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Cancer‐bone microenvironmental interactions promotes STAT3 signaling
Author(s) -
Henderson Veronica M.,
Hawsawi Ohuod,
Burton Liza J.,
Campbell Taaliah,
Trice Kennedi,
Dougan Jodi,
Howard Simone M.,
OderoMarah Valerie A.
Publication year - 2019
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.23019
Subject(s) - paracrine signalling , biology , lncap , cell migration , cancer research , microbiology and biotechnology , viability assay , stat3 , cancer cell , signal transduction , cell , cancer , biochemistry , genetics , receptor
Prostate cancer (PCa) patients’ mortality is mainly attributed to complications caused by metastasis of the tumor cells to organs critical for survival, such as bone. We hypothesized that PCa cell‐bone interactions would promote paracrine signaling. A panel of PCa cell lines were cocultured with hydroxyapatite ([HA]; inorganic component of bone) of different densities. Conditioned media (CM) was collected and analyzed for calcium levels and effect on paracrine signaling, cell migration, and viability in vitro and in vivo. Our results showed that calcium levels were elevated in CM from cancer cell‐bone cocultures, compared to media or cancer cells alone, and this could be antagonized by ethylene glycol‐bis(2‐aminoethyl ether)N,N,N′,N′‐tetraacetic acid (EGTA), a calcium chelator, or knockdown of Snail protein. We also observed increased signal transducer and activator of transcription 3 (STAT3) phosphorylation and paracrine cell proliferation and migration in LNCaP cells incubated with CM from various cell lines; this phosphorylation and cell migration could be antagonized by Snail knockdown or various inhibitors including EGTA, STAT3 inhibitor (WP1066) or cathepsin L inhibitor (Z‐FY‐CHO). In vivo, higher HA bone density increased tumorigenicity and migration of tumor cells to HA implant. Our study shows that cancer‐bone microenvironment interactions lead to calcium‐STAT3 signaling, which may present an area for therapeutic targeting of metastatic PCa.