Dinulescu, D.M. 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

Center for Cancer Research, Massachusetts Institute of Technology, 40 Ames Street, Cambridge, Massachusetts 02139, USA.
Nature Medicine (Impact Factor: 27.36). 02/2005; 11(1):63-70. DOI: 10.1038/nm1173
Source: PubMed

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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    • "To explore the tumorigenic contributions of oncogenic Kras and tumor suppressor Pten pathways throughout the female genital tract of genetically engineered, Cre-loxP mice [21], [26], we injected AdCre adenovirus at three different anatomical locations (Fig. 1A). The mice received one, unilateral AdCre injection either in the ovarian bursa (n = 12), oviduct (the fallopian tube equivalent, n = 9) or uterine horn (n = 12). "
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    ABSTRACT: Activating mutations of Kras oncogene and deletions of Pten tumor suppressor gene play important roles in cancers of the female genital tract. We developed here new preclinical models for gynecologic cancers, using conditional (Cre-loxP) mice with floxed genetic alterations in Kras and Pten. The triple transgenic mice, briefly called MUC1KrasPten, express human MUC1 antigen as self and carry a silent oncogenic KrasG12D and Pten deletion mutation. Injection of Cre-encoding adenovirus (AdCre) in the ovarian bursa, oviduct or uterus activates the floxed mutations and initiates ovarian, oviductal, and endometrial cancer, respectively. Anatomical site-specific Cre-loxP recombination throughout the genital tract of MUC1KrasPten mice leads to MUC1 positive genital tract tumors, and the development of these tumors is influenced by the anatomical environment. Endometrioid histology was consistently displayed in all tumors of the murine genital tract (ovaries, oviducts, and uterus). Tumors showed increased expression of MUC1 glycoprotein and triggered de novo antibodies in tumor bearing hosts, mimicking the immunobiology seen in patients. In contrast to the ovarian and endometrial tumors, oviductal tumors showed higher nuclear grade. Survival for oviduct tumors was significantly lower than for endometrial tumors (p = 0.0015), yet similar to survival for ovarian cancer. Oviducts seem to favor the development of high grade tumors, providing preclinical evidence in support of the postulated role of fallopian tubes as the originating site for high grade human ovarian tumors.
    PLoS ONE 07/2014; 9(7):e102409. DOI:10.1371/journal.pone.0102409 · 3.23 Impact Factor
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    • "The identification of PTEN mutations in endometriotic lesions (20.6%) adjacent to ovarian endometrioid (20%) and clear cell carcinomas (8.3%) supports the notion that endometriosis is a precursor lesion for endometrioid and clear cell carcinomas [27]. In a mouse model of endometrioid ovarian carcinoma, PTEN deletion on the background of oncogenic K-RAS activation within the ovarian surface epithelium gave rise to endometriotic-like precursor lesions which developed into invasive endometrioid ovarian carcinoma within seven to twelve weeks [28]. These results indicate that expression of oncogenic K-RAS and inactivation of the PTEN tumor suppressor gene is an early event in the development of endometrioid carcinoma. "
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    ABSTRACT: Type I ovarian tumors, where precursor lesions in the ovary have clearly been described, include endometrioid, clear cell, mucinous, low grade serous, and transitional cell carcinomas, while type II tumors, where such lesions have not been described clearly and tumors may develop de novo from the tubal and/or ovarian surface epithelium, comprise high grade serous carcinomas, undifferentiated carcinomas, and carcinosarcomas. The carcinogenesis of endometrioid and clear cell carcinoma (CCC) arising from endometriotic cysts is significantly influenced by the free iron concentration, which is associated with cancer development through the induction of persistent oxidative stress. A subset of mucinous carcinomas develop in association with ovarian teratomas; however, the majority of these tumors do not harbor any teratomatous component. Other theories of their origin include mucinous metaplasia of surface epithelial inclusions, endometriosis, and Brenner tumors. Low grade serous carcinomas are thought to evolve in a stepwise fashion from benign serous cystadenoma to a serous borderline tumor (SBT). With regard to high grade serous carcinoma, the serous tubal intraepithelial carcinomas (STICs) of the junction of the fallopian tube epithelium with the mesothelium of the tubal serosa, termed the "tubal peritoneal junction" (TPJ), undergo malignant transformation due to their location, and metastasize to the nearby ovary and surrounding pelvic peritoneum. Other theories of their origin include the ovarian hilum cells.
    BioMed Research International 04/2014; 2014(5-6):934261. DOI:10.1155/2014/934261 · 2.71 Impact Factor
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    • "Indeed, using adenoviral delivery of cre to ovaries of mice with floxed p53 and Rb, Flesken-Nikitin et al. demonstrated the development of malignant ovarian tumors when both p53 and Rb are deleted (11). Mice with conditional expression of K-ras and deletion of pten in ovarian surface epithelial cells were made and found to develop endometriosis and endometrioid carcinomas (62). Since both mutations are associated with endometriosis and endometrioid ovarian cancer in humans, this model appears to recapitulate the genotype and histomorphology of the human disease. "
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    ABSTRACT: DESPITE SIGNIFICANT UNDERSTANDING OF THE GENETIC MUTATIONS INVOLVED IN OVARIAN EPITHELIAL CANCER AND ADVANCES IN GENOMIC APPROACHES FOR EXPRESSION AND MUTATION PROFILING OF TUMOR TISSUES, SEVERAL KEY QUESTIONS IN OVARIAN CANCER BIOLOGY REMAIN ENIGMATIC: the mechanism for the well-established impact of reproductive factors on ovarian cancer risk remains obscure; cell of origin of ovarian cancer continue to be debated; and the precursor lesion, sequence, or events in progression remain to be defined. Suitable mouse models should complement the analysis of human tumor tissues and may provide clues to these questions currently perplexing ovarian cancer biology. A potentially useful model is the germ cell-deficient Wv (white spotting variant) mutant mouse line, which may be used to study the impact of menopausal physiology on the increased risk of ovarian cancer. The Wv mice harbor a point mutation in c-Kit that reduces the receptor tyrosine kinase activity to about 1-5% (it is not a null mutation). Homozygous Wv mutant females have a reduced ovarian germ cell reservoir at birth and the follicles are rapidly depleted upon reaching reproductive maturity, but other biological phenotypes are minimal and the mice have a normal life span. The loss of ovarian function precipitates changes in hormonal and metabolic activity that model features of menopause in humans. As a consequence of follicle depletion, the Wv ovaries develop ovarian tubular adenomas, a benign epithelial tumor corresponding to surface epithelial invaginations and papillomatosis that mark human ovarian aging. Ongoing work will test the possibility of converting the benign epithelial tubular adenomas into neoplastic tumors by addition of an oncogenic mutation, such as of Tp53, to model the genotype and biology of serous ovarian cancer. Model based on the Wv mice may have the potential to gain biological and etiological insights into ovarian cancer development and prevention.
    Frontiers in Oncology 02/2014; 4:36. DOI:10.3389/fonc.2014.00036
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