Targeting Fibrosis to Improve Cancer Outcomes

Abstract

Abstract Scleroderma (SSc) is an idiopathic autoimmune connective tissue disease. The three hallmarks of SSc include 1) vasculopathy resulting in 2) progressive fibrosis or thickening of the skin, lungs, and internal organs and 3) aberrant immune infiltration. Fibrotic pulmonary involvement is the leading cause of death in SSc patients. Recent data from John Hopkins Scleroderma Center have shown a significantly increased risk of lung cancer in SSc patients. However, the mechanisms linking the two diseases are not well understood. Moreover, due to the close temporal relationship between SSc and lung cancer diagnosis, it is unclear whether lung fibrosis precedes tumorigenesis or conversely lung tumorigenesis precedes fibrosis. It has become evident that certain fibrotic diseases can progress towards cancer. Seemingly, non-alcoholic steatohepatitis or HBV/HCV infection-induced liver cirrhosis can progress to hepatocellular carcinoma. Vice versa, many solid tumors are fibrotic, and desmoplasia is referred to the pathological remodeling observed in the tumor microenvironment. There seems to be a tight link between fibrosis and cancer although the directionality of this progression is unknown. Moreover, several fibrotic processes involving the ß-catenin/Wnt, YAP/TAZ and hedgehog pathways in addition to fibrogenic growth factors (TGFß, VEGF, FGF) have been known to drive cancer. We are developing a murine model to study the mechanisms driving fibrosis to cancer progression in the lungs.