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.
|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.;|
|Publisher Name||JOURNAL OF BONE AND MINERAL RESEARCH|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/24676805|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/12503|