Inflammation associated cancers and potential therapeutics

Abstract

Inflammation is a major contributing factor in approximately 20% of cancers, and two types of cancer in which inflammation plays a particularly crucial role are mesothelioma and colorectal carcinoma. Both mesothelioma and colon cancer are induced by the production of TNFα. Moreover, these two cancers are both largely driven by inflammation resulting from macrophage activation. Mesothelioma arises from the transformation of mesothelial cells induced by inflammatory mediators secreted during the aberrant activation of macrophages exposed to asbestos particles. Similarly, colorectal cancer involves the transformation of epithelial cells lining the intestine and tumor progression may be driven by inflammation resulting from macrophage activation by commensal bacteria of the gut. The work described in this thesis focuses on mouse models of mesothelioma and colorectal cancer in an attempt to dissect molecular mechanisms that regulate tumor progression and identify possible intervention strategies for each type of cancer. In the case of mesothelioma we investigated intervention with increasing dietary concentrations of selenium in order to see if the increase in antioxidant enzyme activity could aid the anti-cancer immunity. Independent of any effects on anti-cancer immunity, we found that increasing dietary selenium altered the redox status of certain mesothelioma tumors in a manner that increased tumor progression. Select mesothelioma cell lines were identified that were capable of using higher levels of bioavailable selenium to grow more rapidly and this led to increased in vivo tumor progression. In our second project involving colorectal cancer, we focused on calpain enzymes and their endogenous inhibitor, calpastatin. Our earlier work showed that calpastatin is dynamically regulated in the inflammatory activation of macrophages but not in other immune cell-types and that macrophages express calpain-2. This led us to our hypothesis that using a synthetic inhibitor to decrease calpain-2 activity beyond the normal regulation of calpain-2 activity via the endogenous inhibitor calpastatin will protect mice from colitis and inflammation driven colorectal cancer. Calpain-2 inhibitor treatment showed a significant protective effect against colitis and colorectal cancer in the mouse model of colitis and CAC.