Heart Failure Promotes Cancer Progression in an Integrin β1-Dependent Manner

Abstract

Heart failure and cancer are currently the deadliest diseases in the Western world, posing the most pressing clinical challenges that remain unmet today. Both conditions share similar risk factors, including age, genetics, lifestyle, chronic inflammation, stress, and more. Furthermore, medications that are being used to counteract cancer frequently result in cardiotoxicity and the spontaneous emergence of heart failure. Thus, heart failure and cancer display an intimate connection and share similarities. Recent studies show that cardiac remodeling and heart failure promote cancer progression and metastasis. Using three different mouse models for heart failure revealed that the communication between the remodeled heart and the tumor is facilitated through multiple secreted factors. Among these factors, Periostin was consistently found to be elevated in all models and was shown to be required in vitro. Yet, whether Periostin is necessary for tumor promotion in vivo is unknown. Towards this end, we examined tumor promotion in mice lacking Periostin following transverse aortic constriction (TAC). Despite the loss of Periostin, tumor growth was promoted in the TAC-operated mice. This likely occurred due to increased levels of various cytokines and growth factors in Periostin KO mice. Many of these factors are potential ligands of Integrin receptors. Therefore, we next studied the role of Integrin receptors in the tumor-promotion phenotype following heart failure. We generated cancer cells with an Integrin β1 loss of function mutation and examined tumor growth in the presence and absence of heart failure. Integrin β1 KO cancer cells fail to display cardiac-remodeling-dependent tumor-promotion. Interestingly, a previous study showed that renal cell carcinoma cells (Renca) fail to be promoted following a myocardial infarction. Consistently, we show that Renca cells do not respond to secreted factors derived from the failing heart both in vitro and in vivo. Interestingly, Renca cells display low basal mRNA levels of Integrin β1 which may explain the inability of heart failure to promote their growth. The findings may have significant clinical relevance to cardio–oncology patients who suffer from cancers with high levels of Integrin β1. Chemotherapy leading to cardiotoxicity in these patients may generate a vicious cycle with poor prognosis.