Despite widespread peritoneal metastasis commonly seen in ovarian cancer at diagnosis, the ovary has long been considered the primary origin of this cancer—hence the name ovarian cancer. However, precursor lesions have not been identified in the ovary (1, 7). Over the past decade, new evidence has emerged to propose a different source of ovarian cancer: the fallopian tube (7, 8). After women with hereditary breast and ovarian cancer-susceptibility gene (BRCA1, BRCA2) mutations have their ovaries and fallopian tubes prophylactically removed to prevent ovarian cancer, early serous carcinomas have been found in the fallopian tube—not in the ovary (8). Further studies demonstrated early serous lesions of fallopian tube origin in 64–71% of nonhereditary high-grade ovarian serous carcinomas (9, 10). These studies have spawned a notion that the fallopian tube is a potential primary site of origin of high-grade serous carcinomas (7, 8). Intriguing as this theory is, the direct evidence is still lacking that the fallopian tube not only can initiate but, beyond that, can also advance de novo to the full-spectrum metastatic malignancy of high-grade serous carcinomas.

In the present study, we provide direct evidence to this “fallopian tube hypothesis.” When Dicer and Pten are conditionally disabled with Amhr2-Cre in mice, high-grade serous carcinomas arise from the fallopian tube. These primary fallopian tube cancers subsequently spread to the ovary and then aggressively metastasize throughout the abdominal cavity, leading to ascites and 100% lethality. In addition to these clinical similarities to the human cancer, gene expression analyses also affirm that these fallopian tube tumors resemble human serous ovarian cancer at the molecular level. Moreover, in these Dicer-Pten double-knockout (DKO) mice, the primary epithelial cancers originate in the stroma of the fallopian tube, suggesting that the cancers arise from cells of a mesenchymal lineage (i.e., cell of a nonepithelial lineage). Our study thus presents a paradigm for the origin and initiation of deadly high-grade serous ovarian cancer.