL12γ Promotes Metastatic Castration-Resistant Prostate Cancer by Inducing Cancer Stem Cell and Neuroendocrine Phenotypes

There is evidence that cancer stem-like cells (CSC) and neuroendocrine behavior play critical roles in the pathogenesis and clinical course of metastatic castration-resistant prostate cancer (m-CRPC). However, there is limited mechanistic understanding of how CSC and neuroendocrine phenotypes impact the development of m-CRPC. In this study, we explored the role of the intracellular chemokine CXCL12 gamma in CSC induction and neuroendocrine differentiation and its impact on m-CRPC. CXCL12 gamma expression was detected in small-cell carcinoma of metastatic tissues and circulating tumor cells from m-CRPC patients and in prostate cancer cells displaying an neuroendocrine phenotype. Mechanistic investigations demonstrated that overexpression of CXCL12 gamma induced CSC and neuroendocrine phenotypes in prostate cancer cells through CXCR4-mediated PKC alpha/NF kappa B signaling, which promoted prostate tumor outgrowth, metastasis, and chemoresistance in vivo. Together, our results establish a significant function for CXCL12 gamma in m-CRPC development and suggest it as a candidate therapeutic target to control aggressive disease. Significance: Expression of CXCL12 gamma induces the expression of a cancer stem cell and neuroendocrine phenotypes, resulting in the development of aggressivem-CRPC. (C) 2018 AACR.