CXCL12g 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 CXCL12g in CSC induction and neuroendocrine differentiation and its impact on m-CRPC. CXCL12g 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 CXCL12g induced CSC and neuroendocrine phenotypes in prostate cancer cells through CXCR4-mediated PKCa/NFkB signaling, which promoted prostate tumor outgrowth, metastasis, and chemoresistance in vivo. Together, our results establish a significant function for CXCL12g in m-CRPC development and suggest it as a candidate therapeutic target to control aggressive disease. Significance: Expression of CXCL12g induces the expression of a cancer stem cell and neuroendocrine phenotypes, resulting in the development of aggressive m-CRPC.