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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.


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CEACAM6 Signaling Pathway. Over-expression of CEACAM6 results in alteration and reorganization of the ECM and activation of the TME playing a key role in tumor invasion. CEACAM6 signaling increases SRC activity leading to increased IGF-I secretion with autocrine and paracrine stimulation of the IGF-1R activating the PI3K/AKT pathway. Increased IGF-I expression results in MMP-2 elaboration, subsequently altering the ECM promoting a malignant TME. Aggregation of CEACAM6 at the cell surface enhances anoikis resistance through activation of SRC in a caveolin-1-dependent manner allowing for phosphorylation of its substrate focal adhesion kinase (FAK). TGF-β elaborated in the TME binds to the type II receptor (TβRII), promoting hetero-tetramerization with the type I receptor (TβRI) increasing the phosphorylation of SMAD3 by activated TβRI. Phosphorylated SMAD3 forms a complex with Co-Smad (SD4), which translocates into the nucleus to bind gene promoters and activate expression of target genes, specifically CEACAM6. Also, TGF-β signals through the TGF-β receptors to activate alternate pathways such as AKT/PI3K.
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Figure 2: CEACAM6 Signaling Pathway. Over-expression of CEACAM6 results in alteration and reorganization of the ECM and activation of the TME playing a key role in tumor invasion. CEACAM6 signaling increases SRC activity leading to increased IGF-I secretion with autocrine and paracrine stimulation of the IGF-1R activating the PI3K/AKT pathway. Increased IGF-I expression results in MMP-2 elaboration, subsequently altering the ECM promoting a malignant TME. Aggregation of CEACAM6 at the cell surface enhances anoikis resistance through activation of SRC in a caveolin-1-dependent manner allowing for phosphorylation of its substrate focal adhesion kinase (FAK). TGF-β elaborated in the TME binds to the type II receptor (TβRII), promoting hetero-tetramerization with the type I receptor (TβRI) increasing the phosphorylation of SMAD3 by activated TβRI. Phosphorylated SMAD3 forms a complex with Co-Smad (SD4), which translocates into the nucleus to bind gene promoters and activate expression of target genes, specifically CEACAM6. Also, TGF-β signals through the TGF-β receptors to activate alternate pathways such as AKT/PI3K.

Mentions: CEACAM6 also plays a significant role in pancreatic cancer. Over-expression of CEACAM6 in PDA cell lines confirmed it as a marker of anoikis resistance. Gene silencing of CEACAM6 with siRNA reversed anoikis resistance in MiaPaca-2 PDA cells [29]. CEACAM6-specific siRNA increased the cell lines susceptibility to caspase-mediated anoikis and reduced AKT phosphorylation. Suppression of CEACAM6 resulted in decreased anoikis resistance which in turn diminished the ability of MiaPaca-2 PDA cells to metastasize in a nude mouse orthotopic xenograft model. Over-expression of CEACAM6 in Capan2 PDA cells that normally do not express CEACAM6 resulted in an amplified resistance to gemcitabine [30]. Gene silencing of CEACAM6 in BxPC3 PDA cells that normally express CEACAM6 resulted in improved susceptibility to gemcitabine through modulation of AKT activity in a Src-dependant manner. Activation of the AKT pathway is associated with protection from factors that promote apoptosis as well as chemotherapeutic sensitivity [31, 32]. These findings correlate CEACAM6 over-expression with an increased metastatic phenotype through elevated SRC activity and matrix metalloproteinase 2 (MMP2) expression (Fig. 2). Hence, CEACAM6 over-expression through activation of the SRC-AKT signaling provides chemo-resistance to gemcitabine in PDA cell lines.


Emerging Role and Targeting of Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) in Human Malignancies
CEACAM6 Signaling Pathway. Over-expression of CEACAM6 results in alteration and reorganization of the ECM and activation of the TME playing a key role in tumor invasion. CEACAM6 signaling increases SRC activity leading to increased IGF-I secretion with autocrine and paracrine stimulation of the IGF-1R activating the PI3K/AKT pathway. Increased IGF-I expression results in MMP-2 elaboration, subsequently altering the ECM promoting a malignant TME. Aggregation of CEACAM6 at the cell surface enhances anoikis resistance through activation of SRC in a caveolin-1-dependent manner allowing for phosphorylation of its substrate focal adhesion kinase (FAK). TGF-β elaborated in the TME binds to the type II receptor (TβRII), promoting hetero-tetramerization with the type I receptor (TβRI) increasing the phosphorylation of SMAD3 by activated TβRI. Phosphorylated SMAD3 forms a complex with Co-Smad (SD4), which translocates into the nucleus to bind gene promoters and activate expression of target genes, specifically CEACAM6. Also, TGF-β signals through the TGF-β receptors to activate alternate pathways such as AKT/PI3K.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4997943&req=5

Figure 2: CEACAM6 Signaling Pathway. Over-expression of CEACAM6 results in alteration and reorganization of the ECM and activation of the TME playing a key role in tumor invasion. CEACAM6 signaling increases SRC activity leading to increased IGF-I secretion with autocrine and paracrine stimulation of the IGF-1R activating the PI3K/AKT pathway. Increased IGF-I expression results in MMP-2 elaboration, subsequently altering the ECM promoting a malignant TME. Aggregation of CEACAM6 at the cell surface enhances anoikis resistance through activation of SRC in a caveolin-1-dependent manner allowing for phosphorylation of its substrate focal adhesion kinase (FAK). TGF-β elaborated in the TME binds to the type II receptor (TβRII), promoting hetero-tetramerization with the type I receptor (TβRI) increasing the phosphorylation of SMAD3 by activated TβRI. Phosphorylated SMAD3 forms a complex with Co-Smad (SD4), which translocates into the nucleus to bind gene promoters and activate expression of target genes, specifically CEACAM6. Also, TGF-β signals through the TGF-β receptors to activate alternate pathways such as AKT/PI3K.
Mentions: CEACAM6 also plays a significant role in pancreatic cancer. Over-expression of CEACAM6 in PDA cell lines confirmed it as a marker of anoikis resistance. Gene silencing of CEACAM6 with siRNA reversed anoikis resistance in MiaPaca-2 PDA cells [29]. CEACAM6-specific siRNA increased the cell lines susceptibility to caspase-mediated anoikis and reduced AKT phosphorylation. Suppression of CEACAM6 resulted in decreased anoikis resistance which in turn diminished the ability of MiaPaca-2 PDA cells to metastasize in a nude mouse orthotopic xenograft model. Over-expression of CEACAM6 in Capan2 PDA cells that normally do not express CEACAM6 resulted in an amplified resistance to gemcitabine [30]. Gene silencing of CEACAM6 in BxPC3 PDA cells that normally express CEACAM6 resulted in improved susceptibility to gemcitabine through modulation of AKT activity in a Src-dependant manner. Activation of the AKT pathway is associated with protection from factors that promote apoptosis as well as chemotherapeutic sensitivity [31, 32]. These findings correlate CEACAM6 over-expression with an increased metastatic phenotype through elevated SRC activity and matrix metalloproteinase 2 (MMP2) expression (Fig. 2). Hence, CEACAM6 over-expression through activation of the SRC-AKT signaling provides chemo-resistance to gemcitabine in PDA cell lines.

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.


Related in: MedlinePlus