Muscle wasting, or cachexia, is a severe and debilitating consequence of cancer that occurs in a majority of patients and is thought to contribute to up to one third of all cancer deaths. The molecular mechanisms underlying skeletal muscle cachexia are not well understood, but it is highly likely that effective cachexia therapy might improve patients' quality of life, ability to receive treatment, and survival. To gain insight into the mechanisms underlying muscle wasting in cancer patients, Dr. Denis C. Guttridge from the Human Cancer Genetic Program and the Department of Molecular Virology, Immunology & Medical Genetics at The Ohio State University and colleagues analyzed cachectic muscles in tumor-bearing patients and mice.
The researchers found that wasting associated with cancer in mice is linked to a dysfunctional dystrophin glycoprotein complex (DGC), a structure in the muscle cell membrane that is mutated in the muscle wasting disease muscular dystrophy. Progression of cancer is associated with reduction of dystrophin and abnormal regulation of the DGC proteins. Mice lacking dystrophin exhibit enhanced tumor-induced wasting, while transgenic animals expressing dystrophin were spared from the disease. Significantly, cachectic patients with gastrointestinal cancers had dramatic reductions in dystrophin when compared to weight-stable healthy individuals.
Although cancer cachexia and muscular dystrophy both involve muscle loss, the mechanisms underlying these diseases had been thought to be widely divergent. However, the results of this study point to deregulated DGC as one potentially critical shared characteristic. "Collectively, evidence in this study suggests that DGC dysfunction may be an early event in some cancers contributing to cachexia. Since effective therapies are currently lacking, results imply that approaches targeted to restoring DGC function could also be considered as an option in designing anticancer cachexia therapies," concludes Dr. Guttridge.
The researchers include Swarnali Acharyya, Matthew E.R. Butchbach, Zarife Sahenk, Huating Wang, Motoyasu Saji, Micheal Carathers, Matthew D. Ringel, Arthur H.M. Burghes, Jill A. Rafael-Fortney, Peter Muscarella, and Denis C. Guttridge of the Ohio State University inColumbus, Ohio; Richard J.E. Skipworth and Kenneth C.H. Fearon of the Royal Infirmary in Edinburgh, United Kingdom; Michael A. Hollingsworth, University of Nebraska Medical Center in Omaha, Nebraska. This work was supported by NIH grants CA097953, CA098466, and CA72712 and by the V Foundation.
Acharyya et al.: "Dystrophin Glycoprotein Complex Dysfunction: A Regulatory Link Between Muscular Dystrophy and Cancer Cachexia."" Publishing in Cancer Cell, Vol. 8, November 2005, pages 421-432. DOI 10.1016/j.ccr.2005.10.004 www.cancercell.org