Suppression of choriocarcinoma invasion and metastasis following blockade of BDNF/TrkB signaling.
Suppression of choriocarcinoma invasion and metastasis following blockade of BDNF/TrkB signaling.
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DOI：
10.1002/cam4.158
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发表时间：
2013-12
期刊：
影响因子：
4
通讯作者：
Manabe, Motomu
中科院分区：
文献类型：
--
作者：
Kawamura, Kazuhiro;Kawamura, Nanami;Okamoto, Naoki;Manabe, Motomu
脑源性神经营养因子(BDNF)通过其同源受体酪氨酸激酶B(TrkB)调节生殖和其他组织的多种生理功能。在正常和恶性滋养细胞中，BDNF/TrkB信号促进细胞生长。由于绒毛膜癌的高度恶性，我们研究了该系统在绒毛膜癌细胞侵袭和转移中的可能作用。我们证明，培养的绒毛膜癌细胞同时表达BDNF和TrkB，用可溶性TrkB胞外区或Trk受体抑制剂K252a处理后，细胞侵袭受到抑制，同时细胞侵袭标记物基质金属蛋白酶-2的表达减少。在裸鼠体内使用肿瘤异种移植模型的研究进一步表明，在抑制内源性TrkB信号后，细胞从肿瘤向周围组织的侵袭受到抑制。对于绒毛膜癌转移的体内模型，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)小鼠体内。K252a治疗可抑制肿瘤向远处器官的转移。在体内，K252a治疗还抑制了转移性肿瘤的生长，表现为细胞增殖减少、细胞凋亡和caspase-3/7活性增加，以及肿瘤标记物-人绒毛膜促性腺激素-β的组织水平降低。体内抑制TrkB信号也导致转移瘤中血管生成标志物的表达减少，包括分化簇31和血管内皮生长因子A。我们的研究结果表明，BDNF/TrkB信号系统在绒毛膜癌侵袭和转移中起着重要的自分泌/旁分泌作用。抑制这一信号可以作为开发绒毛膜癌患者新疗法的基础。
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.
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影响因子：
16.2
作者：
IP, NY;STITT, TN;YANCOPOULOS, GD
通讯作者：
YANCOPOULOS, GD
DOI：
10.1002/neu.480251107
发表时间：
1994-11-01
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
BARBACID, M
通讯作者：
BARBACID, M
影响因子：
15.9
作者：
Kermani, P;Rafii, D;Hempstead, BL
通讯作者：
Hempstead, BL
影响因子：
3.7
作者：
Imam JS;Plyler JR;Bansal H;Prajapati S;Bansal S;Rebeles J;Chen HI;Chang YF;Panneerdoss S;Zoghi B;Buddavarapu KC;Broaddus R;Hornsby P;Tomlinson G;Dome J;Vadlamudi RK;Pertsemlidis A;Chen Y;Rao MK
通讯作者：
Rao MK
影响因子：
4.8
作者：
Kim, H;Li, Q;Madri, JA
通讯作者：
Madri, JA