Raf-1, a potential therapeutic target, mediates early steps in endometriosis lesion development by endometrial epithelial and stromal cells

Elizabeth M. De La Garza, De La Garza EM, Peter A Binkley, Binkley PA, Peter Binkley, Manonmani Ganapathy, Ganapathy M, Krishnegowda NK, Naveen K. Krishnegowda, Tekmal RR, Rajeshwar R. Tekmal, Robert S. Schenken, Schenken RS, Kirma NB, Nameer B. Kirma
Endocrinology · 2012 · vol. 153(8) , pp. 3911–3921 · doi:10.1210/en.2011-1879 · PMID:22619359 · W1979762429
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Raf-1 kinase mediates early steps in endometriosis lesion development by promoting endometrial epithelial and stromal cell attachment to and invasion through mesothelial cells, and regulating their growth.

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Abstract

Endometriosis is a hormone-sensitive gynecological disorder characterized by the benign growth of endometrial-like tissue in the pelvic cavity. Endometriotic lesions composed of endometrial stromal cells (ESC) and glandular epithelial cells (EEC) are thought to arise from menstrual endometrial tissue reaching the pelvic cavity via retrograde menstruation. The cause of endometriotic lesion formation is still not clear. Recent evidence suggest that cytokines may play a role in the early development of endometriosis lesions. Because cytokines and growth factors signal via the v-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) kinase pathway, we have examined the role of Raf-1 in early steps of endometriosis lesion formation, specifically attachment of endometrial cells to peritoneal mesothelial cells (PMC) and invasion of endometrial cells through PMC (trans-mesothelial invasion). Raf-1 antagonist GW5074 decreased attachment to PMC and trans-mesothelial invasion by primary EEC and ESC. Raf-1 also mediated TGFβ-induced trans-mesothelial invasion by the established, low-invasive EEC line EM42. TGFβ treatment of EEC resulted in Raf-1 phosphorylation at S338 and phosphorylation of ERK, suggesting that TGFβ activates Raf-1 signaling in these cells. GW5074 had little effect on ESC proliferation but inhibited EEC growth significantly under reduced serum conditions. Antagonizing Raf-1 activity and expression via GW5074 and specific Raf-1 small interfering RNA, respectively, did not alter EEC resistance to growth inhibition by TGFβ. Raf-1 inhibition blocked induction of EEC growth by epidermal growth factor. Our data suggest that Raf-1 may mediate pathologic steps involved in early endometriosis lesion formation and may be a mediator of TGFβ and epidermal growth factor actions in endometriosis.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometrium Endometrium Epithelial Cells Epithelial Cells Proto-Oncogene Proteins c-raf Stromal Cells Stromal Cells Animals Animals Cell Line Cell Line Cells, Cultured Cells, Cultured Endometriosis Endometriosis Endometriosis Endometrium Endometrium Epithelial Cells

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Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. Outer rings show 2-hop neighbours — papers reached through the immediate citers/citees. [ collapse to 1-hop ]

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