197 PREMETASTATIC NICHE INVOLVES RANKL-RANK SIGNALING RECRUITING BYSTANDER CANCER CELLS TO PARTICIPATE CANCER SKELETAL METASTASIS

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research (I)1 Apr 2013197 PREMETASTATIC NICHE INVOLVES RANKL-RANK SIGNALING RECRUITING BYSTANDER CANCER CELLS TO PARTICIPATE CANCER SKELETAL METASTASIS Gina C.Y. Chu, Haiyen E. Zhau, Ruoxiang Wang, Andre Rogatko, Xu Feng, Majd Zayzafoon, and Leland W.K. Chung Gina C.Y. ChuGina C.Y. Chu Los Angeles, CA More articles by this author , Haiyen E. ZhauHaiyen E. Zhau Los Angeles, CA More articles by this author , Ruoxiang WangRuoxiang Wang Los Angeles, CA More articles by this author , Andre RogatkoAndre Rogatko Los Angeles, CA More articles by this author , Xu FengXu Feng Birmingham, AL More articles by this author , Majd ZayzafoonMajd Zayzafoon Birmingham, AL More articles by this author , and Leland W.K. ChungLeland W.K. Chung Los Angeles, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1577AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Activation of RANK, a receptor activator of NF-κB, by its ligand RANKL is critical for osteoclast differentiation/bone remodeling. RANKL can be derived from osteoblasts, infiltrating inflammatory cells and stromal fibroblasts. We found malignant prostate cancer (PCa) cells expressed RANKL; its expression correlated with clinical PCa progression and induced bone metastasis (BM) of RANK+ PCa cells. Our objective is to dissect the mechanism by which PCa-derived RANKL acts on RANK+ PCa cells to promote PCa BM. METHODS Human PCa LNCaP cells were stably transfected with a RANKL expression construct. We identified the common transcription factors (TFs) required for the induction of RANKL and c-Met expression by site-directed mutagenesis and TFs deletion/interference assays. We assessed EMT progression, stem, and neuroendocrine (NE) cell properties by determining changes in their specific markers. Tumorigenic and metastatic potential in vivo was examined by intratibial and intracardiac co-inoculation of RANKL+ and RANKL- PCa cells to male athymic mice. RANKL expression was detected by quantum dot staining and cell-based signal quantification from 20 primary PCa specimens with documented cancer-specific survival data. RESULTS We demonstrated that: 1) RANKL amplifies downstream signaling by activating RANKL and c-Met expression and signaling through a common TF complex, c-Myc/Max. 2) A few RANKL+ PCa cells are sufficient to initiate the metastatic cascade by recruiting non-tumorigenic RANKL- PCa cells to participate in the metastatic process via downstream signaling amplification. This is supported by the observation that recombinant RANKL protein alone is sufficient to induce BM of non-metastatic PCa cells. 3) RANKL also promotes EMT and confers stem and NE cell properties on participating cancer cells.4) RANKL expression at the single cell level in primary PCa specimens predicts PCa patient survival. CONCLUSIONS Small numbers of RANKL+ PCa cells are sufficient to initiate cancer bone colonization by recruiting non-tumorigenic/bystander PCa cells to participate in BM. RANKL-RANK signaling in PCa cells establishes a premetastatic niche through a “vicious cycle”, inducing RANKL and c-Met expression via activation of c-Myc/Max. RANKL-RANK interaction promotes PCa cells to undergo EMT and assume stem and NE cell properties. RANKL expression at the single cell level in primary human cancer tissues predicts PCa patient survival. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e81-e82 Peer Review Report Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Gina C.Y. Chu Los Angeles, CA More articles by this author Haiyen E. Zhau Los Angeles, CA More articles by this author Ruoxiang Wang Los Angeles, CA More articles by this author Andre Rogatko Los Angeles, CA More articles by this author Xu Feng Birmingham, AL More articles by this author Majd Zayzafoon Birmingham, AL More articles by this author Leland W.K. Chung Los Angeles, CA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...