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


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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    • "PTEN gene expression changes in a variety of endometrial lesions (Harada et al., 2004). Some research results have shown that the mRNA expression level of the PTEN gene is closely correlated with the occurrence and severity of EMS, and mRNA expression levels of the PTEN gene have been shown to rise after EMS drug treatment (Dinulescu et al., 2005; Xu et al., 2011). Human umbilical cord mesenchymal stem cells (UCMSCs) are a kind of pluripotent stem cells derived from the mesoderm and a type of adult mesenchymal stem cells. "
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    ABSTRACT: The objective of this study was to observe the effects of human umbilical cord mesenchymal stem cells (UCMSCs) on the proliferation and apoptosis of endometriotic cells. Endometriotic cells and UCMSCs were primarily cultured in vitro. In the experimental group, a UCMSC and endometriotic cell non-contact co-culture system was established. The control group consisted of 1 x 105 endometriotic cells cultured alone. The proliferation and apoptosis of endometriotic cells were respectively detected using the MTT method and flowcytometry. The mRNA expression level of the tensin homologue gene (PTEN) in endometriotic cells was detected by reverse transcription-polymerase chain reaction amplification. Compared with the control group, the proliferation of endometriotic cells in the experimental group was clearly inhibited (P < 0.05) and time-dependent (P < 0.05). In addition, the number of apoptotic cells were significantly increased (P < 0.05), and the amount of cells, which entered S phase from G1 phase, decreased significantly. Furthermore, the mRNA expression level of the PTEN gene in the experimental group was significantly higher than in the control group (P < 0.05). These results suggest that UCMSCs might inhibit the proliferation of human endometriotic cells in vitro and promote their apoptosis by upregulating the expression of PTEN.
    Preview · Article · Dec 2015 · Genetics and molecular research: GMR
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    • "Existing mouse models for serous extra-uterine Müllerian (previously referred to as serous ovarian) carcinomas (Dubeau, 2008; Dubeau and Drapkin, 2013), are based on forced expression of selected oncogenes, often combined with homozygous knockouts of BRCA1 or BRCA2 or other relevant tumor suppressor genes in a tissue-specific manner (Miyoshi et al., 2002; Orsulic et al., 2002; Connolly et al., 2003; Flesken-Nikitin et al., 2003; Dinulescu et al., 2005; Clark-Knowles et al., 2007; Szabova et al., 2012; Perets et al., 2013). None of these models, to our knowledge, are associated with predisposition to both reproductive and mammary cancers. "
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    ABSTRACT: Predisposition to breast and extrauterine Müllerian carcinomas in BRCA1 mutation carriers is due to a combination of cell-autonomous consequences of BRCA1 inactivation on cell cycle homeostasis superimposed on cell-nonautonomous hormonal factors magnified by the effects of BRCA1 mutations on hormonal changes associated with the menstrual cycle. We used the Müllerian inhibiting substance type 2 receptor (Mis2r) promoter and a truncated form of the Follicle stimulating hormone receptor (Fshr) promoter to introduce conditional knockouts of Brca1 and p53 not only in mouse mammary and Müllerian epithelia, but also in organs that control the estrous cycle. Sixty percent of the double mutant mice developed invasive Müllerian and mammary carcinomas. Mice carrying heterozygous mutations in Brca1 and p53 also developed invasive tumors, albeit at a lesser (30%) rate, in which the wild type alleles were no longer present due to loss of heterozygosity. While mice carrying heterozygous mutations in both genes developed mammary tumors, none of the mice carrying only a heterozygous p53 mutation developed such tumors (P<0.0001), attesting to a role for Brca1 mutations in tumor development. This mouse model is attractive to investigate cell-nonautonomous mechanisms associated with cancer predisposition in BRCA1 mutation carriers and to investigate the merit of chemo-preventive drugs targeting such mechanisms.
    Full-text · Article · Sep 2015 · EBioMedicine
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    • "The fact of metaplasia of undifferentiated tissue could possibly explain the existence of endometriosis in distant sites. Dinelescu et al. came up with the hypothesis that activation of K-ras gene may be responsible for the metaplastic process [2] . "
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    ABSTRACT: To provide the review of the macrophage activity products as pathophysiological markers of endometriosis by literature survey (PubMed, Cochrane). Immunoreactive cells and several of their synthesis products concentrations are elevated in the serum and peritoneal fluid in patients with endometriosis. The enhanced reactive proteins contributed to local inflammation and aggregation of endometriotic lesions. Immune response and immune surveillance of tissue play an important role in pathogenesis of endometriosis. Activated macrophages in peritoneal environment secrete immunoreactive cytokines which are responsible for inflammatory cascade of reactions. The immunoreactive cytokines should be a target not only as a disease marker but also as a part of therapeutic protocol.
    Full-text · Article · Jul 2015
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