CXCL12γ Promotes Metastatic Castration-Resistant Prostate Cancer by Inducing Cancer Stem Cell and Neuroendocrine Phenotypes
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 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 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 12, 2018
- Source ID
- 10.1158/0008-5472.can-17-2332
Entities
People
- Amy M. Gursky
- Ann M. Decker
- Eunsohl Lee
- Frank C Cackowski
- Jae-seung Chung
- Jin Koo Kim
- Jingcheng Wang
- Kenji Yumoto
- Kenneth J. Pienta
- Paul H. Krebsbach
- Russell S. Taichman
- Todd M Morgan
- Younghun Jung
- Yugang Wang
Organizations
- Inje University
- Johns Hopkins School of Medicine
- National Cancer Institute
- National Institutes of Health
- Prostate Cancer Foundation
- United States Department of Defense
- University of California, Los Angeles
- University of Michigan