Lay Summary
Proposal No. IBD-0230R2
Principal Investigator: JeanMarie Houghton, M.D., Ph.D.
Applicant Organization: University of Massachusetts Medical School (Boston, U.S.A.)
Project Title: Investigation of bone marrow derived stem cell recruitment to the colon in inflammatory bowel disease; direct and indirect role in carcinogenesis
Period of Award: July 1, 2008 – December 31, 2010
Inflammatory bowel disease is an idiopathic inflammatory condition characterized by dysregulation of the host immune response. However, the factors responsible for initiation and sustaining the inappropriate immune response remain unknown. It is also not clear how this abnormal response leads to colon cancer, one of the most serious complications of IBD. Sporadic colorectal cancer typically arises in older patients and has a long lag time (5-10 years) where a neoplastic polyp progresses through stages of dysplasia to invasive cancer. The genetic alterations that occur as a polyp progresses to invasive cancer are fairly well defined. In contrast, colorectal cancer arising in the setting of IBD typically arises in younger patients and appears to have a much more rapid progression. Neoplasia initiates in flat areas of the mucosa, where it is often visually missed on screening exams. The progression of genetic alterations is also very different between sporadic and IBD related colorectal cancer supporting the notion that the etiology and possibly the initiating cell type are different between these two forms of colon cancer. Chronic inflammation is a stimulus for the migration of bone marrow derived cells (BMDC) into the gastrointestinal tract. Work from our laboratory has shown that in a mouse model of gastric inflammation, BMDC home to the stomach, engraft and transdifferentiate as gastric mucosal cells. Over time, these cells become dysplastic and progress to adenocarcinoma. BMDC also contribute to stromal or support cells of the tumor, providing growth signals to the malignant cells. In a mouse model of inflammatory bowel disease, BMDC home to the colon and small bowel to participate in repair of damaged mucosa, forming the myofibroblast network of cells surrounding regenerating crypts. It is not known what the long term fate of these cells are, or the ramifications of recruiting damaged MSC to an area of continued growth and proliferation. Long-term studies have not been carried out to address the contribution of BMDC to cancer formation in the colon, and will be addressed in this proposal. Using a series of animal models of colitis combined with a novel trackable mesenchymal stem cell (MSC) line our laboratory has isolated, we will test the hypothesize that BMDC (specifically MSC) that migrate to the colon during inflammation contribute to cancer formation directly and indirectly through differentiation as stromal cells. During repair, the myofibroblast pool is replaced by cells derived from the bone marrow, placing these cells in close proximity to the epithelium, allowing cell signaling and cellular crosstalk. Understanding the role BMDCs in colitis and colitis associated colon cancer may provide novel targets for control of colitis, and prevention of colon cancer.