Cardiovascular diseases and cancer are the leading cause of death worldwide. The two diseases share high co-prevalence and affect each other’s outcomes. Recent studies suggest that heart failure promotes cancer progression, although the question of whether cardiac remodeling in the absence of cardiac contractile dysfunction promotes cancer progression remains unanswered. Here, we aimed to examine whether mild cardiac remodeling can promote tumor growth. We used low-phenylephrine (PE)-dose-infused in mice, together with breast cancer cells (polyoma middle T, PyMT), implanted in the mammary fat pad. Although cardiac remodeling, hypertrophy and fibrosis gene hallmarks were identified, echocardiography indicated no apparent loss of cardiac function. Nevertheless, in PE-infused mouse models, PyMT-cell-derived tumors grew larger and displayed increased cell proliferation. Consistently, serum derived from PE-infused mice resulted in increased cancer cell proliferation in vitro. ELISA and gene expression analysis identified periostin, fibronectin and CTGF as cardiac- and tumor-secreted factors that are highly abundant in PE-infused mice serum as compared with non-infused mice. Collectively, a low dose of PE infusion without the deterioration of cardiac function is sufficient to promote cancer progression. Hence, early detection and treatment of hypertension in healthy and cancer patients would be beneficial for improved outcomes.

Heart failure and cancer are the deadliest diseases worldwide. Murine models for cardiac remodeling and heart failure demonstrate that cardiac dysfunction promotes cancer progression and metastasis spread. Yet, no information is available on whether and how tumor progression affects cardiac remodeling. Here, we examined cardiac remodeling following transverse aortic constriction (TAC) in the presence or absence of proliferating cancer cells. We show that tumor-bearing mice, of two different cancer cell lines, display reduced cardiac hypertrophy, lower fibrosis and improved cardiac contractile function following pressure overload induced by TAC surgery. Integrative analysis of qRT-PCR, flow cytometry and immunofluorescence identified tumor-dependent M1-to-M2 polarization in the cardiac macrophage population as a mediator of the beneficial tumor effect on the heart. Importantly, tumor-bearing mice lacking functional macrophages fail to improve cardiac function and display sustained fibrosis.

The interplay between heart failure and cancer represents a double-edged sword. Whereas cardiac remodeling promotes cancer progression, tumor growth suppresses cardiac hypertrophy and reduces fibrosis deposition. Whether these two opposing interactions are connected awaits to be determined. In addition, it is not known whether cancer affects solely the heart, or if other organs are affected as well. To explore the dual interaction between heart failure and cancer, we studied the human genetic disease Duchenne Muscular Dystrophy (DMD) using the MDX mouse model. We analyzed fibrosis and cardiac function as well as molecular parameters by multiple methods in the heart, diaphragm, lungs, skeletal muscles, and tumors derived from MDX and control mice. Surprisingly, cardiac dysfunction in MDX mice failed to promote murine cancer cell growth. In contrast, tumor-bearing MDX mice displayed reduced fibrosis in the heart and skeletal and diaphragm muscles, resulting in improved cardiac function. The latter is at least partially mediated via M2 macrophage recruitment to the heart and diaphragm muscles. Collectively, our data support the notion that the effect of heart failure on tumor promotion is independent of the improved cardiac function in tumor-bearing mice. Reduced fibrosis in tumor-bearing MDX mice stems from the suppression of new fibrosis synthesis and the removal of existing fibrosis. These findings offer potential therapeutic strategies for DMD patients, fibrotic diseases, and cardiac dysfunction.

Heart failure and cancer are the leading cause of deaths worldwide. The diseases share common risk factors, survival pathways and death signals. Recent studies suggest that these diseases are highly connected and affect each other outcome. Murine models for cardiac remodeling and heart failure including: myocardial infraction, pressure overload, cardiac hypertrophy, and chronic hypertension promotes cancer progression and metastasis spread. In addition, heart failure patients have increased risk to develop cancer. Nevertheless, no information is available whether and how tumor progression affects cardiac remodeling. Here we examined cardiac remodeling processes in the presence and absence of tumor. We show that tumor-bearing mice display reduced cardiac hypertrophy, lower fibrosis, and improved cardiac contractile function. While the adaptive immune system is not involved, we found that innate immune cells play a major role. We identified that the cardiac macrophage population undergoes tumor dependent M1 to M2 polarization. Importantly, tumor-bearing mice lacking functional macrophages fail to improve cardiac function and display sustained fibrosis. This is the first study showing the double-edged sword interaction between cancer and heart failure. While heart failure promotes tumor growth, cancer improves cardiac outcome. Harnessing cancer paradigms that are involved in the tumor to heart beneficial outcome may provide novel therapeutics strategies for cardiovascular diseases.

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.