Emerging Role and Targeting of Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) in Human Malignancies

Abstract

Background: Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is a member of the CEA family of cell adhesion proteins that belong to the immunoglobulin superfamily. CEACAM6 is normally expressed on the surface of myeloid (CD66c) and epithelial surfaces. Stiochiomertic expression of members of the CEA family (CEACAM1, 5, 6, 7) on epithelia maintains normal tissue architecture through homo-and hetero-philic interactions. Dysregulated over-expression of CEACAM6 is oncogenic, is associated with anoikis resistance and an invasive phenotype mediated by excessive TGFβ, AKT, FAK and SRC signaling in human malignancies. Methods: Extensive literature review through PubMed was conducted to identify relevant preclinical and clinical research publications regarding CEACAM6 over the last decade and was summarized in this manuscript. Results: CEACAM5 and 6 are over-expressed in nearly 70% of epithelial malignancies including colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDA), hepatobiliary, gastric, breast, non-small cell lung and head/neck cancers. Importantly, CEACAM6 is a poor prognostic marker in CRC, while its expression correlates with tumor stage, metastasis and post-operative survival in PDA. CEACAM6 appears to be an immune checkpoint suppressor in hematologic malignancies including acute lymphoblastic leukemia and multiple myeloma. Several therapeutic monoclonal antibodies or antibody fragments targeting CEACAM6 have been designed and developed as a targeted therapy for human malignancies. A Llama antibody targeting CEACAM6 is being evaluated in early phase clinical trials. Conclusion: This review focuses on the role of CEACAM6 in the pathogenesis and signaling of the malignant phenotype in solid and hematologic malignancies and highlights its potential as a therapeutic target for anti-cancer therapy.

EphA2 signaling is impacted by carcinoembryonic antigen cell adhesion molecule 1-L expression in colorectal cancer liver metastasis in a cell context-dependent manner

“…EPHA2 expression acts as a driver of migration and invasion and represents a poor prognostic marker in CRC [ 26 ]. Previous studies have shown that CEA and CEACAM6 are markers of poor outcome and tumor recurrence in several types of cancers including CRC [ 2 , 47 , 48 ]. In addition, plasma-based CEA levels are utilized for surveillance of CRC recurrence and monitoring of disease status [ 49 ].…”

CEACAM6 promotes cisplatin resistance in lung adenocarcinoma and is regulated by microRNA‐146a and microRNA‐26a

“…CEACAM6 is a multifunctional glycoprotein that mediates homotypic binding with other CEA family members and heterotypic binding with integrin receptors, thus activating integrin signaling and its downstream signaling cascades. 11 Aberrant CEACAM6 expression leads to the development of several solid tumors and hematologic malignancies. [12][13][14] Han et al 5 found that positive expression of CEACAM6 was identified in 86.3% (44/51) of the examined LUAD specimens, and patients with high CEACAM6 expression had significantly worse overall survival than those with low expression, according to the immunohistochemical (IHC) staining score.…”

Levels of CEACAM6 in Peripheral Blood Are Elevated in Patients with Plasma Cell Disorders: A Potential New Diagnostic Marker and a New Therapeutic Target?

“…with advanced-stage gastric cancer [18]. Overexpression of CAECAM6 is associated with an aggressive phenotype mediated via TGF β , AKT, FAK, and SRC signaling [19]. In vitro studies have shown the therapeutic potential of an antibody directed against CEACAM6 in lung adenocarcinoma as an adjuvant therapy combined with paclitaxel [10].…”