Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer

Daniela M Dinulescu, Tan A Ince, Bradley J Quade, Sarah A Shafer, Denise Crowley, Tyler Jacks
Nature medicine · 2004 · vol. 11(1) , pp. 63–70 · doi:10.1038/nm1173 · PMID:15619626 · W2062495971
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Activation of oncogenic K-ras in mice, alone or with Pten deletion, induces peritoneal endometriosis and invasive, metastatic endometrioid ovarian adenocarcinomas.

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The study developed genetic mouse models of peritoneal endometriosis and endometrioid ovarian adenocarcinoma driven by activation of an oncogenic K-ras allele, aiming to clarify mechanisms linking endometriosis and endometrioid ovarian cancer. In addition to showing that oncogenic K-ras expression or conditional Pten deletion in the ovarian surface epithelium induces preneoplastic ovarian lesions with endometrioid glandular morphology, the authors report that combining both mutations in the ovary produces invasive, widely metastatic endometrioid ovarian adenocarcinomas with complete penetrance and a latency of about 7 weeks, recapitulating key histomorphology and metastasis features of the human disease. A major limitation explicitly noted in the framing is that these are the first genetic models based on specific driver alterations, so the causal scope is tied to these engineered genotypes. This paper is centrally about endometriosis — it presents genetic mouse models of peritoneal endometriosis and shows how K-ras and Pten cooperate to drive endometrioid ovarian cancer.

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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. This is a preview of subscription content, access via your institution Access options Subscribe to this journal Receive 12 print issues and online access 251,40 € per year only 20,95 € per issue Buy this article - Purchase on SpringerLink - Instant access to the full article PDF. 39,95 € Prices may be subject to local taxes which are calculated during checkout Similar content being viewed by others

References

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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. Author information Authors and Affiliations Corresponding author Ethics declarations Competing interests The authors declare no competing financial interests. Supplementary information Supplementary Fig. 1 (download PDF ) Histomorphology of control ovaries. (PDF 65 kb) Supplementary Fig. 2 (download PDF ) Gross pathology of endometriotic lesions. (PDF 253 kb) Supplementary Fig. 3 (download PDF ) Histopathology of endometriotic lesions. (PDF 178 kb) Supplementary Fig. 4 (download PDF ) Gross pathology of ovarian malignant tumors. (PDF 37 kb) Supplementary Fig. 5 (download PDF ) Estrogen receptor immunohistochemistry in control ovaries. (PDF 40 kb) Supplementary Fig. 6 (download PDF ) Phospho-AKT and MAPK immunohistochemistry in control ovaries. (PDF 80 kb) Supplementary Fig. 7 (download PDF ) Negative control slides for immunohistochemistry experiments. (PDF 275 kb) Rights and permissions About this article Cite this article 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 Received: Accepted: Published: Issue date: DOI: https://doi.org/10.1038/nm1173 This article is cited by - Dissecting metastasis using preclinical models and methods Nature Reviews Cancer (2023) - Molekulare Pathologie benigner gynäkologischer Erkrankungen – ist sie hilfreich bei zukünftigen Therapieentscheidungen? Die Gynäkologie (2022) - Identification and clinical significance of somatic oncogenic mutations in epithelial ovarian cancer Journal of Ovarian Research (2021) - Therapeutically reprogrammed nutrient signalling enhances nanoparticulate albumin bound drug uptake and efficacy in KRAS-mutant cancer Nature Nanotechnology (2021) - Malignant Transformation and Associated Biomarkers of Ovarian Endometriosis: A Narrative Review Advances in Therapy (2020)

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

Disease Models, Animal Endometriosis Ovarian Neoplasms Protein Tyrosine Phosphatases ras Proteins Tumor Suppressor Proteins Animals Endometriosis Endometriosis Endometriosis Female Mice Ovarian Neoplasms Ovarian Neoplasms Ovarian Neoplasms Protein Tyrosine Phosphatases Protein Tyrosine Phosphatases PTEN Phosphohydrolase ras Proteins ras Proteins

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