title: Activation of mutated K-ras in donor endometrial epithelium and stroma promotes lesion growth in an intact immunocompetent murine model of endometriosis.
abstract: 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.
authors.affiliation: Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.
authors.forename: Ching-wen
authors.initials: CW
authors.lastname: Cheng
authors.forename: Diana
authors.initials: D
authors.lastname: Licence
authors.forename: Emma
authors.initials: E
authors.lastname: Cook
authors.forename: Feijun
authors.initials: F
authors.lastname: Luo
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Smith
authors.forename: Cristin G
authors.initials: CG
authors.lastname: Print
authors.forename: D Stephen
authors.initials: DS
authors.lastname: Charnock-Jones
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004715:Endometriosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004847:Epithelial Cells / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives / Q000627:therapeutic use / Q000633:toxicity; D004965:Estrogen Antagonists / Q000627:therapeutic use; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D000077267:Fulvestrant; D011905:Genes, ras / Q000235:genetics*; D007121:Immunocompetence; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D011960:Receptors, Estrogen / Q000378:metabolism; D017154:Stromal Cells / Q000473:pathology
chemical_list: D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol