Major finding: A mouse model shows high-grade serous carcinomas may arise from the fallopian tube.
Approach: Dicer and Pten were conditionally deleted in the female reproductive tract.
Impact: These findings may affect screening, diagnosis, and treatment methods for ovarian cancer.
High-grade serous carcinoma is the most common and lethal type of ovarian cancer, but its etiology is poorly understood because most cases are not diagnosed until widespread metastasis has occurred. Over the past decade, pathologists have begun to suspect that the site of origin of ovarian cancer is actually the fallopian tube, but genetic and molecular evidence to support “the fallopian tube hypothesis” has been lacking. Because loss of DICER expression and deregulation of PI3K signaling have been implicated in the pathogenesis of ovarian cancer, Kim and colleagues conditionally deleted Dicer and Pten in the reproductive tract of female mice. Interestingly, early serous carcinomas developed in the fallopian tubes, but not the ovaries, of each double-knockout mouse. These murine fallopian tube tumors, which were histologically and molecularly similar to human high-grade serous carcinoma, eventually enveloped the ovaries, metastasized to the abdominal cavity, and killed 100% of the mice within 13 months. When the ovaries were removed, aggressive tumors still formed, but when the fallopian tubes were removed, none of the mice developed cancer. The authors' finding that allelic loss of DICER and PTEN frequently occurs in human high-grade serous ovarian cancers indicates that this model may be relevant to human disease and may be useful for understanding the molecular mechanisms underlying the initiation and metastasis of these aggressive cancers. Furthermore, a finding that suggests high-grade serous carcinomas arises from the fallopian tube and not the ovary has important clinical implications for preventive surgery and treatment of gynecologic cancers.