CXCL12{gamma} Promotes Development of Metastatic Castration Resistant Prostate Cancer by Induction of Cancer Stem Cell and Neuroendocrine Phenotypes

There is evidence that cancer stem-like cells (CSC) and neuroendocrine (NE) behavior play critical roles in the pathogenesis and clinical course of metastatic castration-resistant prostate cancer (m-CRPC). However, there is limiting mechanistic understanding of how CSC and NE phenotypes impact the development of m-CRPC, which could improve opportunities to identify useful biomarkers and therapeutics. In this study, we explored the role of the intracellular chemokine CXCL12γ in CSC induction and NE differentiation and its impact on m-CRPC. CXCL12γ expression was detected in small cell carcinoma of metastatic tissues and circulating tumor cells (CTC) from m-CRPC patients and in prostate cancer cells displaying an NE phenotype. Mechanistic investigations demonstrated that overexpression of CXCL12γ induced CSC and NE phenotypes in prostate cancer cells through CXCR4-mediated PKCalpha/NFkappaB signaling, which promoted prostate tumor outgrowth, metastasis and chemoresistance in vivo. Together, our results establish a significant function for CXCL12γ in m-CRPC development and suggest it as a candidate therapeutic target to control aggressive disease.

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