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Defects in the adenomatous polyposis coli (APC) tumor suppressor pathway are sufficient for neoplastic transformation as the initiating step in colorectal carcinogenesis. In contrast, hyperplastic tumors possess normal APC function, and it is unclear whether they represent significant precursor lesion in cancer development. CEACAM1 is a tumor suppressor whose expression is known to be lost in the great majority of early adenomas and carcinomas. We found that loss of CEACAM1 expression is more common in neoplastic tumors than APC mutations. While APC function was normal in hyperplastic aberrant cypt foci and hyperplastic polyps, loss of CEACAM1 was observed as frequently as in the neoplasias. Moreover, the presence or absence of CEACAM1 expression in the hyperplastic tumors correlates with normal or reduced apoptosis, respectively. In vitro, CEACAM1 acts as a regulator of apoptosis in CEACAM1-transfected Jurkat cells. Finally, in human HT29 colon cancer cells, apoptosis can be specifically restored by induction of CEACAM1 expression. These data suggest an oncodevelopmental link between neoplasia and hyperplasia and demonstrate that CEACAM1 acts as a regulator of apoptosis in the colonic epithelium. Thus, failure of the maturing colon cell to express CEACAM1 is likely to contribute to the development of hyperplastic lesions, which may eventually pave the way to neoplastic transformation and colon cancer development.

CD66a, also known as 'biliary glycoprotein (BGP)', is the human homologue of a cell adhesion molecule (CAM) of the rat (Cell-CAM). CD66a, which belongs to the carcinoembryonic antigen family and the immunoglobulin superfamily, is expressed in cells of myeloid and epithelial origin. The cytoplasmic domain of the major isoform of CD66a (CD66acyt) contains two tyrosine residues in amino acid motifs potentially interacting with protein tyrosine kinases of the Src family. Here we provide evidence that CD66a is associated with pp60c-src. From membrane fractions of granulocytes and the colonic cell line HT29, phosphokinase activity was co-immunoprecipitated with CD66a when monoclonal CD66 antibodies or an antiserum against the recombinant cytoplasmic domain of CD66a were used. From the dissociated immunecomplexes, a phosphokinase of M(r) 60,000 was reprecipitated using antibodies against pp60c-src. In vitro, the recombinant cytoplasmic domain was a substrate and binding partner of pp60c-src. Phosphopeptides corresponding to the tyrosine containing amino acid sequences of CD66acyt activated the kinase activity of pp60c-src to a greater extent than a phosphopeptide containing Tyr527 from the SH2-binding regulatory domain of pp60c-src. The down-regulation of CD66a in about 80% of colorectal carcinomas may contribute to a dysregulation of pp60c-src in colorectal cancer.