A new study shows that cancer cachexia, which causes life-threatening loss of body weight and lean muscle mass, is caused in part by the tumor factors that block muscle repair, according to the research published in the Journal of Clinical Investigation (2013;123:4821-4835).
“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,” principal investigator Denis Guttridge, PhD, Professor of Molecular Virology, Immunology, and Medical Genetics, and a member of Molecular Biology and Cancer Genetics Program, all at The Ohio State University Comprehensive Cancer Center—Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, said in a news release.
For the study the researchers analyzed animal models and tissue from cachectic pancreatic cancer patients to identify the factor in the muscle microenvironment that contributes to cancer cachexia. Key findings were that:
- Cachexia is associated with tumor-induced damage to skeletal muscle cells and tumor-induced proliferation of muscle stem cells;
- Overexpression of the muscle stem cell factor Pax7 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 the transcription factor NF-kappa B (NF-kB), which has been shown 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; and
- Because of Pax7's tissue specificity, inhibition might be an option for therapeutic approaches.
“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,” Guttridge also noted. “It 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.”
The next step is to use this research to determine the fate of muscle stem cells that are blocked in differentiation and unable to fuse to damaged muscle fibers, Guttridge said via email. “Further cell-based and in vivo studies are need to ascertain whether factors identified in this study that were found to contribute to cachexia can be targeted for therapy.”