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.
Cancer Med. 2013 Dec;2(6):849-61. doi: 10.1002/cam4.158. Epub 2013 Nov 7.
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.
脑源性神经营养因子（BDNF）通过其同源受体酪氨酸激酶-B（TrkB）发挥作用，调节生殖和其他组织中的多种生理功能。在正常和恶性滋养细胞中，BDNF/TrkB 信号促进细胞生长。由于绒癌具有高度恶性，我们研究了该系统是否参与绒癌细胞的侵袭和转移。我们证明，用可溶性 TrkB 外显子或 Trk 受体抑制剂 K252a 处理培养的绒癌细胞（已知表达 BDNF 和 TrkB），可抑制细胞侵袭，并伴有细胞侵袭标志物基质金属蛋白酶-2 的表达下调。在无胸腺裸鼠肿瘤异种移植模型的体内研究中，进一步显示抑制内源性 TrkB 信号后，肿瘤向周围组织的细胞侵袭受到抑制。为了研究绒癌转移的体内模型，我们将表达萤火虫荧光素酶的 JAR 细胞静脉注射到严重联合免疫缺陷（SCID）小鼠中。K252a 处理抑制了肿瘤向远处器官的转移。体内 K252a 处理还抑制了转移性肿瘤的生长，表现为细胞增殖减少、凋亡和 caspase-3/7 活性增加，以及肿瘤标志物人绒毛膜促性腺激素-β的组织水平降低。体内抑制 TrkB 信号也导致转移性肿瘤中血管生成标志物的表达减少，包括 CD31 和血管内皮生长因子 A。我们的研究结果表明，BDNF/TrkB 信号系统在绒癌的侵袭和转移中具有重要的自分泌/旁分泌作用。抑制这种信号可能为绒癌患者开发新的治疗方法提供基础。
