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 (K(D) 16 ± 3 nM) and interacts with itself (K(D) 100 ± 17 nM) and more tightly to the IgC-like A(3) domain (K(D) 18 ± 3 nM). Disruption of these molecular associations through the addition of antibodies specific to the CEA N or A(3)B(3) domains, or by adding soluble recombinant forms of the CEA N, A(3) or A(3)B(3) 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 A(3)B(3) 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.

Neisserial Opa Protein–CEACAM Interactions: Competition for Receptors as a Means of Bacterial Invasion and Pathogenesis

“…2 Abul-Wahid and colleagues calculated the affinity of the A 3 soluble IgC-like domain of CEACAM5 to interact with the N-terminal domain with an affinity of 18 nM. 2 The hetero-dimerization of NCCM6 with NCCM8 is 2 μM. 10 NCCM6 forms a homodimer as well, but with a much lower affinity (60 μM).…”

“…1 Related to these various functions, CEACAM dysregulation is often observed in implantation of circulating tumor cells 2 and tumor angiogenesis. 3 Twelve different CEACAM variants have been identified in humans, with differential expression in various cell types.…”

“…5, 6 NCCM is implicated in homotypic and heterotypic interactions. 2, 7–11 Many bacterial pathogens express proteins that interact with NCCMs, especially CEACAM1, 3, 5, and 6. 12–17 Additionally, NCCMs are known to interact specifically with fimbrial structures such as Dr adhesins.…”

Induction of antigen‐specific TH9 immunity accompanied by mast cell activation blocks tumor cell engraftment

“…Ninety percent of all cancer‐related deaths are associated with the occurrence of metastases, with the majority of patients with advanced metastatic cancer given palliative care in the absence of useful curative strategies. Thus, a vaccine strategy designed to induce long term host surveillance to prevent or delay the engraftment of circulating cancer cells, and/or the expansion of micrometastases, would provide an ideal therapy for controlling or limiting relapse in cancer patients …”

“…To address these issues, we recently developed an alternate vaccination approach against CEA that results instead in a focused IgG response towards its IgV‐like N domain and blocks both homotypic (N and A 3 domains of CEA) and heterotypic (fibronectin, ECM) interactions responsible for the implantation of disseminated tumor cells . This novel vaccine strategy was based on the finding that disrupting CEA N domain‐specific interactions with domain‐specific antibodies, aptamers or soluble recombinant CEA N (rCEA N) or A 3 modules reduces the engraftment of CEA‐expressing tumor cells as well as the formation and expansion of tumor foci in vivo . Vaccinating CEA transgenic mice (CEA.Tg) with a recombinant, nonglycosylated form of the CEA Ig V‐like N domain combined with poly I:C, as an adjuvant, led to the production of circulating antibodies exhibiting anti‐adhesive as well as cytocidal properties (ADCC, CDC), which blocked the lodging and formation of CEA‐expressing murine tumor foci in the lungs and peritoneal cavity of vaccinated CEA.Tg mice .…”