Article abstract
Nature Medicine 13, 1333 - 1340 (2007)
Published online: 4 November 2007 | doi:10.1038/nm1677
Tumor-induced anorexia and weight loss are mediated by the TGF-
superfamily cytokine MIC-1
Heiko Johnen1,6, Shu Lin2,6, Tamara Kuffner1,6, David A Brown1, Vicky Wang-Wei Tsai1, Asne R Bauskin1, Liyun Wu1, Greg Pankhurst1, Lele Jiang1, Simon Junankar1, Mark Hunter1, W Douglas Fairlie1, Nicola J Lee2, Ronaldo F Enriquez2, Paul A Baldock2, Eva Corey3, Fred S Apple4, MaryAnn M Murakami4, En-Ju Lin5, Chuansong Wang5, Matthew J During5, Amanda Sainsbury2, Herbert Herzog2,6 & Samuel N Breit1,6
Abstract
Anorexia and weight loss are part of the wasting syndrome of late-stage cancer, are a major cause of morbidity and mortality in cancer, and are thought to be cytokine mediated. Macrophage inhibitory cytokine-1 (MIC-1) is produced by many cancers. Examination of sera from individuals with advanced prostate cancer showed a direct relationship between MIC-1 abundance and cancer-associated weight loss. In mice with xenografted prostate tumors, elevated MIC-1 levels were also associated with marked weight, fat and lean tissue loss that was mediated by decreased food intake and was reversed by administration of antibody to MIC-1. Additionally, normal mice given systemic MIC-1 and transgenic mice overexpressing MIC-1 showed hypophagia and reduced body weight. MIC-1 mediates its effects by central mechanisms that implicate the hypothalamic transforming growth factor-
receptor II, extracellular signal–regulated kinases 1 and 2, signal transducer and activator of transcription-3, neuropeptide Y and pro-opiomelanocortin. Thus, MIC-1 is a newly defined central regulator of appetite and a potential target for the treatment of both cancer anorexia and weight loss, as well as of obesity.
- Centre for Immunology, St. Vincent's Hospital and University of New South Wales, Sydney, New South Wales 2010, Australia.
- Neuroscience Program, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
- Department of Urology, University of Washington, Seattle, Washington 98195, USA.
- Clinical Laboratories, Hennepin County Medical Center, and University of Minnesota School of Medicine, Minneapolis, Minnesota 55415, USA.
- Human Cancer Genetics Program, The Ohio State University, Columbus, Ohio 43210, USA.
- These authors contributed equally to this work.
Correspondence to: Samuel N Breit1,6 e-mail: s.breit@cfi.unsw.edu.au
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