CXCL12γ Promotes Development of Metastatic Castration Resistant Prostate Cancer by Induction of Cancer Stem Cell and Neuroendocrine Phenotypes

The development of metastatic castration resistant prostate cancer (m-CRPC) poses significant challenges for treatment. Specifically, the emergence of elevated levels of cancer stem cells (CSC) coupled with neuroendocrine (NE) carcinoma behavior is likely to play a critical role in m-CRPC and ultimately leads to an aggressive clinical course. Thus, understanding the mechanisms by which CSC and NE phenotypes impact the development of mCRPC will facilitate the identification of biomarkers and development of potentially novel therapeutics. Here, the role of the intracellular chemokine CXCL12γ in CSC induction and NE differentiation impact on m-CRPC was explored. We show that CXCL12γ expression was detected in small cell carcinoma of metastatic tissues and circulating tumor cells (CTCs) from m-CRPC patients and in PCa cells expressing a NE phenotype. CXCL12γ overexpression induces CSC and NE phenotypes through CXCR4-mediated PKCα/NFκB signaling, which promote prostate tumor outgrowth, metastasis, and chemoresistance. Together, these data suggest that CXCL12γ plays a significant role in induction of CSC and NE phenotypic cells leading to the development of m-CRPC and reveals a potential central molecular pathway for targeting of aggressive disease.