Cancer wasting, muscular dystrophy show common change

New research shows that a wasting condition responsible for nearly a third of all cancer deaths involves the loss of an essential muscle protein that is also lost in people with muscular dystrophy.

The findings provide a better understanding of cancer wasting, also known as cancer cachexia, a condition first described more than 100 years ago that still lacks effective therapy. The findings also might lead to new ways to diagnose and treat the condition.

The study, led by researchers with The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, is published in the November issue of the journal Cancer Cell.

The research shows that muscle cells lose significant amounts of the protein dystrophin during cancer wasting, and that subtle changes occur in two other proteins associated with dystrophin in the membrane of muscle cells. These proteins form the dystrophin glycoprotein complex (DGC). Dystrophin and DGC are also lost in Duchenne muscular dystrophy.

“The loss of dystrophin and damage to the DGC appear to be key players in the development of both cancer wasting and muscular dystrophy,” says principal investigator Denis C. Guttridge, assistant professor of molecular virology, immunology and cancer genetics and a researcher with the OSU Human Cancer Genetics Program, “although the damage to muscle cells seen in cancer cachexia is not as severe as that seen in muscular dystrophy.”

Muscular dystrophy is a genetic disease that usually begins in childhood and results in the complete loss of dystrophin and the DGC from muscle.

Cancer wasting occurs most often in esophageal, stomach, colorectal, pancreatic, lung, and head and neck cancers. The condition is induced by growth of the tumor, and it results in the loss of both fat and skeletal muscle mass.

Cancer patients who develop wasting usually respond more poorly to therapy and have a shorter life span and lower quality of life.

Guttridge and a group of colleagues began this study after noticing that mice with cancer cachexia showed damage to the membranes of their muscle cells, as in muscular dystrophy. This caused them to suspect that dystrophin and the DGC might be involved.

In muscle cells, the long, thin dystrophin molecule joins the cell skeleton to the DGC located in the membrane. The DGC is a cluster of proteins that extends from the membrane into the surrounding tissue and anchors the muscle cell in place. Dystrophin works like a shock absorber during muscle contraction.

“Dystrophin prevents the cell membrane from being torn by the shear forces produced during muscle contraction,” says first author Swarnali Acharyya, a pre-doctoral student in Guttridge’s laboratory.

The researchers found that dystrophin levels were reduced in the muscles of mice with cancer cachexia, and that two DGC proteins were altered. The researchers then showed that cachexia is accelerated in mice that lack dystrophin and develop cancer. Furthermore, they showed that they could prevent cancer wasting in the mice by causing their muscle cells to over-produce dystrophin.

Last, the researchers tested muscle biopsies from 27 patients with gastrointestinal cancers for dystrophin and DGC. Eleven of the patients were confirmed cachectic, and ten of those showed dramatic reductions in dystrophin and significant loss of the DGC.

Overall, Guttridge says, “our evidence strongly suggests that the loss of dystrophin and the DGC are important contributing factors in tumor-induced muscle wasting.”

Other OSU researchers involved in this study were Matthew E. R. Butchback, Zarife Sahenk, Huating Wang, Motoyasu Saji, Michael Carathers, Matthew D. Ringel, Peter Muscarella, Arthur H. M. Burghes and Jill A. Rafael-Fortney.

Funding from the National Cancer Institute and the V Foundation supported this research.