Abstract
Over three decades have passed since the first report on the expression of CA125 by ovarian tumors. Since that time our understanding of ovarian cancer biology has changed significantly to the point that these tumors are now classified based on molecular phenotype and not purely on histological attributes. However, CA125 continues to be, with the recent exception of HE4, the only clinically reliable diagnostic marker for ovarian cancer. Many large-scale clinical trials have been conducted or are underway to determine potential use of serum CA125 levels as a screening modality or to distinguish between benign and malignant pelvic masses. CA125 is a peptide epitope of a 3–5 million Da mucin, MUC16. Here we provide an in-depth review of the literature to highlight the importance of CA125 as a prognostic and diagnostic marker for ovarian cancer. We focus on the increasing body of literature describing the biological role of MUC16 in the progression and metastasis of ovarian tumors. Finally, we consider previous and on-going efforts to develop therapeutic approaches to eradicate ovarian tumors by targeting MUC16. Even though CA125 is a crucial marker for ovarian cancer, the exact structural definition of this antigen continues to be elusive. The importance of MUC16/CA125 in the diagnosis, progression and therapy of ovarian cancer warrants the need for in-depth research on the biochemistry and biology of this mucin. A renewed focus on MUC16 is likely to culminate in novel and more efficient strategies for the detection and treatment of ovarian cancer.
Highlights
Cancer Antigen 125 (CA125) is best known as a biomarker to monitor epithelial ovarian cancer and for the differential diagnosis of pelvic masses [1,2]
Serum levels of CA125 are routinely monitored in patients with ovarian cancer, and an increase from an individualized nadir concentration is a prognostic indicator of cancer recurrence
We observe that trypsin digestion significantly reduces VK8 binding to Mucin 16 (MUC16)-expressing cells, but only slightly reduces OC125 binding to cells under the same conditions (Figure 3)
Summary
CA125 is best known as a biomarker to monitor epithelial ovarian cancer and for the differential diagnosis of pelvic masses [1,2]. One important conclusion drawn from our studies with the peptides and those reported by Bressan et al is that the CA125 epitope most likely does not reside in the loop region of the tandem repeat as predicted initially [21,75] The implications of this conclusion are serious as it indicates that even though the CA125 assay is routinely used to monitor the vast majority of patients with serous ovarian cancer, the exact molecular nature of the antigen is not accurately characterized. Repeated administration of the anti-CA125 antibodies results in increased anti-tumor T cell responses and the generation of anti-idiotypic antibodies [158,159,160,161,162,163,164,165] These positive results led to the testing of Oregovomab in larger clinical trials in ovarian cancer patients [166,167]. These results are encouraging and support further development of MUC16-targeted therapies for cancer
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