Tumor Growth Ameliorates Cardiac Dysfunction

Abstract

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.

Cardioprotection and Suppression of Fibrosis by Diverse Cancer and Non-Cancer Cell Lines in a Murine Model of Duchenne Muscular Dystrophy

“…One such disease is DMD, an X-linked genetic disease, that involves fibrosis in cardiac, diaphragm, and skeletal muscles [20]. While recent studies have shown that injecting two aggressive murine cancers (PyMT and LLC cell line) reduces cardiac hypertrophy and fibrosis and enhances cardiac function in multiple mouse models [2,3,5], it was not addressed whether the aggressiveness and nature of cancer types impacted this improvement.…”

“…Fibrotic diseases contribute to approximately half of the mortality rate in developed countries and present an unresolved clinical need [1]. In recent studies, we demonstrated that injecting two different murine cancer cell lines representing breast and lung cancer resulted in the amelioration of cardiac dysfunction, reduced cardiac hypertrophy, and lower cardiac fibrosis, in a pressure overload [2] and transgenic mouse model for heart hypertrophy [3]. To further establish the suppression of fibrosis in other organs as well, we used the MDX mouse model for Duchenne muscular dystrophy (DMD).…”

“…Cancer cell line implantation led to decreased fibrosis in the skeletal, heart, and diaphragm muscles of MDX mice, thereby leading to improved cardiac function [5]. This phenomenon was partially mediated by altered gene expression in the heart and other organs [2,5]. These findings were established using aggressive cell lines: Polyoma Middle T (PyMT) and Lewis lung carcinoma (LLC).…”

Tumor Progression Reverses Cardiac Hypertrophy and Fibrosis in a Tetracycline-Regulated ATF3 Transgenic Mouse Model

“…While the effect of HF on cancer progression is well defined, less is known about the opposite direction, namely, tumors’ effect on cardiac dysfunction. A case in point is a recently published study that demonstrated that cancer cell growth of either breast or lung cancer ameliorates cardiac dysfunction and suppresses remodeling processes following pressure overload induced by Transverse Aortic Constriction (TAC) surgery [ 12 ]. Tumor-bearing mice showed an enhanced cardiac contractility function, and a decrease in cardiac hypertrophy and fibrosis levels.…”

“…Tumor-bearing mice showed an enhanced cardiac contractility function, and a decrease in cardiac hypertrophy and fibrosis levels. This phenotype was shown to be mediated by the involvement of the innate immune system and more specifically an M2 macrophage switch in the heart [ 12 , 13 ]. The TAC model involves a major surgical intervention that may have side effects.…”