Activated fibroblasts in cardiac and cancer fibrosis: An overview of analogies and new potential therapeutic options

Heart disease and cancer are two major causes of morbidity and mortality in the industrialized countries, and their increasingly recognized connections are shifting the focus from single disease studies to an interdisciplinary approach. Fibroblast-mediated intercellular crosstalk is critically involved in the evolution of both pathologies. In healthy myocardium and in non-cancerous conditions, resident fibroblasts are the main cell source for synthesis of the extracellular matrix (ECM) and important sentinels of tissue integrity. In the setting of myocardial disease or cancer, quiescent fibroblasts activate, respectively, into myofibroblasts (myoFbs) and cancerassociated fibroblasts (CAFs), characterized by increased production of contractile proteins, and by a highly proliferative and secretory phenotype. Although the initial activation of myoFbs/CAFs is an adaptive process to repair the damaged tissue, massive deposition of ECM proteins leads to maladaptive cardiac or cancer fibrosis, a recognized marker of adverse outcome. A better understanding of the key mechanisms orchestrating fibroblast hyperactivity may help developing innovative therapeutic options to restrain myocardial or tumor stiffness and improve patient prognosis. Albeit still unappreciated, the dynamic transition of myocardial and tumor fibroblasts into myoFbs and CAFs shares several common triggers and signaling pathways relevant to TGF-& beta; dependent cascade, metabolic reprogramming, mechanotransduction, secretory properties, and epigenetic regulation, which might lay the foundation for future antifibrotic intervention. Therefore, the aim of this review is to highlight emerging analogies in the molecular signature underlying myoFbs and CAFs activation with the purpose of identifying novel prognostic/diagnostic biomarkers, and to elucidate the potential of drug repositioning strategies to mitigate cardiac/cancer fibrosis.