Letter | Published:

Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia

Nature volume 513, pages 100104 (04 September 2014) | Download Citation

Abstract

Cachexia is a wasting disorder of adipose and skeletal muscle tissues that leads to profound weight loss and frailty. About half of all cancer patients suffer from cachexia, which impairs quality of life, limits cancer therapy and decreases survival. One key characteristic of cachexia is higher resting energy expenditure levels than in healthy individuals, which has been linked to greater thermogenesis by brown fat1,2,3,4,5,6. How tumours induce brown fat activity is unknown. Here, using a Lewis lung carcinoma model of cancer cachexia, we show that tumour-derived parathyroid-hormone-related protein (PTHrP) has an important role in wasting, through driving the expression of genes involved in thermogenesis in adipose tissues. Neutralization of PTHrP in tumour-bearing mice blocked adipose tissue browning and the loss of muscle mass and strength. Our results demonstrate that PTHrP mediates energy wasting in fat tissues and contributes to the broader aspects of cancer cachexia. Thus, neutralization of PTHrP might hold promise for ameliorating cancer cachexia and improving patient survival.

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Gene Expression Omnibus

Data deposits

The microarray data set has been deposited in the Gene Expression Omnibus (GEO) database under the accession GSE57797.

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Acknowledgements

We thank M. Mourtzakis and C. Prado for their help with the human study. S. Kir is a Robert Black Fellow of the Damon Runyon Cancer Research Foundation (DRG-2153-13), and J.P.W. is supported by a postdoctoral fellowship from the American Cancer Society (PF-13-385-01-TBE). This work was supported by National Institutes of Health grant DK31405 to B.M.S.

Author information

Affiliations

  1. Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA

    • Serkan Kir
    • , James P. White
    • , Sandra Kleiner
    • , Lawrence Kazak
    • , Paul Cohen
    •  & Bruce M. Spiegelman
  2. Department of Oncology, Division of Palliative Care Medicine, University of Alberta, Edmonton T6G 1Z2, Canada

    • Vickie E. Baracos

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Contributions

S. Kir and B.M.S. conceived and designed the experiments. S. Kir, J.P.W., S. Kleiner., L.K. and P.C. performed the experiments. S. Kir, J.P.W. and V.E.B. analysed the data. S. Kir and B.M.S. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Bruce M. Spiegelman.

Extended data

Supplementary information

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    Supplementary Data

    This file contains all metabolic and clinical data for the cancer patients included in the study.

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DOI

https://doi.org/10.1038/nature13528

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