PMID- 32329031 OWN - NLM STAT- MEDLINE DCOM- 20201214 LR - 20201214 IS - 1933-7205 (Electronic) IS - 1933-7191 (Linking) VI - 27 IP - 7 DP - 2020 Jul TI - Focal Adhesion Kinase-Mediated Sequences, Including Cell Adhesion, Inflammatory Response, and Fibrosis, as a Therapeutic Target in Endometriosis. PG - 1400-1410 LID - 10.1007/s43032-019-00044-1 [doi] AB - Endometriosis has several distinguishing features in the ectopic endometrium, including chronic inflammation and fibrosis. According to the retrograde menstruation theory, endometriotic cells are derived from eutopic endometrial cells, and adhesion of endometrial cells to the extracellular matrix can be the initial step in the development of endometriosis. Therefore, we hypothesized that cell adhesion, which mediates a sequence of events in the development of endometriosis triggering inflammatory responses and tissue fibrosis could be a possible therapeutic target for endometriosis. We found co-upregulation of focal adhesion kinase (FAK) and monocyte chemoattractant protein-1 (MCP-1) in the endometriotic tissues compared with that in the normal endometrium. MCP-1 secretion was significantly higher in the endometriotic stromal cells than in the eutopic endometrial stromal cells. Furthermore, co-culture of U937 cells and endometriotic stromal cells upregulated secretion of transforming growth factor-beta1 (TGF-beta1). A FAK inhibitor significantly inhibited the secretion of MCP-1 in the endometriotic stromal cells and TGF-beta1 in the co-culture with macrophages. FAK inhibitor treatment in the murine endometriosis model demonstrated a decrease in the formation of endometriotic lesions as well as the expression of MCP-1 and TGF-beta1. Our results suggest that the FAK-mediated sequential development of endometriosis, including inflammatory response and tissue fibrosis, can be a new therapeutic target in endometriosis. FAU - Nagai, Takashi AU - Nagai T AD - Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. FAU - Ishida, Chiharu AU - Ishida C AD - Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. chiharu.t@med.nagoya-u.ac.jp. FAU - Nakamura, Tomoko AU - Nakamura T AD - Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. tomonakamura@med.nagoya-u.ac.jp. FAU - Iwase, Akira AU - Iwase A AD - Department of Obstetrics and Gynecology, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, 371-8511, Japan. FAU - Mori, Masahiko AU - Mori M AD - Department of Gynecologic Oncology, Aichi Cancer Center, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan. FAU - Murase, Tomohiko AU - Murase T AD - Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. FAU - Bayasula AU - Bayasula AD - Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. FAU - Osuka, Satoko AU - Osuka S AD - Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. AD - Department of Maternal and Perinatal Medicine, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. FAU - Takikawa, Sachiko AU - Takikawa S AD - Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. FAU - Goto, Maki AU - Goto M AD - Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. FAU - Kotani, Tomomi AU - Kotani T AD - Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. FAU - Kikkawa, Fumitaka AU - Kikkawa F AD - Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200423 PL - United States TA - Reprod Sci JT - Reproductive sciences (Thousand Oaks, Calif.) JID - 101291249 RN - 0 (6-(4-(3-(methylsulfonyl)benzylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one) RN - 0 (CCL2 protein, human) RN - 0 (Chemokine CCL2) RN - 0 (Inflammation Mediators) RN - 0 (Quinolones) RN - 0 (Sulfones) RN - EC 2.7.10.2 (Focal Adhesion Kinase 1) RN - EC 2.7.10.2 (PTK2 protein, human) SB - IM MH - Animals MH - Cell Adhesion/drug effects/*physiology MH - Chemokine CCL2/antagonists & inhibitors/metabolism MH - Coculture Techniques MH - Drug Delivery Systems/*methods MH - Endometriosis/drug therapy/*metabolism/*pathology MH - Female MH - Fibrosis MH - Focal Adhesion Kinase 1/antagonists & inhibitors/*metabolism MH - Humans MH - Inflammation Mediators/antagonists & inhibitors/*metabolism MH - Leiomyoma/drug therapy/metabolism/pathology MH - Mice MH - Mice, Inbred BALB C MH - Quinolones/administration & dosage MH - Sulfones/administration & dosage MH - U937 Cells OTO - NOTNLM OT - Endometriosis OT - FAK OT - MCP-1 OT - Macrophage OT - TGF-beta1 EDAT- 2020/04/25 06:00 MHDA- 2020/12/15 06:00 CRDT- 2020/04/25 06:00 PHST- 2018/12/16 00:00 [received] PHST- 2019/05/06 00:00 [accepted] PHST- 2020/04/25 06:00 [pubmed] PHST- 2020/12/15 06:00 [medline] PHST- 2020/04/25 06:00 [entrez] AID - 10.1007/s43032-019-00044-1 [pii] AID - 10.1007/s43032-019-00044-1 [doi] PST - ppublish SO - Reprod Sci. 2020 Jul;27(7):1400-1410. doi: 10.1007/s43032-019-00044-1. Epub 2020 Apr 23.