Antifibrotic therapy to normalize the tumor microenvironment.

Most tumors develop abnormal fibrotic regions consisting of fibroblasts, immune cells, and a dense extracellular matrix (ECM) immersed in a viscous interstitial fluid, and an abundant fibrotic tumor microenvironment (TME) is associated with poor outcome of treatment. It has been hypothesized that the treatment of cancer may be improved by interventions aiming to normalize this TME. The approaches used in attempts to normalize the fibrotic TME can be categorized into three strategies of targeted antifibrotic therapy: targeting of components of the ECM, targeting of the producers of the ECM components-the activated cancer-associated fibroblasts (CAFs), and targeting of the signaling pathways activating CAFs. To target the ECM, enzymes against components of the ECM have been used, including collagenase, relaxin, hyaluronidase, and lyxyl oxidase. Targeting of CAFs have been investigated by using agents aiming to eliminate or reprogram CAFs. CAFs are activated primarily by transforming growth factor-β (TGF-β), hedgehog, or focal adhesion kinase signaling, and several agents have been used to target these signaling pathways, including angiotensin II receptor I blockers (e.g., losartan) to inhibit the TGF-β pathway. Taken together, these studies have revealed that antifibrotic therapy is a two-edged sword: while some studies suggest enhanced response to treatment after antifibrotic therapy, others suggest that antifibrotic therapy may lead to increased tumor growth, metastasis, and impaired outcome of treatment. There are several possible explanations of these conflicting observations. Most importantly, tumors contain different subpopulations of CAFs, and while some subpopulations may promote tumor growth and metastasis, others may inhibit malignant progression. Furthermore, the outcome of antifibrotic therapy may depend on stage of disease, duration of treatment, treatment-induced activation of alternative profibrotic signaling pathways, and treatment-induced recruitment of tumor-supporting immune cells. Nevertheless, losartan-induced suppression of TGF-β signaling appears to be a particularly promising strategy. Losartan is a widely prescribed antihypertensive drug and highly advantageous therapeutic effects have been observed after losartan treatment of pancreatic cancer. However, improved understanding of the mechanisms governing the development of fibrosis in tumors is needed before safe antifibrotic treatments can be established.