ALTERATIONS IN CLASSICAL CADHERINS ASSOCIATED WITH PROGRESSION IN ULCERATIVE AND CROHNS COLITIS

Human colitis is a condition associated with a spectrum of altered mor phologic changes and cellular adhesion. The role of cadherins, which a re powerful morphoregulatory cell adhesion molecules, in colitis is pr ovocative and as yet unknown. Herein, we present results that suggest a strong correlation between the deregulation of two cadherin molecule s, E- and P-cadherins, and the progression of human colitis. We examin ed the expression and structural integrity of E- and P-cadherins in in flamed, dysplastic, or neoplastic human ulcerative colitis (UC) (n = 5 8), human Crohn's colitis (n = 30), and normal tissue (n = 20) to asse ss cadherin function in normal and abnormal epithelium. E-cadherin is strongly expressed in normal colorectal epithelium, whereas in left-si ded UC it is either down-regulated or has a single-base pair mutation in exon 4 resulting in an amino acid alteration (6 of 58 UC cases). By contrast, P-cadherin is dramatically up-regulated in both Crohn's dis ease and ulcerative colitis and especially in dysplastic ulcerative ti ssue. In vitro transfected SW-480 colorectal cells containing E-cadher in mutations identical to those in vivo were associated with increased spontaneous disaggregation compared with cells transfected with wild- type E-cadherin. Based on this evidence, we hypothesize that a small s ubset of colorectal cells expressing mutant E-cadherin are associated with widespread ulceration, whereas those expressing P-cadherin are as sociated with a rapidly dividing immature phenotype that includes dysp lasia. The differential expression of mutated and wild-type cadherins examined herein are associated with a broad spectrum of abnormal epith elial phenotypes, lymphocyte integrin binding, and resistance to denud ation, as is seen in the colitis adenocarcinoma sequence.