Tumor and Stem Cell Biology Suppressing TGFb Signaling in Regenerating Epithelia in an Inflammatory Microenvironment Is Sufficient to Cause Invasive Intestinal Cancer

Genetic alterations in the TGFb signaling pathway in combination with oncogenic alterations lead to cancer development in the intestines. However, the mechanisms of TGFb signaling suppression in malignant progression of intestinal tumors have not yet been fully understood. We have examined Apc Tgfbr2 compound mutant mice that carry mutations in Apc and Tgfbr2 genes in the intestinal epithelial cells. We found inflammatory microenvironment only in the invasive intestinal adenocarcinomas but not in noninvasive benign polyps of the same mice. We thus treated simple Tgfbr2 mice with dextran sodium sulfate (DSS) that causes ulcerative colitis. Importantly, these Tgfbr2 mice developed invasive colon cancer associated with chronic inflammation.We also found that TGFb signaling is suppressed in human colitis–associated colon cancer cells. In the mouse invasive tumors, macrophages infiltrated and expressed MT1-MMP, causingMMP2activation. These results suggest that inflammatory microenvironment contributes to submucosal invasion of TGFb signaling–repressed epithelial cells through activation of MMP2. We further found that regeneration was impaired in Tgfbr2 mice for intestinal mucosa damaged by DSS treatment or X-ray irradiation, resulting in the expansion of undifferentiated epithelial cell population. Moreover, organoids of intestinal epithelial cells cultured from irradiated Tgfbr2 mice formed "long crypts" in Matrigel, suggesting acquisition of an invasive phenotype into the extracellular matrix. These results, taken together, indicate that a simple genetic alteration in the TGFb signaling pathway in the inflamed and regenerating intestinal mucosa can cause invasive intestinal tumors. Such a mechanism may play a role in the colon carcinogenesis associated with inflammatory bowel disease in humans. Cancer Res; 75(4); 766–76. 2015 AACR.