| Human carcinoembryonic antigen (CEA) and the related CEA family member nonspecific cross-reacting antigen (NCA), function in vitro as intercellular adhesion molecules. Changes in the expression pattern of CEA and NCA in a wide variety of cancerous tissues has raised the possibility that they could contribute to neoplastic and malignant transformation by influencing tissue architecture and differentiation. This study revisits the expression pattern of CEA and NCA in colorectal tumorigenesis by emphasizing the accurate quantitation of cell-surface levels in the context of tissue architecture. FACSRTM analysis of highly purified tumor versus normal colonic epithelial cell suspensions, revealed dramatically higher levels of cell-surface associated CEA and NCA in tumor cells that was inversely correlated with histologic differentiation. Furthermore, a marked tendency towards delocalized expression and a multilayered tissue architecture was noted in less differentiated tumors. Increased levels of call-surface CEA and/or NCA (CEA/NCA) in colonocytes capable of differentiation was directly tested for effects on tissue architecture and differentiation with established in vitro assays and a novel in vivo colonic tissue architecture assay developed and presented as part of this thesis. The results demonstrate that overexpression of CEA/NCA on the surface of colonocytes can prevent cellular polarization, disrupt colonic tissue architecture and block differentiation both in vitro and in vivo. |
