Integrins are the largest and most diverse class of adhesion molecules expressed by gastrointestinal epithelial cells. ß1 integrins comprise the most diverse subclass of integrins expressed by gastrointestinal epithelial cells, and, integrin expression is specifically lost during colorectal tumorigenesis.

In order to understand the roles of integrins in gastrointestinal cancers, one must first understand their roles in normal gastrointestinal epithelial biology. The study of the mechanism(s) by which ß1 integrins regulate epithelial proliferation in vivo is limited, so we have utilized the Cre-lox genetic system in mice to conditionally delete ß1 integrins in the intestinal epithelial cells. ß1 integrin homodimerizes with several alpha integrins to form cell surface receptors that bind to collagens, fibronectin, laminins, and vitronectin, which are principal constituents of the intestinal basement membrane. Conditional deletion of ß1 integrins in the intestinal epithelium causes epithelial hyperproliferation, dysplasia, polyp formation, and, stromal expansion-features in common with intestinal tumors. The mice die shortly after birth due to severe malnutrition from defective epithelial cell differentiation. Surprisingly, deletion of ß1 integrins had no effects on intestinal epithelial anchorage or survival. We have found that aberrant activation of Wnt signaling is responsible for the disruption of intestinal homeostasis in these mice. Further studies have shown that Wnt signaling in the normal intestinal epithelium is regulated by stromal-dependent Hedgehog signaling.

We are currently utilizing in vivo genetic mouse models and in vitro co-culture systems to understand the dynamic epithelial-stromal crosstalk mediated by ß1 integrins.