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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-04, Vol.78 (8), p.2026-2039
• Main Authors: Jung, Younghun, Cackowski, Frank C, Yumoto, Kenji, Decker, Ann M, Wang, Jingcheng, Kim, Jin Koo, Lee, Eunsohl, Wang, Yugang, Chung, Jae-Seung, Gursky, Amy M, Krebsbach, Paul H, Pienta, Kenneth J, Morgan, Todd M, Taichman, Russell S
• Format: Article
• Language: English
• Subjects: Animals; Bone Neoplasms - secondary; Castration; Cell Line, Tumor; Cell Proliferation - physiology; Cellular Reprogramming; Chemokine CXCL12 - physiology; Chemoresistance; CXCR4 protein; Heterografts; Humans; Male; Metastases; Metastasis; Mice, SCID; Neoplastic Stem Cells - pathology; Neuroendocrine Cells - pathology; NF-kappa B - metabolism; NF-κB protein; Phenotype; Phenotypes; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - pathology; Protein kinase C; Protein Kinase C-alpha - metabolism; Receptors, CXCR4 - metabolism; Signal Transduction; Stem cells; Therapeutic applications; Tumor cells
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-17-2332

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 CXCL12γ in CSC induction and neuroendocrine differentiation and its impact on m-CRPC. CXCL12γ 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 CXCL12γ induced CSC and neuroendocrine phenotypes in prostate cancer cells through CXCR4-mediated PKCα/NFκB signaling, which promoted prostate tumor outgrowth, metastasis, and chemoresistance 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. Expression of CXCL12γ induces the expression of a cancer stem cell and neuroendocrine phenotypes, resulting in the development of aggressive m-CRPC. .