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[Cancer Research 65, 11001-11009, December 1, 2005]
© 2005 American Association for Cancer Research

Cell and Tumor Biology

Tumor-Derived Interleukin-8 Stimulates Osteolysis Independent of the Receptor Activator of Nuclear Factor-{kappa}B Ligand Pathway

Manali S. Bendre1,2, Aaron G. Margulies3, Brandon Walser1,2, Nisreen S. Akel1,2, Sudeepa Bhattacharrya2, Robert A. Skinner2, Frances Swain2, Vishnu Ramani1,2, Khalid S. Mohammad4, Lisa L. Wessner4, Alfredo Martinez5, Theresa A. Guise4, John M. Chirgwin4, Dana Gaddy1,2 and Larry J. Suva1,2

1 Department of Orthopaedic Surgery, Center for Orthopaedic Research, Barton Research Institute; 2 Department of Physiology and Biophysics; 3 Division of Breast Surgical Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas; 4 Division of Endocrinology, Department of Medicine, University of Virginia, Charlottesville, Virginia; and 5 Department of Neuroanatomy and Cell Biology, Instituto Cajal, Consejo Superior de Investigaciones Cientificas, Madrid, Spain

Requests for reprints: Larry J. Suva, Center for Orthopaedic Research, Department of Orthopaedic Surgery, Slot 644, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205. Phone: 501-526-6110; Fax: 501-686-8987; E-mail: suvalarryj{at}uams.edu.

Bone is a common site of cancer metastasis. Breast, prostate, and lung cancers show a predilection to metastasize to bone. Recently, we reported that the chemokine interleukin 8 (IL-8) stimulates both human osteoclast formation and bone resorption. IL-8 mRNA expression was surveyed in a panel of human breast cancer lines MDA-MET, MDA-MB-231, MDA-MB-435, MCF-7, T47D, and ZR-75, and the human lung adenocarcinoma cell line A549. IL-8 mRNA expression was higher in cell lines with higher osteolytic potential in vivo. Human osteoclast formation was increased by MDA-MET or A549 cell-conditioned medium, but not by MDA-MB-231. Pharmacologic doses of receptor activator of nuclear factor-{kappa}B (RANK)-Fc or osteoprotogerin had no effect on the pro-osteoclastogenic activity of the conditioned medium; however, osteoclast formation stimulated by conditioned medium was inhibited 60% by an IL-8-specific neutralizing antibody. The data support a model in which tumor cells cause osteolytic bone destruction independently of the RANK ligand (RANKL) pathway. Tumor-produced IL-8 is a major contributor to this process. The role of secreted IL-8 isoforms was examined by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, which detected distinct IL-8 isoforms secreted by MDA-MET and MDA-231 cells, suggesting different pro-osteoclastogenic activities of the two IL-8-derived peptides. These data indicate that (a) osteoclast formation induced by MDA-MET breast cancer cells and A549 adenocarcinoma cells is primarily mediated by IL-8, (b) cell-specific isoforms of IL-8 with distinct osteoclastogenic activities are produced by tumor cells, and (c) tumor cells that support osteoclast formation independent of RANKL secrete other pro-osteoclastogenic factors in addition to IL-8.




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Molecular Cancer Research Cancer Prevention Research
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Copyright © 2005 by the American Association for Cancer Research.