Colorectal Hyperplasia and Dysplasia Due to Human Carcinoembryonic Antigen (CEA) Family Member Expression in Transgenic Mice

Abstract

CEA and CEACAM6 are immunoglobulin family intercellular adhesion molecules that are up-regulated without structural mutations in approximately 70% of human cancers. Results in in vitro systems showing tumorigenic effects for these molecules suggest that this correlation could indicate an instrumental role in tumorigenesis. To test whether this applies in vivo, transgenic mice harboring 187 kb of the human genome containing four CEA family member genes including the CEA and CEACAM6 genes were created and their copy numbers increased by mating until colonocyte expression levels reached levels seen in human colorectal carcinomas. The colonocyte surface level of integrin α5 and the activation of AKT increased progressively with the expression levels of CEA/CEACAM6. Colonic crypts showed a progressive increase in colonocyte proliferation, an increase in crypt fission, and a strong inhibition of both differentiation and anoikis/apoptosis. All transgenic mice showed massively enlarged colons comprising a continuous mosaic of severe hyperplasia, dysplasia and serrated adenomatous morphology. These results suggest that up-regulated non-mutated adhesion molecules could have a significant instrumental role in human cancer.

Dynamic expression of CEACAM7 in precursor lesions of gastric carcinoma and its prognostic value in combination with CEA

“…Furthermore, CEA may cooperate with CEACAM7 at the GINs stage. Consistent with our results, CEA transgenic mice showed massively enlarged colons comprising a continuous mosaic of severe hyperplasia, dysplasia, and serrated adenomatous morphology, suggesting that up-regulation of CEA could be an instrumental step in human cancer progression [27]. It appears that up-regulation of CEACAM7 or CEA expression may be an early molecular event in tumorigenesis, and both proteins could be used as screening biomarkers in precancerous lesions to identify patients with a high risk of malignant conversion.…”

Adherent-Invasive Escherichia coli Induce Claudin-2 Expression and Barrier Defect in CEABAC10 Mice and Crohnʼs Disease Patients§

“…This can be explained by the observation that the colonic mucosa of CEABAC10 mice exhibit many abnormalities in epithelial appearance, such as hyperproliferation and differentiation blocking in colonic epithelium, which cause a decrease in goblet cell composition. 32 We also hypothesized that CEACAMs molecules, which are intercellular adhesion molecules, may paradoxically weaken adhesion between adult colonocytes by interfering with other adhesion molecules situated between their lateral membranes. This could lead to a disruption of normal pointed by arrows) associated with colonic mucosa (DNA was stained in blue) 5 hours after infection (n ¼ 5/group).…”

Soluble Carcinoembryonic Antigen Activates Endothelial Cells and Tumor Angiogenesis

“…However, in many different cancers, CEA is highly upregulated, but no clear biologic role has emerged so far. Only recently, autocrine CEA signaling in cancer cells was described to inhibit tumor cell differentiation and apoptosis in vitro (10)(11)(12) and in vivo (13). Although CEA is highly released by tumor cells, paracrine effects of soluble CEA have hitherto not been described.…”