Carcinoembryonic antigen-related cell adhesion molecule 1 in cancer: Blessing or curse?

Abstract

The Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, also CD66a), a transmembrane glycoprotein of the immunoglobulin superfamily, is a pivotal mediator of various physiological and pathological processes, including oncologic disorders. However, its precise role in tumorigenicity is contradictory discussed by several clinical studies. This review aims to elucidate the clinical significance of CEACAM1 in different cancer entities focusing on tumour formation, progression and metastasis as well as on CEACAM1-mediated treatment resistance. Furthermore, we discuss the contribution of CEACAM1 to cancer immunity and modulation of the inflammatory microenvironment and finally provide a comprehensive review of treatment regimens targeting this molecule.

Keywords: CD66a; CEACAM1; cancer; inflammation; tumorigenicity; tumour microenvironment.

FIGURE 1

Alternative splicing of human CEACAM1 yields 12 isoforms with distinct protein structures. Each CEACAM1 isoform is characterised by variations in the number of extracellular Ig‐like domains, transmembrane regions, and the length of the cytoplasmic tail. They include combinations with four extracellular Ig‐like domains (N, A1, B and A2), three domains (N, A and B), or one domain (N), alongside variations in cytoplasmic tail lengths designated as long (L) and short (S). The long tail isoforms (L) contain immunoreceptor tyrosine‐based inhibitory motifs (ITIMs) critical for intracellular signalling, while the short tail isoforms (S) lack these motifs. Soluble CEACAM1 isoforms (3, 3C2 and 4C1) miss the transmembrane and cytoplasmic domains and are secreted into the extracellular environment. CEACAM1‐4L and CEACAM1‐4S are the most commonly expressed isoforms playing crucial roles in immune response, cell signalling and intercellular adhesion.

FIGURE 2

Multifaceted role of CEACAM1 in tumorigenesis and cancer progression. In cancer cells, upregulation of CEACAM1 promotes several key processes of tumorigenesis and cancer progression, that is epithelial‐to‐mesenchymal transition (EMT), proliferation, invasion, metastasis, chemoresistance and inflammation. CEACAM1‐dependent signalling is mainly determined by the expression ratio of the long (L) and short (S) isoforms, which differentially mediate the binding of SHP phosphatases or SFK kinases by specific dimer formations. Further it facilitates immune evasion by suppression of the anti‐tumour activity of T cells and NK cells. CEACAM1 interactions either impair T cell function through trans or cis ligation with TIM3 or CEACAM6, or directly inhibit cytotoxic NKG2D receptors on NK cells. CEACAM1 also contributes to tumour vascularization by enhancing endothelial cell migration and blood vessel formation, supporting tumour growth. This process potentially involves interactions between CEACAM1 on endothelial and tumour cells, though this mechanism requires further investigation.