Abstract
Tyrosine kinase inhibitors, affecting angiogenesis, have shown therapeutic efficacy in renal cell carcinoma (RCC). The increased overall survival is not fully explained by their anti-tumor activity, since these drugs frequently induce disease stabilization rather than regression. RCC patients frequently develop cachectic syndrome. We used the RXF393 human renal carcinoma xenograft that recapitulates the characteristics of the disease, including the growth in the mouse kidney (orthotopic implantation), and the induction of cachexia with subsequent premature death. Sunitinib prevents body weight loss and muscle wasting and significantly improves the survival of RXF393-bearing nude mice. The anti-cachectic effect was not associated to direct anti-tumor activity of the drug. Most relevant is the ability of sunitinib to reverse the cachectic phenotype and rescue the animals from the loss of fat tissue. Body weight loss is prevented also in mice bearing the C26 colon carcinoma, classically reported to induce cachexia in immunocompetent mice. Among the mechanisms, we herein show that sunitinib is able to restrain the overactivation of STAT3 and MuRF-1 pathways, involved in enhanced muscle protein catabolism during cancer cachexia. We suggest that off-target effects of angiogenesis inhibitors targeting STAT3 are worth considering as a therapeutic option for patients who develop cachexia, independently of their anti-tumor activity.
Highlights
Cachexia is a dramatic wasting syndrome associated with several chronic diseases, including cancer, and primarily involves loss of muscle mass [1]
We show that mice bearing renal cell carcinoma (RCC)-derived RXF393 develop cachexia, which is prevented and/or reversed upon treatment with sunitinib, resulting in increased survival
All the RXF393-bearing mice treated with vehicle developed cachexia (BWL > 20%) and ought to be killed within 23 days after tumor transplantation (Fig.1C, middle), whereas the overall survival of sunitinib-treated mice was significantly higher (MST 51 days; increment of life span (ILS) 250%) (Fig.1C, right) and, surprisingly, the tumor reached the maximal ethically accepted weight (< 2000mg) without causing cachexia
Summary
Cachexia is a dramatic wasting syndrome associated with several chronic diseases, including cancer, and primarily involves loss of muscle mass [1]. Cancer cachexia affects up to 80% of cancer patients and causes reduced physical function, low tolerance to anti-cancer therapy and shorter survival [1, 2]. Muscle wasting results from excess of protein catabolism over synthesis and during cancer it is triggered by increased levels of proinflammatory cytokines [3, 4]. Given the complexity of this syndrome, progress in the treatment of cancer cachexia has been slow. Cancer cachexia is an important unmet medical need for which multimodal management is www.impactjournals.com/oncotarget normally aimed at the best supportive care [5, 6]. Patients afflicted by renal cell carcinoma (RCC)
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