Activation of mutated K-ras in donor endometrial epithelium and stroma promotes lesion growth in an intact immunocompetent murine model of endometriosis
Activation of mutated K-ras in donor endometrial epithelium and stroma promotes lesion growth in an intact immunocompetent murine model of endometriosis
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DOI：
10.1002/path.2852
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发表时间：
2011-06-01
影响因子：
7.3
通讯作者：
Charnock-Jones, D. Stephen
中科院分区：
文献类型：
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作者：
Cheng, Ching-wen;Licence, Diana;Charnock-Jones, D. Stephen
子宫内膜异位症是一种常见的慢性妇科疾病，影响5-10%的育龄妇女。由于缺乏基因上可控制的模型，它的研究一直受到阻碍。我们将K-ras(G12V/+)/Ah-Cre(+/+)/ROSA26R-LacZ（+/+）小鼠经类固醇处理的月经样子宫内膜移植到性腺完整的免疫功能野生型小鼠中。这导致了子宫内膜异位症样病变的发展。病变的长期存活取决于成熟病变中一小部分经过cre介导的K-ras活化的细胞中活化的K-ras的存在。LacZ在子宫内膜上皮细胞和间质细胞中均表现出cre介导的重组活性，RT-PCR证实了转基因K-ras的表达。在没有外源性雌二醇补充和抗雌激素（氟维司汀，ICI 182780）治疗的情况下，子宫内膜异位症病变的发展大大抑制了它们的生长。免疫组织化学证实，与人子宫内膜异位症一样，成纤维细胞、内皮细胞和巨噬细胞侵袭和活化，病变内有明显的胶原沉积。该模型提供了一个机会来研究子宫内膜异位症病变的建立、生长和消退，在遗传易感性、免疫能力和激素完整的小鼠中。此外，该研究首次提供了一个合适的模型，在易感子宫内膜异位症病变的忠实小鼠模型中测试临床验证的驱动基因，从而为卵巢透明细胞癌的发生提供了正确的细胞背景和微环境。版权所有(C) 2011英国和爱尔兰病理学会。约翰·威利父子有限公司出版。
Endometriosis is a common chronic gynaecological condition, affecting 5-10% of women of child-bearing age. Its study has been hampered by lack of genetically tractable models. We transplanted steroid-manipulated, menstrual-like endometrium from K-ras(G12V/+)/Ah-Cre(+/+)/ROSA26R-LacZ(+/+) mice into gonad-intact immunocompetent wild-type mice. This led to endometriosis-like lesion development. Long-term lesion survival depended on the presence of the activated K-ras in the small proportion of the cells in the mature lesion that had undergone Cre-mediated K-ras activation. LacZ activity demonstrated Cre-mediated recombination in both endometrial epithelial cells and stromal cells, and transgenic K-ras expression was confirmed by RT-PCR. The endometriosis lesions developed without exogenous oestradiol supplementation and anti-oestrogen (fulvestrant, ICI 182780) treatment greatly suppressed their growth. Immunohistochemistry confirmed that as in human endometriosis, there was invasion and activation of fibroblasts, endothelial cells, and macrophages, with marked collagen deposition in the lesions. This model provides an opportunity to investigate endometriosis lesion establishment, growth, and regression in genetically tractable, immunocompetent, and hormonally intact mice. Furthermore, for the first time it provides a suitable model to test clinically validated driver genes in a faithful mouse model of the predisposing endometriotic lesion, thus providing the correct cellular context and microenvironment for ovarian clear cell carcinogenesis. Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.