Cancer cachexia is a life-threatening syndrome characterized by severe body weight loss, due to depletion of adipose tissue and skeletal muscle, and affects up to 80% of patients with advanced cancers. The rapid loss of muscle mass is the main cause of function impairment, fatigue and respiratory complications, leading to death in 20-48% of cases. To date, no effective treatment is available. By using Ingenuity Pathways Analysis software, I have analyzed the cancer cachexia-specific genes, found previously by others, and discovered a specific signaling pathway altered in muscles of cachectic rats. By over-expressing and repressing genes of this pathway in in vitro (adenoviral infection of myotubes) and in vivo (muscle electroporation of plasmids in mice) approaches, I will dissect the role of this signaling cascade during cachexia. Since agonists and antagonists for this pathway are already available, they will be also tested for their possible protective effects against cancer cachexia. Physical activity extends life span of cancer patients and correlates with lower incidence of many cancers but its modes of action are still unclear. The concept that muscle is an endocrine organ able to release molecules (myokines) is quiet new and opens exciting fields to explore. Interestingly, the unique resistance of muscle to cancer and metastasis makes reasonable that anti-cancer myokines may exist. Their secretion especially during physical activity could explain why exercise protects from cancers and retards its progression. So, I propose to search for novel anti-cancer molecules from exercised muscles by taking advantage of adenoviral infection of myotubes to express molecules able to mimic some of the effects of (strength or endurance) exercise. The isolation of anti-cancer myokines may greatly help cancer patients, especially those that cannot exercise, and may clarify which type of exercise (i.e. strength and/or endurance) could be more beneficial for cancer patients.
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