title: Direct crosstalk between cancer and osteoblast lineage cells fuels metastatic growth in bone via auto-amplification of IL-6 and RANKL signaling pathways.
abstract: 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.
authors.affiliation: Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia; The Kinghorn Cancer Centre and Cancer Research Program, Garvan Institute of Medical Research, Sydney, Australia.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zheng
authors.forename: Shu-Oi
authors.initials: SO
authors.lastname: Chow
authors.forename: Katja
authors.initials: K
authors.lastname: Boernert
authors.forename: Dennis
authors.initials: D
authors.lastname: Basel
authors.forename: Anastasia
authors.initials: A
authors.lastname: Mikuscheva
authors.forename: Sarah
authors.initials: S
authors.lastname: Kim
authors.forename: Colette
authors.initials: C
authors.lastname: Fong-Yee
authors.forename: Trupti
authors.initials: T
authors.lastname: Trivedi
authors.forename: Frank
authors.initials: F
authors.lastname: Buttgereit
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: Colin R
authors.initials: CR
authors.lastname: Dunstan
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Seibel
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary*; D001862:Bone Resorption / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000187:drug effects; D018920:Coculture Techniques; D018450:Disease Progression; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000097:blood / Q000473:pathology*; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology*; D053245:RANK Ligand / Q000097:blood / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D015850:Interleukin-6; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; C505686:TNFRSF11A protein, human
keywords: BONE METASTASIS; BREAST CANCER; INTERLEUKIN-6; OSTEOBLAST; RANKL