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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


The CEACAM Gene Superfamily. The CEACAM immunoglobulin-like domain superfamily are a large family of proteins encoded by 12 independent genes on chromosome 19q13.1-13.2 consisting of membrane-linked glycoproteins that are anchored to the cell surface either by glycophosphatidyl-inositol (GPI) anchor or a trans-membrane domain, and secretory glycoproteins. These glycosylated proteins show a complex stoichiometric expression pattern in normal versus cancerous tissue. The GPI-anchored members of the family include CEACAM5, CEACAM6, CEACAM7 and CEACAM8. CEACAM1, CEACAM3, CEACAM4, CEACAM19, CEACAM20, and CEACAM21 are all anchored to the cell membrane through trans-membrane domains.
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Figure 1: The CEACAM Gene Superfamily. The CEACAM immunoglobulin-like domain superfamily are a large family of proteins encoded by 12 independent genes on chromosome 19q13.1-13.2 consisting of membrane-linked glycoproteins that are anchored to the cell surface either by glycophosphatidyl-inositol (GPI) anchor or a trans-membrane domain, and secretory glycoproteins. These glycosylated proteins show a complex stoichiometric expression pattern in normal versus cancerous tissue. The GPI-anchored members of the family include CEACAM5, CEACAM6, CEACAM7 and CEACAM8. CEACAM1, CEACAM3, CEACAM4, CEACAM19, CEACAM20, and CEACAM21 are all anchored to the cell membrane through trans-membrane domains.

Mentions: The carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) are a large family of proteins in humans that are encoded by 12 independent genes on chromosome 19q13.1-13.2 (Fig. 1). CEACAMs are known to be highly glycosylated proteins that belong to members of the immunoglobulin (Ig) supergene family and are composed of an N domain (aside from CEACAM16) [1]. Each N domain is subsequently followed by zero or as many as six constant C2-like Ig domains, referred to as A or B [2]. The CEACAM family consists of membrane-linked glycoproteins anchored to the cell surface either by glycophosphatidyl-inositol (GPI) anchor or a transmembrane domain, as well as secretory glycoproteins [3]. The GPI-anchored members of the family include CEACAM5, CEACAM6, CEACAM7 and CEACAM8 [4]. CEACAM1, CEACAM3, CEACAM4, CEACAM19, CEACAM20, and CEACAM21 are all anchored to the cell membrane through transmembrane domains. CEACAMs manifest their function as an intercellular adhesion molecule via GPI anchorage to the cell surface or transmembrane domains.


Emerging Role and Targeting of Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) in Human Malignancies
The CEACAM Gene Superfamily. The CEACAM immunoglobulin-like domain superfamily are a large family of proteins encoded by 12 independent genes on chromosome 19q13.1-13.2 consisting of membrane-linked glycoproteins that are anchored to the cell surface either by glycophosphatidyl-inositol (GPI) anchor or a trans-membrane domain, and secretory glycoproteins. These glycosylated proteins show a complex stoichiometric expression pattern in normal versus cancerous tissue. The GPI-anchored members of the family include CEACAM5, CEACAM6, CEACAM7 and CEACAM8. CEACAM1, CEACAM3, CEACAM4, CEACAM19, CEACAM20, and CEACAM21 are all anchored to the cell membrane through trans-membrane domains.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4997943&req=5

Figure 1: The CEACAM Gene Superfamily. The CEACAM immunoglobulin-like domain superfamily are a large family of proteins encoded by 12 independent genes on chromosome 19q13.1-13.2 consisting of membrane-linked glycoproteins that are anchored to the cell surface either by glycophosphatidyl-inositol (GPI) anchor or a trans-membrane domain, and secretory glycoproteins. These glycosylated proteins show a complex stoichiometric expression pattern in normal versus cancerous tissue. The GPI-anchored members of the family include CEACAM5, CEACAM6, CEACAM7 and CEACAM8. CEACAM1, CEACAM3, CEACAM4, CEACAM19, CEACAM20, and CEACAM21 are all anchored to the cell membrane through trans-membrane domains.
Mentions: The carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) are a large family of proteins in humans that are encoded by 12 independent genes on chromosome 19q13.1-13.2 (Fig. 1). CEACAMs are known to be highly glycosylated proteins that belong to members of the immunoglobulin (Ig) supergene family and are composed of an N domain (aside from CEACAM16) [1]. Each N domain is subsequently followed by zero or as many as six constant C2-like Ig domains, referred to as A or B [2]. The CEACAM family consists of membrane-linked glycoproteins anchored to the cell surface either by glycophosphatidyl-inositol (GPI) anchor or a transmembrane domain, as well as secretory glycoproteins [3]. The GPI-anchored members of the family include CEACAM5, CEACAM6, CEACAM7 and CEACAM8 [4]. CEACAM1, CEACAM3, CEACAM4, CEACAM19, CEACAM20, and CEACAM21 are all anchored to the cell membrane through transmembrane domains. CEACAMs manifest their function as an intercellular adhesion molecule via GPI anchorage to the cell surface or transmembrane domains.

View Article: PubMed Central - PubMed

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.

No MeSH data available.