The research, published in Cancer Cell, describes an unexpected link between muscular dystrophy and muscle wasting associated with cancer, and suggests a potential strategy for development of therapies to combat cancer-associated muscle wasting.

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.

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Bushman and his team made cells that were depleted of LEDGF and found that integration was less frequent in transcription units and in genes regulated by LEDGF. "This implies that LEDGF is part of the machinery that helps dictate the placement of retroviral integration sites within chromosomes," says Bushman.

Bushman notes that finding that LEDGF is part of the cellular apparatus necessary for HIV replication is important to the field of gene therapy. Controlling where gene-therapy vehicles insert in the human genome could help make the delivery of new therapeutic sequences safer. The new findings about LEDGF suggest that engineered tethering interactions might some day allow control over integration site selection during gene therapy. According to Bushman, this finding is of particular importance in light of recent cases where integration of gene-therapy vectors near cancer genes contributed to the development of leukemia in gene-therapy patients.

"This is first example of a cellular factor that's a clear player in target site selection," says Bushman. "This isn't engineering yet, but it's a key piece of information on the way."

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