The carbohydrate antigen CA125, also known as mucin 16 (MUC16), is a glycoprotein encoded by the MUC16 gene. It is expressed in epithelial ovarian tumors and various other pathological and normal tissues of Müllerian origin and can be detected in serum. It is the most commonly used ovarian cancer marker, primarily used for auxiliary diagnosis of ovarian cancer, particularly epithelial ovarian cancer, and can also be used as a differential diagnostic indicator for benign and malignant pelvic tumors in postmenopausal women.
The structure of CA125
MUC16 is a transmembrane mucin with a molecular weight between 3 and 5 million Da. The mucin glycoprotein MUC16 consists of three regions: the C-terminal domain, the tandem repeat (TR) region, and the N-terminal domain. The C-terminal domain is the smallest part of MUC16, containing 283 amino acids near the transmembrane domain. Multiple studies have revealed its oncogenic potential. The TR region, known as CA125, occupies the majority of MUC16 and consists of nearly 60 repeats. While no two repeats are identical, all contain two conserved cysteines at positions 59 and 79, which are believed to play a key role in maintaining mucin structure. The N-terminal domain, the domain furthest from the membrane, consists of 12,068 amino acids and is rich in potential glycosylation sites, including O- and N-linked glycosylation.
(Data source: ZhangM, et al. Biochim Biophys Acta Rev Cancer. 2021)
The mechanism of CA125-induced tumorigenesis and metastasis
CA125 binds to a glycoprotein called mesothelin. CA125 interacts with GPI-linked mesothelin to initiate cancer cell adhesion to the mesothelium and promote peritoneal metastasis of ovarian cancer. CA125 binds to inhibitory receptors such as siglec-9 and downregulates activating receptors such as CD16, inhibiting immune responses and ADCC. In addition to its role in metastasis through interaction with mesothelin and downregulation of the immune system, CA125 also has direct oncogenic effects. CA125 promotes protein synthesis and inhibits apoptosis in ovarian cancer cells through a p13K/Akt-dependent pathway. β-Catenin participates in cell adhesion and the formation of multicellular aggregates, which serve as vehicles for tumor metastasis. Inhibiting GSK-3β-mediated phosphorylation can inhibit β-catenin expression. MUC16 activates Rho GTPases to induce the translocation of p120ctn into the cytoplasm, promoting the proliferation and migration of ovarian cancer cells.
(Data source: ZhangM, et al. Biochim Biophys Acta Rev Cancer. 2021)
Treatment strategies based on CA125
Monoclonal antibodies targeting CA 125: Oregovomab is a murine monoclonal antibody with high affinity for CA 125 that stimulates a host cytotoxic immune response against tumor cells expressing CA 125. It is being studied as a maintenance first-line treatment option for patients with advanced ovarian cancer and for recurrent disease.
Vaccination: Vaccination with anti-idiotypic monoclonal antibodies (such as abagovomab) that mimic the structure and function of CA125 can induce an active immune response against CA125.
Bispecific antibodies: Developing bispecific antibodies, such as REGN4018, that can simultaneously bind to CD3 and MUC16 (CA125). This antibody can promote immune clearance of ovarian cancer cells with high MUC16 expression by activating CD3+ T cells.
CAR-T: MUC16-CTD-modified CAR-T cells secrete IL-12, which not only exhibits enhanced tumor-directed cytolysis but also promotes the endogenous immune system to break through the limitations of CAR T therapy for solid malignancies.
(Data source: Zhang M, et al. Biochim Biophys Acta Rev Cancer. 2021)
