Cancer‐bone microenvironmental interactions promotes STAT3 signaling

• Published in: Molecular carcinogenesis 2019-08, Vol.58 (8), p.1349-1361
• Main Authors: Henderson, Veronica M., Hawsawi, Ohuod, Burton, Liza J., Campbell, Taaliah, Trice, Kennedi, Dougan, Jodi, Howard, Simone M., Odero‐Marah, Valerie A.
• Format: Article
• Language: English
• Subjects: Animals; Bone and Bones - pathology; Bone cancer; Bone density; Bone Neoplasms - pathology; Bone Neoplasms - secondary; Calcium; Calcium - metabolism; Calcium signalling; Cancer; cancer‐bone microenvironmental interactions; Cathepsin L; Cathepsin L - antagonists & inhibitors; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Cell Movement - physiology; Cell proliferation; Cell Proliferation - physiology; Complications; Conditioning; Durapatite - pharmacology; Egtazic Acid - pharmacology; epithelial to mesenchymal transition; Ethylene glycol; HEK293 Cells; Humans; Hydroxyapatite; Kinases; Male; Metastases; Mice; Mice, Inbred BALB C; Mice, Nude; Organs; Paracrine signalling; Phosphorylation; Prostate cancer; prostate cancer cells; Prostatic Neoplasms - pathology; Pyridines; RNA Interference; RNA, Small Interfering - genetics; signal transducer and activator of transcription 3; Signal Transduction; Snail; Snail Family Transcription Factors - genetics; Snail protein; Stat3 protein; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - metabolism; Therapeutic targets; Transcription; Tumor cells; Tumor Microenvironment - physiology; Tumorigenicity; Tyrphostins; Viability
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.23019

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.