A tumorigenic role for human glycophosphatidyl inositol-anchored carcinoembryonic antigen family members CEA and CEACAM6 in vivo /

Human carcinoembryonic antigen (CEA), a well-known clinical tumor marker, belongs to the CEACAM family of cell surface intercellular adhesion molecules that represent a subset of the immunoglobulin superfamily. The glycophosphatidyl inositol-anchored family members, CEA and CEACAM6, are over-expressed in as many as 70% of all human cancers. This correlation suggested their role in tumor progression, which was supported by extensive results obtained with several systems in vitro and ex vivo. But their contribution and relevance in vivo remains uncertain without further validation. Since mice do not possess homologs of the CEA and CEACAM6 genes, transgenic mice harboring a 187 kb portion of the human CEACAM family gene locus contained in a bacterial artificial chromosome (CEABAC) that includes CEA, CEACAM3, CEACAM6, and CEACAM7 genes were constructed in this study. The spatiotemporal expression pattern of these genes is very similar to that in humans. The expression levels of these genes are gene dosage dependent. Moreover, these CEABAC mice are more susceptible to develop carcinogen-induced colon tumors and spontaneous lung tumors. At low to moderate expression levels of CEA/CEACAM6, a partial block in cell differentiation and a mild to moderate hyperproliferation were evident in the transgenic colon; however, these mice develop normally. At higher or tumor-like expression levels, a complete block in cell differentiation, an extreme hyperproliferation and an inhibition of apoptosis were observed. These mice showed reduced survival, growth retardation and chronic diarrhea, and showed massively enlarged colons comprising continuous non-focal cytological and architectural abnormalities, including a dysplastic and serrated adenomatous morphology, by only 3 months of age. These results suggested that, while moderate expression levels of CEA/CEACAM6 cause an imbalance of tissue homeostasis leading to increased tumor susceptibility, tumor-like ex