CA125 is a biomarker that is useful in monitoring the progression of ovarian cancer. This marker however cannot be effectively used for early detection of ovarian tumors because elevated levels of CA125 are also observed in pregnant women and patients with benign conditions such as endometriosis, preeclampsia, and others. Our recent research suggests a novel CA125-based method to differentiate between ovarian cancer and pregnant women and patients with the above mentioned benign conditions. CA125 is a repeating peptide epitope present in the very large molecular weight mucin MUC16. We have previously shown that MUC16 is a potent immunosuppressive agent that prevents immune cells from lysing tumor targets. In our analysis of immune cells from ovarian cancer patients we demonstrated that a select subset of the cells bind to MUC16 produced by ovarian tumors. It is now clear that MUC16 binds to the immune cell surface via the I-type lectin Siglec-9. MUC16 binding to the cells can be very conveniently detected by performing flow cytometry. Immune cell bound MUC16 is detected even when the serum CA125 levels, measured by the clinical assay, are low to undetectable. Furthermore, Siglec-9 expression pattern on immune cell subsets is different in pregnant women and ovarian cancer patients. Hence the MUC16 binding pattern on immune cells from pregnant women and ovarian cancer patients is also distinct. Therefore, we are hypothesizing that distinguishing the immune cell binding patterns of MUC16 and also detecting the binding of this mucin to select subsets of immune cells may provide a more efficient assay for the diagnosis and monitoring of ovarian cancer. We are proposing to test this hypothesis under three separate clinical settings.
In specific aim 1 we will perform exhaustive experiments to clearly identify the MUC16 binding pattern to defined immune cell subsets in pre-menopausal and post menopausal healthy women, normal pregnant women, women with preeclampsia and endometriosis, and in patients with ovarian cancer.
This specific aim will provide fundamental information on the potential use of the immune cell bound MUC16 assay for early detection of cancer.
In specific aim 2 we will determine if the immune cell bound MUC16 assay can be used to distinguish between women with ovarian cancer and those with benign pelvic mass. Finally, in Specific aim 3 we will determine if monitoring immune cell bound MUC16 will help in better identifying regression and recurrence of ovarian cancer in patients undergoing treatment for this disease. Monitoring tumor antigens bound to the surface of immune cells is a novel approach that may potentially be used in conjunction with the serum CA125 test, other biomarkers, ultrasound, clinical symptom index, or imaging techniques to better predict the occurrence and progression of ovarian tumors. The data obtained in this study will help us design multi-center based clinical studies to develop a novel diagnostic assay for ovarian cancer.

Public Health Relevance

CA125 is a well known marker for ovarian cancer. This marker is a protein epitope present in a very large biomolecule, MUC16. Specific white blood cells from ovarian cancer patients bind to MUC16 that is produced by ovarian tumors. In this proposal we will investigate if monitoring the levels of MUC16 bound to specific subsets of immune cells can lead to the development of a novel diagnostic test for early detection and monitoring of ovarian cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Cancer Biomarkers Study Section (CBSS)
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Kim, Kelly Y
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University of Wisconsin Madison
Obstetrics & Gynecology
Schools of Medicine
United States
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Carroll, Molly J; Fogg, Kaitlin C; Patel, Harin A et al. (2018) Alternatively-Activated Macrophages Upregulate Mesothelial Expression of P-Selectin to Enhance Adhesion of Ovarian Cancer Cells. Cancer Res 78:3560-3573
Kapur, Arvinder; Felder, Mildred; Fass, Lucas et al. (2016) Modulation of oxidative stress and subsequent induction of apoptosis and endoplasmic reticulum stress allows citral to decrease cancer cell proliferation. Sci Rep 6:27530
Carroll, Molly J; Kapur, Arvinder; Felder, Mildred et al. (2016) M2 macrophages induce ovarian cancer cell proliferation via a heparin binding epidermal growth factor/matrix metalloproteinase 9 intercellular feedback loop. Oncotarget 7:86608-86620
Felder, Mildred; Kapur, Arvinder; Gonzalez-Bosquet, Jesus et al. (2014) MUC16 (CA125): tumor biomarker to cancer therapy, a work in progress. Mol Cancer 13:129
Patankar, Manish S; Gubbels, Jennifer A A; Felder, Mildred et al. (2012) The immunomodulating roles of glycoproteins in epithelial ovarian cancer. Front Biosci (Elite Ed) 4:631-50
Tyler, Chanel; Kapur, Arvinder; Felder, Mildred et al. (2012) The mucin MUC16 (CA125) binds to NK cells and monocytes from peripheral blood of women with healthy pregnancy and preeclampsia. Am J Reprod Immunol 68:28-37