Mast cells and inflammation-associated colorectal carcinogenesis

Abstract

Close association between chronic inflammation and cancer has been recently highlighted. Indeed, inflammatory bowel disease (IBD) has been strongly linked with an increased risk of development of colorectal cancer (CRC). Inflammatory cell-produced inflammatory mediators, such as proinflammatory cytokines and inducible enzymes, contribute to this association. In an inflammatory microenvironment, infiltrating macrophages and mast cells mediate production of these inflammatory mediators to promote growth of tumors in target tissues. In contrast to macrophages, contribution of mast cells to CRC development in inflamed colon is not well understood. This study aimed to determine the role of mast cells in inflammation-associated colorectal carcinogenesis. CRC was induced by administration of the colonic carcinogen, azoxymethane (AOM), and the tumor promoter dextran sodium sulfate (DSS) in male mast cell-deficient WBBF(1)-kit (W/W-v) (W/W(v)) and mast cell-normal WBB6F(1)-+/+(WT) mice. At week 12, the W/W(v) mice had markedly lower inflammation scores in the colon when compared with WT mice. The mRNA levels of colonic proinflammatory cytokines and inducible enzymes were also decreased in W/W(V) mice at weeks 12 and 20, when compared with WT counterparts. Colorectal tumors, including CRC, were identified by histopathological analysis performed 20weeks thereafter. Importantly, there were less neoplastic and preneoplastic colonic lesions in the W/W(v) mice compared with the WT mice. Thus, for the first time, our study shows that mice lacking mast cells are less susceptible to inflammation-associated colorectal carcinogenesis. Our findings also suggest that mast cells and their selected cytokines could play an important role in inflammation-mediated tumorigenesis through regulation of proinflammatory cytokines and inducible inflammatory enzymes.