Abstract 1950: Differential expression of MUC16 mucin (CA125) depending on the architecture of the tumors developed in an orthotopic mouse model of high-grade serous ovarian cancer

Abstract

Abstract The histopathology of high-grade serous ovarian cancer (HGSOC) in orthotopic mouse models has received limited attention. Using immunosuppressed mice, we generated intraperitoneal HGSOC disease that includes formation of ascites and/or pleural effusions, together with a myriad of intra-abdominal growths. We studied 3 HGSOC cell lines evolved from the same patient along disease progression—a platinum-sensitive, PEO1; a platinum-resistant after further relapse, PEO4; and another at the end of life, PEO6. We found that the animals were prone to develop the disease sooner when implanted with cells obtained from the most advanced disease. Using these models, we characterized the histopathology of the masses preferably developed in the stomach-spleen-pancreas region enclosing the omentum. Other sites of tumor formation we found where the lower pelvic cavity, the peritoneal wall, the liver base, the diaphragm, the lungs, the uterus, and the ovaries. The architecture of the tumors was more often represented by slit-like fenestrations, yet certain zones displayed papillary, glandular, or solid structures sometimes including infiltrating lymphocytes. When we studied the expression of antigen CA125, we found that its pattern of staining was highly heterogeneous. In PEO1/4/6 cells maintained in culture CA125 was expressed in all cell types, yet with a major abundance aligned with disease evolution. In vivo, within the tumors, the expression of CA125 was mostly limited to the apical region of cells facing slit-like spaces generated in between solid sheets of tumor cells surrounded by fibrovascular stroma. When tumor cells were located deep within homogeneous solid masses devoid of slit-like fenestrations, they usually did not express CA125. In contrast, when cells were found gathered as multicellular structures free-floating in open spaces surrounding target organs—e.g. within the bursa around the ovaries—CA125 was highly expressed. This is coincident with the high expression of CA125 observed in vitro in cells spontaneously forming multicellular aggregates in suspension. It is likely that HGSOC cells express CA125 to face or invade into open spaces. In summary, this work reveals tissue heterogeneity and polarity in the expression of CA125 in solid tumors of HGSOC developed in immunosuppressed mice. This selected pattern of expression may be related to the oncogenic functions of CA125 (a.k.a. MUC16, a glycoprotein), such as protecting cells from immunological attacks, or promoting metastases by binding to mesothelin produced by mesothelial cells that line the peritoneal cavity. Citation Format: Alicia A. Goyeneche, Michael A. Lisio, Zu-hua Gao, Carlos M. Telleria. Differential expression of MUC16 mucin (CA125) depending on the architecture of the tumors developed in an orthotopic mouse model of high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1950.