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Hepatocyte Growth Factor/Met System Promotes Endometrial and Endometriotic Stromal Cell Invasion via Autocrine and Paracrine Pathways

Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago 683-8504, Japan

Address all correspondence and requests for reprints to: Souichi Yoshida, M.D. Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago 683-8504, Japan. E-mail: souichi{at}grape.med.tottori-u.ac.jp.

Endometrial stromal cells reportedly have a role in the initial invasion of endometrial tissue into the peritoneum. Hepatocyte growth factor (HGF), which is a ligand for the c-met protooncogene product (Met), stimulates proliferation and invasion of a large number of cells. In this study we investigated the role of the HGF/Met system in the pathogenesis of endometriosis. HGF concentrations in the peritoneal fluid of patients with endometriosis were significantly higher than in those without endometriosis and correlated positively with revised American Society of Reproductive Medicine scores. We showed that the peritoneum and endometriotic stromal cells may be major sources of HGF in peritoneal fluid. Endometrial and endometriotic stromal cells expressed the Met receptor, which was activated by endogenous and exogenous HGF. HGF enhanced stromal cell proliferation and invasion. We also demonstrated that the HGF-stimulated stromal cell invasion was due in part to the induction of urokinase-type plasminogen activator, a member of the extracellular proteolysis system. In conclusion, the HGF/Met system is involved in the pathogenesis of endometriosis by promoting stromal cell proliferation and invasion of shed endometria and endometrial lesions via autocrine and paracrine pathways.

Abbreviations: Brdu, 5-Bromo-2'-deoxyuridine; ECM, extracellular matrix; FBS, fetal bovine serum; GAPDH, glycerol-3-phosphate dehydrogenase; HGF, hepatocyte growth factor; MMP, matrix metalloproteinase; MTT, 3-[4,5-dimethlthiazol-2-yl]-2,5-diphenyltetrazolium bromide; PA, plasminogen activator; PAI-1, plasminogen activator inhibitor-1; PF, peritoneal fluid; uPA, urokinase-type plasminogen activator.

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