Tumor factors block muscle repair to cause muscle wasting

A new study reveals that tumors release factors into the bloodstream that inhibit the repair of damaged muscle fibers, and that this contributes to muscle loss during cancer wasting. The condition, also called cancer cachexia, accompanies certain types of cancer, causes life-threatening loss of body weight and lean muscle mass, and is responsible for up to one in four cancer deaths. The condition has no treatment.

The study was led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC–James), and it points to new strategies and new drug targets for treating cancer cachexia. The findings were published in the Journal of Clinical Investigation (2013; doi:10.1172/JCI68523).

The researchers looked at muscle stem cells, which are also called satellite cells. These cells are associated with muscle fibers and are essential for repairing damaged fibers. Normally, damage to muscle fibers causes these stem cells to proliferate and to differentiate into mature muscle cells. These muscle cells then fuse with damaged surrounding fibers to limit muscle wasting. This process is blocked during cancer cachexia, the researchers said.

"Our study showed that although muscle stem cells are activated during cachexia, factors released by the tumor block these cells from differentiating into muscle cells, which leaves them unable to repair cachectic muscle fibers," said principal investigator Denis Guttridge, PhD, of OSUCCC–James.

"By identifying agents that overcome the block and allow muscle stem cells to differentiate, it might be possible to restore muscle mass and enhance the quality of life of cancer patients with cachexia," he said.

For this study, Guttridge and his colleagues used animal models and tissue from cachectic pancreatic-cancer patients to identify factors in the muscle microenvironment that contribute to cancer cachexia. They found that cachexia is associated with tumor-induced damage to skeletal muscle cells and tumor-induced proliferation of muscle stem cells. The muscle stem cell factor, Pax7, is overexpressed, which blocks the cells' ability to differentiate and promotes cancer-induced wasting.

The overexpression of Pax7 promotes cancer wasting by blocking the maturation of muscle cells and their fusion with surrounding fibers, which allows muscle to gain mass. The overexpression of Pax7 is controlled by NF-kappa B (NF-kB), which is known to play multiple roles in cancer. In cachexia, NF-kB causes the deregulation of Pax7 expression, which in turn impairs differentiation of muscle progenitor cells and promotes muscle atrophy. The tissue specificity of Pax7 suggests that inhibiting it might be an attractive therapy for cancer cachexia.

"For decades, studies in cachexia have focused on mechanisms that lead to muscle wasting from within skeletal muscle fibers," Guttridge said. "Our study is the first to show proof of concept that events occurring outside the muscle fiber and within the muscle microenvironment also play a part in driving muscle wasting in cancer.
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