Non-polypoid (flat) colorectal neoplasms account for as many as two-thirds of all colorectal lesions in patients with inflammatory bowel disease (IBD), a high risk factor for the development of colorectal cancer (CRC), namely, colitis-associated colon cancer (CAC). Flat lesions are five times more likely than polypoid lesions to progress to invasive colorectal adenocarcinoma, in part because they are more difficult to detect and completely remove. Thus, identifying the molecular pathways responsible for determining whether tumors become flat or polypoid may provide valuable insight into cancer prevention and/or treatment. Previous studies suggest that the timing of p53 alterations in colorectal cancer development determine whether the tumors are flat or polypoid, and our recent studies suggest that the transcription factor STAT2 may be an essential molecule in the development of flat colorectal adenomas. Thus, we propose to test the hypothesis that STAT2 contributes to the preferential development of flat non-polypoid as opposed to polypoid colorectal tumors following p53 inactivation. We plan to address this by performing the following central aim: Determine the role of STAT2 in the development of flat non-polypoid colorectal tumors in the setting of p53 inactivation to address two important questions: 1) does colonic epithelial cell intrinsic STAT2 signaling play a role in the formation of flat non-polypoid tumors?, and 2) does STAT2 activate and sustain a pro-inflammatory microenvironment conducive to the preferential development of flat non-polypoid colorectal tumors when p53 is inactivated in the colonic epithelium? To investigate the effect of STAT2 in the development of flat non-polypoid lesions, we will employ the well-established dextran sulfate sodium (DSS)-induced colitis model using conditional p53 and Stat2 knockout mice and conventional Stat2 knockout mice. With this model, we are in a unique position to monitor disease development and progression. Significance: Our findings will provide crucial information on the initial cellular transformation events that give rise to flat non-polypoid colorectal tumors, which are more likely to become cancer under conditions of p53 inactivation; a major gap in knowledge to which we still understand very little. Hence defining the role of STAT2 in the development of flat colonic tumors is key in the identification of tumor biomarkers as predictive tools for cancer prevention and development of novel targeted therapies.
Statement It is estimated that in 2016 colorectal cancer will claim the lives of approximately 50,000 people in the United States alone. Our knowledge of the genetic and molecular alterations that cause colorectal tumor development remains far from complete. Our project will investigate the role of the transcription factor STAT2 in the preferential development of non-polypoid colorectal neoplasms (flat lesions), which are often missed during routine colonoscopy and are more prone to develop into cancer than polypoid shaped intestinal lesions. This resulting information will be of great utility to understand the molecular basis in the formation of colorectal tumors that originated from lesions with flat morphology that are more aggressive and their response to therapeutic interventions.
