title: Suppression of choriocarcinoma invasion and metastasis following blockade of BDNF/TrkB signaling.
abstract: 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-β. 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.
authors.affiliation: 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.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kawamura
authors.forename: Nanami
authors.initials: N
authors.lastname: Kawamura
authors.forename: Naoki
authors.initials: N
authors.lastname: Okamoto
authors.forename: Motomu
authors.initials: M
authors.lastname: Manabe
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002822:Choriocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology / Q000627:therapeutic use*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D020813:Receptor, trkB / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D026121:Indole Alkaloids; D047428:Protein Kinase Inhibitors; C049985:staurosporine aglycone; D020813:Receptor, trkB; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
keywords: BDNF; TrkB; choriocarcinoma; invasion; metastasis