Tumor growth ameliorates cardiac dysfunction and dampens fibrosis in a mouse model for Duchenne Muscular Dystrophy

Abstract

Abstract Heart failure and cancer are known to share common risk factors. Nevertheless, until recently, these two were considered separate diseases. Nevertheless, it appears that heart failure and cancer are more connected than initially anticipated. The interplay between heart failure and cancer represents a double-edged sword. While Cardiac remodeling promotes cancer progression, tumor growth suppresses cardiac hypertrophy and reduces fibrosis deposition. Whether these two opposing interactions are connected is currently unknown. In addition, the experimental setup used was unable to distinguish whether tumor growth suppresses de novo fibrosis synthesis or is capable of dissolving existing fibrosis as well. Here we studied a clinically relevant human disease, Duchenne Muscular Dystrophy (DMD), using MDX mouse as a model for a fibrotic disease in multiple organs. Duchenne patients suffer from fibrosis of the skeletal, cardiac, and diaphragm muscles leading to cardiomyopathy, and respiratory failure with no cure. To study the mutual interaction between heart failure and cancer, we implanted murine cancer cells in MDX mice and monitored tumor growth, cardiac function, and fibrosis. Surprisingly, cardiac dysfunction failed to promote cancer progression in MDX mice. In contrast, MDX tumor-bearing mice displayed reduced fibrosis in the lungs, heart and diaphragm muscles resulting in an improvement of cardiac contractile function. The latter is at least partially mediated via macrophage polarization towards M2 in the heart and diaphragm muscles. Collectively, our data support the notion that tumor promotion due to heart failure is an independent of cardiac dysfunction amelioration by tumor growth. Additionally, these results suggest that the reduced overall fibrosis in tumor-bearing MDX mice represents suppression of de novo fibrosis deposition as well as dissolving existing fibrosis in the heart and diaphragm muscles. Harnessing tumor paradigms may provide novel therapeutic strategies for DMD patients, human fibrotic diseases, and cardiac dysfunction.