Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1

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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-β 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.

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Figure 1: Effect of MIC-1 on mouse weight, food intake and body composition.
Figure 2: Effect of MIC-1 on body weight in mice and in humans with advanced prostate cancer.
Figure 3: Effect of prolonged action of MIC-1.
Figure 4: MIC-1 receptor identification.
Figure 5: MIC-1 induces alteration in expression of neuropeptide Y and POMC in neurons expressing phosphorylated Stat3.
Figure 6: MIC-1, injected systemically or locally, induces Stat3 phosphorylation in the hypothalamus, even in db/db mice.

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Acknowledgements

This work was supported by grants from the National Health and Medical Research Council of Australia (NHMRC), Cancer Council New South Wales, the Richard M. Lucas Foundation and a New South Wales Health Research and Development Infrastructure grant. A.S. and H.H. are both recipients of NHMRC Fellowships and D.A.B. is a Neil Hamilton Fairley Postdoctoral Fellow of the NHMRC. We would like to thank D. Hume (Institute for Molecular Biosciences, The University of Queensland) for the gift of the promoter construct used to create the transgene for the fmsMIC transgenic mice and P. Sawchenko for critical evaluation of this manuscript. This work is dedicated to the memory of Mary Christine Kennedy.

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Correspondence to Samuel N Breit.

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Competing interests

S.N.B., D.A.B., and A.R.B. declare that St. Vincent's Hospital Sydney, Ltd. has taken out patents and provisional patents covering some aspects of the area of MIC-1 research. Under this institution's intellectual property policy, should aspects of MIC-1 be commercialized and should financial returns flow, the inventors would receive a share of those returns, in line with the institutional policy.

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Supplementary Figs. 1–8, Supplementary Table 1 and Supplementary Methods (PDF 442 kb)

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Johnen, H., Lin, S., Kuffner, T. et al. Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1. Nat Med 13, 1333–1340 (2007) doi:10.1038/nm1677

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