The carcinoembryonic antigen IgV-like N domain plays a critical role in the implantation of metastatic tumor cells

Abstract

The human carcinoembryonic antigen (CEA) is a cell adhesion molecule involved in both homotypic and heterotypic interactions. The aberrant overexpression of CEA on adenocarcinoma cells correlates with their increased metastatic potential. Yet, the mechanism(s) by which its adhesive properties can lead to the implantation of circulating tumor cells and expansion of metastatic foci remains to be established. In this study, we demonstrate that the IgV-like N terminal domain of CEA directly participates in the implantation of cancer cells through its homotypic and heterotypic binding properties. Specifically, we determined that the recombinant N terminal domain of CEA directly binds to fibronectin (Fn) with a dissociation constant in the nanomolar range (KD 16 ± 3 nM) and interacts with itself (KD 100 ± 17 nM) and more tightly to the IgC-like A3 domain (KD 18 ± 3 nM). Disruption of these molecular associations through the addition of antibodies specific to the CEA N or A3B3 domains, or by adding soluble recombinant forms of the CEA N, A3 or A3B3 domains or a peptide corresponding to residues 108–115 of CEA resulted in the inhibition of CEA-mediated intercellular aggregation and adherence events in vitro. Finally, pretreating CEA-expressing murine colonic carcinoma cells (MC38.CEA) with rCEA N, A3 or A3B3 modules blocked their implantation and the establishment of tumor foci in vivo. Together, these results suggest a new mechanistic insight into how the CEA IgV-like N domain participates in cellular events that can have a macroscopic impact in terms of cancer progression and metastasis.