Molecular and functional characteristics of ovarian surface epithelial cells transformed by KrasG12D and loss of Pten in a mouse model in vivo

Mullany, Lisa K.; Fan, Heng‐Yu; Liu, Zhilin; White, Lisa D.; Marshall, Alexandra; Gunaratne, Preethi H.; Anderson, Matthew L.; Creighton, Chad J.; Li, Xin; Deavers, Michael T.; Wong, Kwong-Kwok; Richards, JoAnne S.

doi:10.1038/onc.2011.70

Cited by 68 publications

(68 citation statements)

References 65 publications

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“…Although mouse models for serous ovarian carcinomas have been reported before (20)(21)(22), the detailed molecular map underlying this deadly cancer has yet to emerge (7). Our DKO model shows a clear progression of the cancers from the fallopian tube stroma to the ovary and eventual metastasis to peritoneal tissues.…”

Section: Resultsmentioning

confidence: 99%

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

Kim

Coffey²,

Creighton

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

351

317

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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 doubleknockout 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.epithelial ovarian cancer | oviduct | mesenchymal-to-epithelial transition | carcinoma initiation E pithelial ovarian cancer, accounting for 90% of all ovarian tumors, is grouped into four major histologic types: serous (70%), endometrioid (10-15%), clear-cell (10%), and mucinous (3%) carcinomas (1). The serous-type cancers are also overwhelmingly high-grade (90%)-the culprit of 70% of ovariancancer deaths and a key contributor to an overall ovarian cancer 5-yr survival rate of 31% (2-4). Most cases of high-grade serous ovarian cancers are diagnosed at advanced stages, when the tumors have already metastasized. Despite the steady improvement of surgery and chemotherapy, >90% of women with advanced ovarian cancers die after the cancer relapses (5). Early detection of these high-grade serous carcinomas is thus key to reducing ovarian cancer deaths (6). However, the origin and molecular pathogenesis of these high-grade serous ovarian cancers are largely unknown (1, 6).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 fallop...

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Section: Resultsmentioning

confidence: 99%

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

Kim

Coffey²,

Creighton

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

351

317

View full text Add to dashboard Cite

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“…The immortalized mouse ovarian surface epithelium (mOSE) was reported previously (15,16). All cells were cultured in DMEM (Invitrogen) supplemented with 10% fetal bovine serum (FBS; Hyclone) and 1% penicillin/streptomycin solution (Invitrogen) at 37°C in a humidified 5% CO 2 incubator.…”

Section: Methodsmentioning

confidence: 99%

Death Domain-associated Protein DAXX Promotes Ovarian Cancer Development and Chemoresistance

Pan

Zhou

Liu

et al. 2013

Journal of Biological Chemistry

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Background:The role of DAXX in ovarian cancer development and metastasis has not been investigated before now. Results: Overexpression of DAXX enhanced ovarian cancer cell proliferation, colony formation, and migration, whereas Daxx depletion had the opposite effects. Conclusion: DAXX promotes ovarian cancer cell proliferation and chemoresistance. Significance: Modulating DAXX may be an effective strategy for preventing the recurrence and chemoresistance of ovarian cancers.

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“…PTEN is a negative regulator of Akt, a kinase downstream of PI 3-kinase that is often altered in human cancers (87,88). Constitutive activation of PI 3-kinase signaling was combined with expression of an activating mutation in K-Ras to generate low grade serous papillary adenocarcinoma (87).…”

Section: Promoter-driven Expression Of Transgenesmentioning

confidence: 99%

Molecular and functional characteristics of ovarian surface epithelial cells transformed by KrasG12D and loss of Pten in a mouse model in vivo

Cited by 68 publications

References 65 publications

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

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

Death Domain-associated Protein DAXX Promotes Ovarian Cancer Development and Chemoresistance

Evaluating the progenitor cells of ovarian cancer: analysis of current animal models

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