Abstract
Epithelial ovarian tumors present a complex clinical, diagnostic and therapeutic challenge because of the difficulty of early detection, lack of known precursor lesions and high mortality rates. Endometrioid ovarian carcinomas are frequently associated with endometriosis, but the mechanism for this association remains unknown. Here we present the first genetic models of peritoneal endometriosis and endometrioid ovarian adenocarcinoma in mice, both based on the activation of an oncogenic K-ras allele. In addition, we find that expression of oncogenic K-ras or conditional Pten deletion within the ovarian surface epithelium gives rise to preneoplastic ovarian lesions with an endometrioid glandular morphology. Furthermore, the combination of the two mutations in the ovary leads to the induction of invasive and widely metastatic endometrioid ovarian adenocarcinomas with complete penetrance and a disease latency of only 7 weeks. The ovarian cancer model described in this study recapitulates the specific tumor histomorphology and metastatic potential of the human disease.
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Acknowledgements
We thank C. P. Crum and D. H. Castrillon for additional pathological analysis and comments and advice. We are grateful to A.Y. Nikitin, A. Flesken-Nikitin, T. C. Hamilton, and R. Bao for sharing their technical expertise and advice. In addition, we would like to thank E. Jarmon for technical assistance, H. Wu for the gift of PtenloxP/loxP mice, and D. Kirsch and D. MacPherson for critical reading of the manuscript. This work was supported by grants from the American Cancer Society and the Shoreline Circle of Hope (D.M.D.), the Anna Fuller Fellowship (D.M.D.), the Mouse Models of Human Cancer Consortium of the National Cancer Institute (T.J.), and a KO8 award (CA 92013) from the National Cancer Institute (T.A.I.). T.J. is an Investigator of the Howard Hughes Medical Institute. This paper is dedicated to the memory of a good friend, I. Triculescu, who fought a courageous battle with ovarian cancer.
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Supplementary information
Supplementary Fig. 1
Histomorphology of control ovaries. (PDF 65 kb)
Supplementary Fig. 2
Gross pathology of endometriotic lesions. (PDF 253 kb)
Supplementary Fig. 3
Histopathology of endometriotic lesions. (PDF 178 kb)
Supplementary Fig. 4
Gross pathology of ovarian malignant tumors. (PDF 37 kb)
Supplementary Fig. 5
Estrogen receptor immunohistochemistry in control ovaries. (PDF 40 kb)
Supplementary Fig. 6
Phospho-AKT and MAPK immunohistochemistry in control ovaries. (PDF 80 kb)
Supplementary Fig. 7
Negative control slides for immunohistochemistry experiments. (PDF 275 kb)
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Dinulescu, D., Ince, T., Quade, B. et al. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat Med 11, 63–70 (2005). https://doi.org/10.1038/nm1173
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DOI: https://doi.org/10.1038/nm1173
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