Angiotensin Inhibition, TGF-β and EMT in Cancer

SIMPLE SUMMARY: Angiotensin inhibitors are broadly applied in the treatment of renal and cardiovascular diseases. This review aims to show that these drugs have also been beneficial in cancer therapies. Underlying molecular mechanisms are elucidated. Angiotensin signaling and the antifibrotic properties of inhibiting this signaling are discussed in detail. In essence, these antifibrotic effects are due to crosstalk with TGF-β signaling, which is also described in detail. Due to the altered matrix synthesis by cancer associated fibroblasts under these therapies, TGF-β signaling affects more than just the composition of the extracellular matrix itself, extending to cellular behaviors. Beyond the stroma, TGF-β signaling is also of interest in the epithelial mesenchymal transition, which is also covered. ABSTRACT: Angiotensin inhibitors are standard drugs in cardiovascular and renal diseases that have antihypertensive and antifibrotic properties. These drugs also exert their antifibrotic effects in cancer by reducing collagen and hyaluronan deposition in the tumor stroma, thus enhancing drug delivery. Angiotensin II signaling interferes with the secretion of the cytokine TGF-β—a known driver of malignancy. TGF-β stimulates matrix production in cancer-associated fibroblasts, and thus drives desmoplasia. The effect of TGF-β on cancer cells itself is stage-dependent and changes during malignant progression from inhibitory to stimulatory. The intracellular signaling for the TGF-β family can be divided into an SMAD-dependent canonical pathway and an SMAD-independent noncanonical pathway. These capabilities have made TGF-β an interesting target for numerous drug developments. TGF-β is also an inducer of epithelial–mesenchymal transition (EMT). EMT is a highly complex spatiotemporal-limited process controlled by a plethora of factors. EMT is a hallmark of metastatic cancer, and with its reversal, an important step in the metastatic cascade is characterized by a loss of epithelial characteristics and/or the gain of mesenchymal traits.