CXCL12g promotes metastatic castration-resistant prostate cancer by inducing cancer stem cell and neuroendocrine phenotypes

Younghun Jung, Frank C. Cackowski, Kenji Yumoto, Ann M. Decker, Jingcheng Wang, Jin Koo Kim, Eunsohl Lee, Yugang Wang, Jae Seung Chung, Amy M. Gursky, Paul H. Krebsbach, Kenneth J. Pienta, Todd M. Morgan, Russell S. Taichman

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2026-2039
Number of pages14
JournalCancer Research
Volume78
Issue number8
DOIs
StatePublished - Apr 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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