Abstract
Successful translation of preclinical data relies on valid and comprehensive animal models. While high-grade serous ovarian cancer (HGSOC) is the most prevalent subtype, the most commonly used ovarian cancer cell lines are not representative of HGSOC. In addition, 50% of ovarian cancer patients present with dysfunctional BRCA1/2, however currently there is a shortage of BRCA-deficient models. By utilizing the OVCAR8 cell line, which contains a hypermethylated BRCA1 promoter, the aim of the current study was to establish and characterize an animal model for BRCA-deficient HGSOC. Transfection of the luciferase gene to OVCAR8 cells enabled bioluminescent imaging for real-time, non-invasive monitoring of tumor growth. The resulting model was characterized by peritoneal metastasis and ascites formation at late stages of disease. Immunohistochemical staining revealed high-grade serous histology in all resected tumor nodules. Immunoblotting and qPCR analysis demonstrated BRCA1 deficiency was maintained in vivo. Moderate to strong correlations were observed between bioluminescent signal and tumor weight. Lastly, intraperitoneal administration of carboplatin significantly reduced tumor growth as measured by bioluminescence. The current model demonstrated BRCA1 deficiency and a high resemblance of the clinical features of HGSOC. This model may be well-suited for evaluation of therapeutic efficacy in BRCA-deficient HGSOC.
Highlights
Ovarian cancer accounts for the majority of gynecological malignancy-associated deaths in North America
Mice injected with 5 million OVCAR8luc cells exhibited significantly longer median survival times than mice injected with 10 million cells (57 days versus 51 days respectively) (Figure S2)
All tumor samples exhibited higher degrees of methylation than cells grown in culture, as demonstrated by over 80% methylation of the promoter region. These results suggest that BRCA1 epigenetic changes in OVCAR8 cells are maintained in vivo during the development of peritoneal xenografts
Summary
Ovarian cancer accounts for the majority of gynecological malignancy-associated deaths in North America. Out of the 200,000 new diagnoses in 2018, over half of the patients will eventually die from the disease [1]. Diagnosis for ovarian cancer is clinically challenging due to a lack of obvious symptoms at early stages of disease [2]. Patients often present at an advanced stage, at which point the rate of survival is low [3]. While the majority of patients achieve clinical remission following first-line chemotherapy, most relapse with platinum resistant diseases [6]. Only 5% of new antitumor agents reach phase III clinical trials largely due to a lack of preclinical models resembling the human disease [7]
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