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Direct crosstalk between cancer and osteoblast lineage cells fuels metastatic growth in bone via auto-amplification of IL-6 and RANKL signaling pathways


The bone microenvironment and its modification by cancer and host cell interactions is a key driver of skeletal metastatic growth. Interleukin-6 (IL-6) stimulates RANKL expression in bone cells, and serum IL-6 levels are associated with poor clinical outcomes in cancer patients. We investigated the effects of RANKL on cancer cells and the role of tumor-derived IL-6 within the bone microenvironment. Using human breast cancer cell lines to induce tumors in the bone of immune-deficient mice, we first determined whether RANKL released by cells of the osteoblast lineage directly promotes IL-6 expression by cancer cells in-vitro and in-vivo. We then disrupted of IL-6 signaling in-vivo either via knock-down of IL-6 in tumor cells or through treatment with specific anti-human or anti-mouse IL-6 receptor antibodies to investigate the tumor effect. Finally, we tested the effect of RANK knockdown in cancer cells on cancer growth. We demonstrate that osteoblast lineage-derived RANKL up-regulates secretion of IL-6 by breast cancers in-vivo and in-vitro. IL-6 in turn induces expression of RANK by cancer cells, which sensitizes the tumor to RANKL and significantly enhances cancer IL-6 release. Disruption in-vivo of this auto-amplifying crosstalk by knockdown of IL-6 or RANK in cancer cells, or via treatment with anti-IL-6 receptor antibodies, significantly reduces tumor growth in bone but not in soft tissues. RANKL and IL-6 mediate direct paracrine-autocrine signaling between cells of the osteoblast lineage and cancer cells significantly enhancing the growth of metastatic breast cancers within bone. (c) 2014 American Society for Bone and Mineral Research.

Type Journal
ISBN 1523-4681 (Electronic) 0884-0431 (Linking)
Authors Zheng, Y. ; Chow, S. O. ; Boernert, K. ; Basel, D. ; Mikuscheva, A. ; Kim, S. ; Fong-Yee, C. ; Trivedi, T. ; Buttgereit, F. ; Sutherland, R. L. ; Dunstan, C. R. ; Zhou, H. ; Seibel, M. J.;
Published Date 2014-12-01
Published Volume 29
Published Issue 9
Published Pages 1938-49
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version