PMID- 24403258 OWN - NLM STAT- MEDLINE DCOM- 20140904 LR - 20211021 IS - 2045-7634 (Electronic) IS - 2045-7634 (Print) IS - 2045-7634 (Linking) VI - 2 IP - 6 DP - 2013 Dec TI - Suppression of choriocarcinoma invasion and metastasis following blockade of BDNF/TrkB signaling. PG - 849-61 LID - 10.1002/cam4.158 [doi] AB - Brain-derived neurotrophic factor (BDNF) acts through its cognate receptor tyrosine kinase-B (TrkB) to regulate diverse physiological functions in reproductive and other tissues. In normal and malignant trophoblastic cells, the BDNF/TrkB signaling promotes cell growth. Due to the highly malignant nature of choriocarcinoma, we investigated possible involvement of this system in choriocarcinoma cell invasion and metastasis. We demonstrated that treatment of cultured choriocarcinoma cells, known to express both BDNF and TrkB, with a soluble TrkB ectodomain or a Trk receptor inhibitor K252a suppressed cell invasion accompanied with decreased expression of matrix metalloproteinase-2, a cell invasion marker. In vivo studies using a tumor xenograft model in athymic nude mice further showed inhibition of cell invasion from tumors to surrounding tissues following the suppression of endogenous TrkB signaling. For an in vivo model of choriocarcinoma metastasis, we performed intravenous injections of JAR cells expressing firefly luciferase into severe combined immunodeficiency (SCID) mice. Treatment with K252a inhibited metastasis of tumors to distant organs. In vivo K252a treatment also suppressed metastatic tumor growth as reflected by decreased cell proliferation and increased apoptosis and caspases-3/7 activities, together with reduced tissue levels of a tumor marker, human chorionic gonadotropin-beta. In vivo suppression of TrkB signaling also led to decreased expression of angiogenic markers in metastatic tumor, including cluster of differentiation 31 and vascular endothelial growth factor A. Our findings suggested essential autocrine/paracrine roles of the BDNF/TrkB signaling system in choriocarcinoma invasion and metastasis. Inhibition of this signaling could serve as the basis to develop a novel therapy for patients with choriocarcinoma. CI - (c) 2013 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. FAU - Kawamura, Kazuhiro AU - Kawamura K AD - Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kanagawa, 216-8511, Japan; Department of Obstetrics and Gynecology, Akita University Graduate School of Medicine, Akita, 010-8543, Japan. FAU - Kawamura, Nanami AU - Kawamura N FAU - Okamoto, Naoki AU - Okamoto N FAU - Manabe, Motomu AU - Manabe M LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20131107 PL - United States TA - Cancer Med JT - Cancer medicine JID - 101595310 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Carbazoles) RN - 0 (Indole Alkaloids) RN - 0 (Protein Kinase Inhibitors) RN - 97161-97-2 (staurosporine aglycone) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - EC 3.4.24.24 (Mmp2 protein, mouse) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/*antagonists & inhibitors/metabolism MH - Carbazoles/pharmacology/*therapeutic use MH - Cell Line, Tumor MH - Cell Movement/drug effects MH - Choriocarcinoma/*drug therapy/metabolism/pathology MH - Female MH - Humans MH - Indole Alkaloids/pharmacology/*therapeutic use MH - Matrix Metalloproteinase 2/metabolism MH - Mice MH - Mice, Nude MH - Mice, SCID MH - Neoplasm Invasiveness MH - Protein Kinase Inhibitors/pharmacology/*therapeutic use MH - Receptor, trkB/*antagonists & inhibitors/metabolism MH - Signal Transduction MH - Tumor Burden/drug effects MH - Uterine Neoplasms/*drug therapy/metabolism/pathology MH - Xenograft Model Antitumor Assays PMC - PMC3892389 OTO - NOTNLM OT - BDNF OT - TrkB OT - choriocarcinoma OT - invasion OT - metastasis EDAT- 2014/01/10 06:00 MHDA- 2014/09/05 06:00 PMCR- 2013/12/01 CRDT- 2014/01/10 06:00 PHST- 2013/08/16 00:00 [received] PHST- 2013/10/04 00:00 [revised] PHST- 2013/10/08 00:00 [accepted] PHST- 2014/01/10 06:00 [entrez] PHST- 2014/01/10 06:00 [pubmed] PHST- 2014/09/05 06:00 [medline] PHST- 2013/12/01 00:00 [pmc-release] AID - 10.1002/cam4.158 [doi] PST - ppublish SO - Cancer Med. 2013 Dec;2(6):849-61. doi: 10.1002/cam4.158. Epub 2013 Nov 7.