Final Progress Report
Proposal No. IBD-0106
Principal Investigator: Lillian Maggio-Price, V.M.D., Ph.D.
Applicant Organization: University of Washington (Seattle, U.S.A.)
Project Title: Molecular mechanism of colon carcinogenesis: collaborative effects of Helicobacter infection and TGF-β dysregulation
Period of Award: May 1, 2004 – November 30, 2006
Summary of Project Aims
Our laboratory has developed a mouse model in which colon cancer is triggered by bacteria which first induce inflammation, followed by development of invasive cancer in the large bowel. This mutant mouse model (Smad3-knockout mice) has particular relevance to human colon cancer because Smad3-/- mice have a defect in the transforming growth factor-beta (TGFβ) pathway, the most commonly affected cellular pathway in colorectal cancer in humans.
In Aim 1, we proposed to examine how Helicobacter infection synergizes with impairment or dysregulation of the TGFβ pathway to induce colon cancer by altering production of pro-inflammatory cytokines like interleukin-1 and by activating the NF-κB transcriptional program within intestinal epithelial cells. In Aim 2, we proposed to examine whether Smad3-/- lymphocytes, also defective in TGFβď€ signaling, were contributing to the inflammation and cancer.
Accomplishments and significant results
Towards Aim 1, we were able to determine that TGFβ dysregulation in Smad3-/- mice results in a pro-inflammatory phenotype, with upregulation of multiple cytokines and the oncogene, c-myc, and introduction of bacteria exacerbates this inflammatory phenotype during the pre-tumor phase. Results of these studies were published in Cancer Research in 2006 (see Publications). Regarding changes in NF-κB in epithelial cells, we did not make any significant progress. At a research symposium for which I was an invited speaker (IBD Symposium May 2005, Johns Hopkins University, Baltimore, MD), IBD investigators and NIH review group participants were present and there was less enthusiasm for this part of the project.
Towards Aim 2, we have made significant progress. In crossing the Smad3-/- to Rag2-/-mice (Smad3/Rag2-DKO mice), the severity of the inflammation and cancer was greatly increased. This suggested that TGFβ signaling abnormalities in lymphocytes as well as intestinal epithelial cells as well as cells of the innate immune system were playing a role in inflammation-related cancer. These findings are currently being written up for publication (see below). Additionally, there has been interest in this more severe model of inflammation-related cancer and preliminary data from this model was used to obtain funding from the Crohn’s and Colitis Foundation of America (CCFA) to continue these studies. Two additional grants are also pending from the American Institute of Cancer Research (AICR) and a R21 (NCI) in response to a RFA on inflammation and gastrointestinal cancer.
Lay Summary
Patients with inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer. Cancer associated with IBD develops through a sequence of chronic and relapsing inflammation which progresses from hyperplasia to dysplasia and finally to carcinoma. Mouse models of IBD and colon cancer can be useful to understand mechanisms by which inflammation progresses to cancer. Our laboratory has developed a mouse model in which colon cancer is triggered by bacteria which first induce inflammation, followed by development of invasive cancer in the large bowel. This mutant mouse model (Smad3-knockout mice) has particular relevance to human colon cancer because Smad3-knockout mice have a defect in the transforming growth factor-beta (TGFβ) pathway, the most commonly affected cellular pathway in colon cancer in humans. Using Smad3-knockout mice, we were able to determine that TGFβ dysregulation results in a pro-inflammatory state and infection with bacteria exacerbates this inflammatory phenotype during the pre-tumor phase. When we eliminate controls imposed by lymphocytes by breeding Smad3-knockout mice with Rag2-knockout mice, bacterial infection induces a much more severe and extensive inflammation and cancer. Since nearly 20% of the worldwide burden of cancer is known to have an infectious cause, mouse models such as these will be useful to understand the relationship between an infectious microorganism, inflammation and cancer. Understanding these associations will provide opportunities for prevention, early detection and treatment.