COLUMBUS, Ohio – 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. There is no treatment for the condition.
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.
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 say.
"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," says principal investigator Denis Guttridge, PhD, professor of molecular virology, immunology and medical genetics and a member of the OSUCCC – James Molecular Biology and Cancer Genetics Program.
"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 says.
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. Key findings include:
- 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 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;
- Because of its tissue specificity, Pax7 inhibition might offer 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 says. "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."
Funding from the National Institutes of Health(NIH)/National Cancer Institute (grants CA097953, CA098466, CA124692) and the NIH/Center for Clinical and Translational Science (grant UL1TR000090) supported this research.
Other researchers involved in this study were first author Wei He, Jingxin Wang, Mark Bloomston, Peter Muscarella, Peter Nau, Nilay Shah, Matthew E.R. Butchbach and Katherine Ladner, The Ohio State University; Emanuele Berardi, Veronica M. Cardillo, Paola Aulino, Sergio Adamo, Dario Coletti, Sapienza University, Rome, Italy; Swarnali Acharyya, Memorial Sloan Kettering Cancer Center; Jennifer Thomas-Ahner, Federica Montanaro, Nationwide Children's Hospital; Michael A. Rudnicki, Ottawa Health Research Institute, Ottawa, Ontario, Canada; Charles Keller, Oregon Health and Science University.
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only four centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State's cancer program as "exceptional," the highest rating given by NCI survey teams. As the cancer program's 228-bed adult patient-care component, The James is a "Top Hospital" as named by the Leapfrog Group and one of the top cancer hospitals in the nation as ranked by U.S.News & World Report.
Journal
Journal of Clinical Investigation