Endometrial-Peritoneal Interactions during Endometriotic Lesion Establishment

M. Louise Hull^*, Claudia Rangel Escareno, Jane M. Godsland^*, John R. Doig^¶, Claire M. Johnson^||, Stephen C. Phillips^||, Stephen K. Smith^**, Simon Tavaré, Cristin G. Print^* and D. Stephen Charnock-Jones^*

From the Departments of Pathology,^* and Obstetrics and Gynaecology, University of Cambridge, Cambridge, United Kingdom; the Research Centre for Reproductive Health, University of Adelaide, South Australia, Australia; the Program in Molecular and Computational Biology, University of Southern California, Los Angeles, California; the National Institute of Genomic Medicine, México City, México; The Oxford Clinic,^¶ Christchurch, New Zealand; Pfizer Central Research,|| Sandwich, Kent, United Kingdom; the Faculty of Medicine Centre,^*^* Imperial College London, London, United Kingdom; the Department of Oncology, University of Cambridge Li Ka Shing Centre, Cambridge, United Kingdom; and the Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

The pathophysiology of endometriosis remains unclear but involvesa complex interaction between ectopic endometrium and host peritonealtissues. We hypothesized that disruption of this interactionwould suppress endometriotic lesion formation. We hoped to delineatethe molecular and cellular dialogue between ectopic human endometriumand peritoneal tissues in nude mice as a first step toward testingthis hypothesis. Human endometrium was xenografted into nudemice, and the resulting lesions were analyzed using microarrays.A novel technique was developed that unambiguously determinedwhether RNA transcripts identified via microarray analyses originatedfrom human cells (endometrium) or mouse cells (mesothelium).Four key pathways (ubiquitin/proteasome, inflammation, tissueremodeling/repair, and ras-mediated oncogenesis) were revealed,demonstrating communication between host mesothelial cells andectopic endometrium. Morphometric analysis of nude mouse lesionsconfirmed that necrosis, inflammation, healing and repair, andcell proliferation occurred during xenograft development. Theseprocesses were entirely consistent with the molecular networksrevealed by the microarray data. The transcripts detected inthe xenografts overlapped with differentially expressed transcriptsin a comparison between paired eutopic and ectopic endometriafrom human endometriotic patients. For the first time, componentsof the interaction between ectopic endometrium and peritonealstromal tissues are revealed. Targeted disruption of this dialogueis likely to inhibit endometriotic tissue formation and mayprove to be an effective therapeutic strategy for endometriosis.