Activation of mutated K-ras in donor endometrial epithelium and stroma promotes lesion growth in an intact immunocompetent murine model of endometriosis

Ching-wen Cheng, Diana Licence, Emma Cook, Feijun Luo, Mark J Arends, Stephen K Smith, Cristin G Print, D Stephen Charnock-Jones

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)261-9
Number of pages9
JournalThe Journal of Pathology
Volume224
Issue number2
DOIs
Publication statusPublished - Jun 2011

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Disease Models, Animal
  • Endometriosis
  • Epithelial Cells
  • Estradiol
  • Estrogen Antagonists
  • Extracellular Matrix
  • Female
  • Genes, ras
  • Immunocompetence
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Receptors, Estrogen
  • Stromal Cells

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