The primary goal of Project 8 is to improve the estimation of prognosis of human colorectal carcinoma through the use of biologically defined markers. Conventional clinicopathologic staging provides imprecise estimates of prognosis. Our hypothesis is that molecules involved in differentiation, tissue invasion, or cell adhesion within primary colon or rectal carCinomas are associated with the development of visceral metastases. Thus, we will study the intratumoral expression of molecules whose potential as markers has been demonstrated in pilot studies in Projects I - V. We will assess whether these markers improve the prognostication of colorectal carcinoma when included in a multivariate analysis with standard stage and grade information. Our group has demonstrated that the disaccharidase sucrase-isomaltase (S-I), the galactose-binding lectin galactin 3, and the MUC1 mucin DF3 are upregulated at different times during the neoplastic transformation of bowel epithelium. We have also found that S-I expression is an independent indicator of poor prognosis in a series of 162 stage I-III colon and rectal carcinomas operated upon between 1965 and 1977. We and others have found that CD44 isoforms are upregulated during neoplastic transformation and participate in the adhesion of colorectal carcinomas to hepatic endothelial cells and basement membrane proteins. Thus, we propose to study the following specific aims: l) to study whether potential tumor markers (specific CD44 isoforms, TC-1, TC-3 (Project IV), E-cadherin, alpha6beta4 integrin, alpha-catenin (Project I)) are independent prognostic factors in primary colorectal cancer patients operated on between 1965 and 1977 at the New England Deaconess Hospital; 2) to determine whether markers that are significant prognostic factors in Aim 1, including S-I, are independent covariates in a multivariate analysis with stage and grade variables in patients prospectively accrued between 1985 and the present; 3) to determine whether interactions among the expression of tumor markers identify subsets of patients with significantly altered outcome. Thus, we will test the biological function of the CD44 cell adhesion molecule and continue to develop tumor markers that complement standard clinicopathologic staging in colorectal carcinoma. Our intention is to develop and """"""""pilot"""""""" candidate markers that may be suitable for use in clinical practice.
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