Medical College of Wisconsin
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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. J Bone Miner Res 2014 Sep;29(9):1938-49 PMID: 24676805

Pubmed ID

24676805

DOI

10.1002/jbmr.2231

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.

Author List

Zheng Y, Chow SO, Boernert K, Basel D, Mikuscheva A, Kim S, Fong-Yee C, Trivedi T, Buttgereit F, Sutherland RL, Dunstan CR, Zhou H, Seibel MJ

Author

Donald Basel MD Chief, Associate Professor in the Pediatrics department at Medical College of Wisconsin




Scopus

2-s2.0-84905845850   20 Citations

MESH terms used to index this publication - Major topics in bold

Animals
Bone Neoplasms
Bone Resorption
Bone and Bones
Cell Line, Tumor
Cell Lineage
Coculture Techniques
Disease Progression
Gene Knockdown Techniques
Humans
Interleukin-6
Mice
Neoplasm Metastasis
Neoplasms
Osteoblasts
RANK Ligand
Receptor Activator of Nuclear Factor-kappa B
Receptors, Interleukin-6
Recombinant Proteins
Signal Transduction
Xenograft Model Antitumor Assays
jenkins-FCD Prod-332 f92a19b0ec5e8e1eff783fac390ec127e367c2b5