In February 2024, the Elsevier database published a article based on bioinformatics analysis. This study identified 42 differentially expressed genes through transcriptomic analysis of multiple sclerosis patients during pregnancy, utilizing bioinformatics tools such as GEO, STRING, and KEGG, all of which incorporate pathways like IL-10, ErbB2, and IL-17. Notably, CEACAM8 was also involved. These findings suggest that CEACAM8 could represent a significant target for autoimmune or inflammatory diseases research [1].
Since as early as 2010, a drug targeting CEACAM8 has been utilized in treating osteomyelitis. Despite limited recent clinical reports on CEACAM8, it has emerged as a promising candidate target within the CEA family, particularly in various tumors, notably those affecting the reproductive and digestive systems/gynaecological or gastrointestinal cancer research. Therefore, further exploration of CEACAM8 could provide valuable insights for future research directions.
4. Prospects for Clinical Drug Research of CEACAM8
5. CUSABIO CEACAM8 Recombinant Proteins & Antibodies for Research Use
Carcinoembryonic antigen-associated cell adhesion molecule 8 (CEACAM8) is a member of the CEA family, also known as CD66b, NCA-95, or CD67. It's a GPI-anchored protein with high glycosylation, featuring eleven N-glycosylation sites and a molecular weight of 95 kDa. Studies suggest isolating purified CEACAM8 for deeper understanding of its structure and function, confirming its origin from the CGM6 (NCA-W272) gene. Additionally, research indicates CEACAM8's role in regulating interactions of CEACAM6, potentially binding with other CEACAMs to exert regulatory functions. However, further elucidation of CEACAM8's structure is needed (Figure 1) [2-4].
CEACAM8 serves as a granulocyte lineage cell-specific activation antigen, primarily expressed in human neutrophils and eosinophils. While resting neutrophils exhibit CEACAM8 in a limited fraction of the plasma membrane, its expression is swiftly up-regulated upon activation, originating from intracellular pools. As a member of the carcinoembryonic antigen family, CEACAM8 not only regulates cell-to-cell adhesion but also plays a crucial role in cellular signaling. This includes functions such as pathogen binding regulation, inflammation modulation, immune response regulation in normal cell growth or differentiation, and modulation of tumor growth, angiogenesis, among others [6-8].
Figure 1. CEACAM8 structure [5]
CEACAM8 primarily regulates neutrophil adhesion and activation, pivotal processes in acute inflammatory responses where neutrophils act as early effector cells. Neutrophils recruited to tumor environments exhibit unique characteristics, including reduced granules and reactive oxygen species (ROS), contributing to complex functions. Various activation states of neutrophils entail corresponding roles. Tumor cells can induce the polarization of tumor-associated neutrophils via TGF-β, promoting cancer progression. These neutrophils produce growth factors such as vascular endothelial growth factor (VEGF), matrix metalloproteinase 9 (MMP9), and hepatocyte growth factor (HGF), which inhibit cytotoxic lymphocytes. The expression of CEACAM8 in neutrophils suggests its regulatory role in tumorigenesis and progression [9-11].
Furthermore, CEACAM8's role in immune regulation extends beyond tumors, as evidenced by several studies. For instance, in the regulation of lower respiratory tract bacterial infections, soluble recombinant CEACAM8-Fc effectively inhibited the expression of CEACAM1 in human lung epithelial cells responding to TLR2 immune activation [12]. Additionally, CEACAM8 overexpression was closely linked to phagocytic dysfunction, characterized by alterations in the CEACAM8 to CD11b ratio and reductions in the C5a receptors (C5aR1) and C5L2. The extent of neutrophil paralysis was directly correlated with CEACAM8 receptor expression levels, offering insights for novel marker development. These findings underscore the significance of CEACAM8 in immune response regulation [13-15].
CEACAM8/CD66b is widely acknowledged as a marker for tumor-associated neutrophils (TANs), serving as a valuable indicator for monitoring TAN density within tumor parenchyma. Studies demonstrate that in invasive breast cancer, elevated CEACAM8/CD66b expression correlates significantly with the proliferative subtype, while survival rates are lower within this subgroup. Notably, CD66b-positive TANs exhibit strong associations with both lymph node and distant metastasis. Further investigations reveal that CD66b+ TANs influence the expression of PD-L1 on immune cells, with a positive correlation observed between the two. In summary, TANs play a pivotal role in breast cancer, closely linked to tumor metastasis and recurrence. Assessing the density of CD66b-positive TANs holds promise as a potential indicator for predicting breast cancer metastasis and recurrence [16-17].
