Scientific Abstract
Proposal No. IBD-0068R
Principal Investigator: Christine Cartwright, M.D.
Applicant Organization: Stanford University (California, U.S.A.)
Project Title: Ulcerative colitis: molecular mechanisms of carcinogenesis
Period of Award: September 1, 2003 - March 31, 2006
Longstanding ulcerative colitis (UC) carries an increased risk of colon cancer. The risk of developing cancer is fifteen-fold higher, and the risk of dying from cancer is five-fold higher than expected in age-matched populations without colitis. Moreover, colon cancer accounts for about one-third of UC deaths. The cancers are thought to arise from areas of dysplasia within the affected region of the colon. However, the precise molecular and cellular basis for UC colon cancer is unclear. Although much is known about molecular events underlying the progression of adenoma to carcinoma in sporadic colon cancer, relatively little is known about these events in the progression of dysplasia to carcinoma in UC.
Activation of the Src tyrosine kinase has been implicated in the genesis of UC colon cancer. Thus, we will analyze mechanisms by which Src is activated in UC colon cancers, and assess the functional consequences on cell growth and transformation. These studies involve downregulating Src activity in UC colon cancer cells, and upregulating Src activity in normal colonic epithelial cells and assessing the functional consequences on tyrosine phosphorylation and activity of Src substrates, downstream signaling events that require Src activation, cell cycle progression, cell transformation and gene expression.
These studies should generate significant new information regarding the influence of an oncogenic tyrosine kinase on the malignant transformation of colonic epithelia in UC.
Understanding how normal colonic cells regulate their growth and how loss of that regulation results in uncontrolled growth and malignant transformation should impact our basic understanding of UC carcinogenesis and lead to development of novel, more selective therapy.