High-grade serous ovarian cancer arises from fallopian tube in a mouse model

Jaeyeon Kim, Donna M. Coffey, Chad J. Creighton, Zhifeng Yu, Shannon M. Hawkins, Martin M. Matzuk

Research output: Contribution to journalArticlepeer-review

248 Scopus citations

Abstract

Although ovarian cancer is the most lethal gynecologic malignancy in women, little is known about how the cancer initiates and metastasizes. In the last decade, new evidence has challenged the dogma that the ovary is the main source of this cancer. The fallopian tube has been proposed instead as the primary origin of high-grade serous ovarian cancer, the subtype causing 70% of ovarian cancer deaths. By conditionally deleting Dicer, an essential gene for microRNA synthesis, and Pten, a key negative regulator of the PI3K pathway, we show that high-grade serous carcinomas arise from the fallopian tube in mice. In these Dicer-Pten double-knockout mice, primary fallopian tube tumors spread to engulf the ovary and then aggressively metastasize throughout the abdominal cavity, causing ascites and killing 100% of the mice by 13 mo. Besides the clinical resemblance to human serous cancers, these fallopian tube cancers highly express genes that are known to be up-regulated in human serous ovarian cancers, also demonstrating molecular similarities. Although ovariectomized mice continue to develop high-grade serous cancers, removal of the fallopian tube at an early age prevents cancer formation - confirming the fallopian tube origin of the cancer. Intriguingly, the primary carcinomas are first observed in the stroma of the fallopian tube, suggesting that these epithelial cancers have a mesenchymal origin. Thus, this mouse model demonstrates a paradigm for the origin and initiation of high-grade serous ovarian carcinomas, the most common and deadliest ovarian cancer.

Original languageEnglish (US)
Pages (from-to)3921-3926
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number10
DOIs
StatePublished - Mar 6 2012

Keywords

  • Carcinoma initiation
  • Epithelial ovarian cancer
  • Mesenchymal-to-epithelial transition
  • Oviduct

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'High-grade serous ovarian cancer arises from fallopian tube in a mouse model'. Together they form a unique fingerprint.

Cite this