Therapeutic Targets for the Treatment of Cardiac Fibrosis and Cancer: Focusing on TGF-β Signaling

Abstract

Transforming growth factor-β (TGF-β) is a common mediator of cancer progression and fibrosis. Fibrosis can be a significant pathology in multiple organs, including the heart. In this review, we explain how inhibitors of TGF-β signaling can work as antifibrotic therapy. After cardiac injury, profibrotic mediators such as TGF-β, angiotensin II, and endothelin-1 simultaneously activate cardiac fibroblasts, resulting in fibroblast proliferation and migration, deposition of extracellular matrix proteins, and myofibroblast differentiation, which ultimately lead to the development of cardiac fibrosis. The consequences of fibrosis include a wide range of cardiac disorders, including contractile dysfunction, distortion of the cardiac structure, cardiac remodeling, and heart failure. Among various molecular contributors, TGF-β and its signaling pathways which play a major role in carcinogenesis are considered master fibrotic mediators. In fact, recently the inhibition of TGF-β signaling pathways using small molecule inhibitors, antibodies, and gene deletion has shown that the progression of several cancer types was suppressed. Therefore, inhibitors of TGF-β signaling are promising targets for the treatment of tissue fibrosis and cancers. In this review, we discuss the molecular mechanisms of TGF-β in the pathogenesis of cardiac fibrosis and cancer. We will review recent in vitro and in vivo evidence regarding antifibrotic and anticancer actions of TGF-β inhibitors. In addition, we also present available clinical data on therapy based on inhibiting TGF-β signaling for the treatment of cancers and cardiac fibrosis.

Trypanosoma cruzi Induces the PARP1/AP-1 Pathway for Upregulation of Metalloproteinases and Transforming Growth Factor β in Macrophages: Role in Cardiac Fibroblast Differentiation and Fibrosis in Chagas Disease

“…This is because its diverse effects elicit multiple and often opposing cellular responses. In brief, the TGF-β superfamily transduces signal to downstream effectors primarily through the SMAD family of proteins, but it may also activate other signaling cascades, including extracellular signal-regulated kinase (Erk), c-Jun N-terminal kinase (JNK), TGF-β-activated kinase 1 (TAK1), and p38 mitogen-activated protein kinase (MAPK) pathways ( 37 , 38 ). Depending on the time, extent, and types of surface receptors and intracellular signaling cascades engaged, TGF-β may play a crucial role in repression of the inflammatory response and mediate resolution of the inflammatory infiltrate after injuries caused by infectious or genotoxic stimuli ( 9 ).…”

Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge

“…In multiple animal models of cardiomyopathies, including experimental diabetes in rats, tranilast was reported to reduce myocardial fibrosis [ 164 ]. For instance, in streptozotocin-induced diabetic (mRen-2) 27 rats, tranilast attenuated cardiac matrix deposition by reducing phospho-Smad2 levels [ 168 ]. In a similar model, tranilast improved LV systolic and diastolic function without affecting SMAD phosphorylation but attenuated TGF-β-induced p44/42 MAPK phosphorylation [ 168 ].…”

Innate Immunity Effector Cells as Inflammatory Drivers of Cardiac Fibrosis

“…TGF-β has been recognized as a major inducer and regulator of fibrosis in CVDs and cancers [ 55 , 56 , 57 ]. Following induction of inflammatory response, TGF-β acts by increasing the production of ECM components [ 58 , 59 ], together with enhanced mesenchymal cell proliferation, migration, and accumulation [ 60 , 61 ].…”