K. K. and N. K. contributed equally to this work.
Suppression of choriocarcinoma invasion and metastasis following blockade of BDNF/TrkB signaling
Article first published online: 7 NOV 2013
© 2013 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 2, Issue 6, pages 849–861, December 2013
How to Cite
Cancer Medicine 2013; 2(6): 849–861
- Issue published online: 2 DEC 2013
- Article first published online: 7 NOV 2013
- Manuscript Accepted: 8 OCT 2013
- Manuscript Revised: 4 OCT 2013
- Manuscript Received: 16 AUG 2013
- Uehara Memorial Foundation
- Naito Foundation
- Astellas Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Life Science Foundation of Japan
- Smoking Research Foundation
- Takeda Science Foundation
- Yamaguchi Endocrine Research Foundation
- BDNF ;
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.