Lack of thrombospondin‐1 increases tumorigenesis and decreases survival of in a new mouse model of colorectal cancer

Abstract

According to the National Cancer Institute more than 140,000 people will be diagnosed in the United States with colorectal cancer this year alone. The adenomatus polyposis coli (APC) gene is frequently mutated in colorectal cancer, the APC‐min mouse correspondingly is a widely used model for the study of this type of cancer. Yet, intestinal tumors develop predominately in the small intestine reflecting familial adenomatous polyposis rather than colorectal cancer. Studies indicate that the matricellular protein Thrombospondin 1 (TSP1), a key component in modifying inflammatory processes, is lost during the development of colon cancer. To study the role of TSP1 during inflammation driven colorectal carcinogenesis we developed an APC‐min and TSP−/− APC‐min mouse model. A lack of TSP1 increases tumor size and multiplicity predominately in the large intestine of these mice. Our data indicate that expression of TSP1 in the APC‐min mouse prevents the development of adenomas in the large intestine in mice fed a low fat diet. Moreover, TSP−/− APC‐min mice show 50% reduction in survival when compared to TSP+/+APC‐min mice alone (P<0.05). Our in vitro experiments indicate that this difference may be due to TSP1 regulation of pro‐inflammatory mechanisms. Together this data indicates TSP1 regulates progression of colon carcinogenesis and define cellular and molecular targets of TSP1 in the prevention of colorectal cancer.