In uterine precancerous tissues, higher neutrophil infiltration is linked to better recurrence-free survival (RFS), while increased neutrophil numbers independently predict recurrence in cervical cancer patients. CEACAM8/CD66b, a specific marker for neutrophils, shows elevated levels in both cervical cancer tumors and adjacent stromal tissues, especially around tumor sites. Moreover, in cervical cancer, elevated CD66b and CD8 Ratio (Neutrophil to Lymphocyte Ratio, NLR) correlate with poorer prognosis. Studies suggest CEACAM8 as a potential predictor for recurrence-free survival and prognosis in cervical cancer patients [18-19].
Recent studies have begun to explore the relationship between CEACAM8 and bladder cancer. Additionally, in bladder cancer, changes in the Neutrophil to Lymphocyte Ratio (NLR) can predict treatment response and patient survival. Elevated NLR is associated with a significantly higher risk of cancer-specific death. Furthermore, an ELISA-based study revealed higher levels of CEACAM8 in the urine of bladder cancer patients compared to non-bladder cancer individuals. Moreover, CEACAM8 concentrations varied among bladder cancer groups with different pathological grades. These findings underscore the potential clinical significance of CEACAM8 in the diagnosis, screening, and monitoring of bladder cancer [20-22].
In non-small cell lung cancer (NSCLC), CEACAM8 is closely linked to disease-specific survival and lymph node metastasis, indicating poor prognosis. Interestingly, in squamous lung cancer (SCC), higher CEACAM8 levels predict better survival, while in adenocarcinoma of the lung (ADC), they signal poorer outcomes. Especially in ADC patients, elevated CEACAM8 is associated with worse prognosis. However, in mesenchymal tissue, CEACAM8 doesn't significantly impact patient prognosis. These findings suggest CEACAM8 may have different effects in various NSCLC subtypes, possibly influenced by tumor stage and immune activity [23-24].
CD66b-positive neutrophils serve as markers for tumor-associated neutrophils (TANs), pivotal players in the tumor microenvironment's role in tumorigenesis and progression. Notably, CEACAM8 has been identified in various digestive system tumors, including gastric, liver, esophageal, and oral cancers. For instance, in gastric cancer, heightened CEACAM8 infiltration closely correlates with prognosis, with significant associations observed with tumor size, differentiation degree, and early TNM stage [25-26]. TANs have been shown to inhibit T-cell proliferation and function via the GM-CSF-PD-L1 pathway, thereby promoting gastric cancer progression [27-28].
In hepatocellular carcinoma patients, CEACAM8 exhibits higher expression density in peri-tumor tissues compared to tumors themselves [29]. TANs are implicated in inhibiting T-cell proliferation and function by secreting BMP2 and TGF-β, enhancing their stem cell properties [30]. Additionally, TANs facilitate invasion and migration of colon cancer cells via IL-7a signaling [31]. In patients with esophageal squamous cell carcinoma, elevated intra-tumoral CEACAM8 is strongly associated with lymph node metastasis and advanced pathological staging [32].
CEACAM8 emerges as a promising target for tumor research, offering potential avenues for clinical drug development. Tc 99m besilesomab, an inhibitor of CEACAM8, has received marketing approval for treating osteomyelitis and holds promise for applications in infection, dermatological, and musculoskeletal disorders. Its development is led by CIS Bio International SA. Presently, there are relatively few domestic and international clinical trials focusing on CEACAM8, with only one CEACAM8-targeted drug available on the market. However, ongoing development of two other drugs, Yttrium-90 besilesomab and Besilesomab, underscores active research in this area. This progress provides optimism for the future clinical utility of CEACAM8-related diseases research.
CEACAM8, a member of the CEA family, plays multifaceted roles in immune regulation and tumor microenvironments. Its expression correlates with various cancers, including breast, lung, and digestive system tumors. CEACAM8 serves as a marker for tumor-associated neutrophils (TANs), impacting tumor progression and patient prognosis. While research on CEACAM8-targeted therapies is ongoing, promising developments like Tc 99m besilesomab hint at its potential clinical applications, offering hope for improved cancer management strategies.
In order to assist pharmaceutical companies in the clinical research of CEACAM8 in gynaecological or gastrointestinal cancers, CUSABIO has launched CEACAM8 active protein & antibody products to help you in the research of CEACAM8 mechanism or its potential clinical value.
CUSABIO CEACAM8 Protein
Purity was greater than 95% as determined by SDS-PAGE.
Immobilized Human CEACAM8 at 2μg/mL can bind Anti-CEACAM8 recombinant antibody (CSB-RA005168MA1HU). The EC50 is 19.38-21.68 ng/mL.
References
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