Mouse Models Identify a Potential Ovarian Cancer Cell of Origin

Most cases of high-grade serous ovarian carcinoma (HGSC), the most common and lethal type of ovarian cancer, are not diagnosed until late stages of disease, making it difficult to determine early events in ovarian cancer development and discern the cell of origin. Increasing evidence suggests HGSC may arise not only from the ovarian surface epithelium but may also arise from dissemination of precursor lesions originating in the fallopian tube epithelium. To formally prove that HGSC can arise from the fallopian tube, Perets and colleagues developed a genetically engineered mouse model in which Trp53, Pten, and Brca1 or Brca2—genes that are often simultaneously altered in human HGSC—were deleted by Cre-mediated recombination specifically in cells expressing Pax8, a transcription factor gene required for development of the female genital tract that is expressed in the fallopian tubes (specifically in secretory epithelial cells) but not the ovaries. Deletion of Trp53, Pten, and Brca1/2 led to the transformation of fallopian tube secretory epithelial cells and the development of PAX8-positive invasive carcinomas that frequently metastasized to the ovary and peritoneum and were histologically and molecularly similar to human HGSC. HGSC could only be prevented in these mice by surgical removal of the fallopian tubes, but not removal of the ovaries or uterus, further indicating that HGSC can arise from the fallopian tube epithelium. In addition to establishing a faithful mouse model of human HGSC with the potential to provide insight into the early stages of ovarian cancer development and facilitate preclinical drug testing, these findings strongly suggest that early detection and prevention strategies for ovarian cancer should not only focus on the ovaries, but also on the fallopian tubes.

Perets R, Wyant GA, Muto KW, Bijron JG, Poole BB, Chin KT, et al. Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten models. Cancer Cell 2013;24:751–65.

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