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 receptor activator of NF-κB ligand (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 knockdown 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 upregulates 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.
['Zheng|Yu|Y|', 'Chow|Shu-Oi|SO|', 'Boernert|Katja|K|', 'Basel|Dennis|D|', 'Mikuscheva|Anastasia|A|', 'Kim|Sarah|S|', 'Fong-Yee|Colette|C|', 'Trivedi|Trupti|T|', 'Buttgereit|Frank|F|', 'Sutherland|Robert L|RL|', 'Dunstan|Colin R|CR|', 'Zhou|Hong|H|', 'Seibel|Markus J|MJ|']
D000818:Animals D001859:Bone Neoplasms D001862:Bone Resorption D001842:Bone and Bones D045744:Cell Line, Tumor D019070:Cell Lineage D018920:Coculture Techniques D018450:Disease Progression D055785:Gene Knockdown Techniques D006801:Humans D015850:Interleukin-6 D051379:Mice D009362:Neoplasm Metastasis D009369:Neoplasms D010006:Osteoblasts D053245:RANK Ligand D053246:Receptor Activator of Nuclear Factor-kappa B D019947:Receptors, Interleukin-6 D011994:Recombinant Proteins D015398:Signal Transduction D023041:Xenograft Model Antitumor Assays
OSTEOBLAST RANKL INTERLEUKIN-6 BREAST CANCER BONE METASTASIS