Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis
Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis
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DOI：
10.1215/s1152851705000050
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发表时间：
2005-10-01
期刊：
影响因子：
15.9
通讯作者：
Laterra, J
中科院分区：
文献类型：
--
作者：
Abounader, R;Laterra, J
多功能生长因子分散因子/肝细胞生长因子（SF/HGF）及其受体酪氨酸激酶c-Met已成为脑肿瘤生长和血管生成的关键决定因素。SF/HGF和c-Met在脑肿瘤中表达，其表达水平通常与肿瘤分级、肿瘤血管密度和不良预后相关。脑肿瘤细胞中SF/HGF和/或c-Met的过表达增强其致瘤性、肿瘤生长和肿瘤相关血管生成。相反，在实验性肿瘤异种移植物中抑制SF/HGF和c-Met导致抑制肿瘤生长和肿瘤血管生成。SF/HGF主要由肿瘤细胞表达和分泌，并作用于肿瘤细胞和血管内皮细胞中表达的c-Met受体。c-Met的活化导致肿瘤细胞以及肿瘤血管内皮细胞的增殖、迁移和侵袭的诱导以及凋亡的抑制。肿瘤内皮细胞c-Met的活化也诱导细胞外基质降解、小管形成和体内血管生成。SF/HGF通过部分已知的机制直接诱导脑肿瘤血管生成，并通过调节其他血管生成途径如VEGF间接诱导脑肿瘤血管生成。最近开发了抑制SF/HGF和c-Met的不同方法。这些包括用SF/HGF片段如NK 4、SF/HGF的受体拮抗作用和用UlsnRNA/核酶的c-Met表达抑制;与可溶性Met受体的竞争性配体结合; SF/HGF的中和抗体;和小分子酪氨酸激酶抑制剂。在实验肿瘤模型中使用这些抑制剂导致肿瘤生长和血管生成的抑制。在这篇综述中，我们总结了目前的知识如何SF/HGF：c-Met途径有助于脑肿瘤恶性胶质瘤血管生成的重点。
The multifunctional growth factor scatter factor/hepatocyte growth factor (SF/HGF) and its receptor tyrosine kinase c-Met have emerged as key determinants of brain tumor growth and angiogenesis. SF/HGF and c-Met are expressed in brain tumors, the expression levels frequently correlating with tumor grade, tumor blood vessel density, and poor prognosis. Overexpression of SF/HGF and/or c-Met in brain tumor cells enhances their tumorigenicity, tumor growth, and tumor-associated angiogenesis. Conversely, inhibition of SF/HGF and c-Met in experimental tumor xenografts leads to inhibition of tumor growth and tumor angiogenesis. SF/HGF is expressed and secreted mainly by tumor cells and acts on c-Met receptors that are expressed in tumor cells and vascular endothelial cells. Activation of c-Met leads to induction of proliferation, migration, and invasion and to inhibition of apoptosis in tumor cells as well as in tumor vascular endothelial cells. Activation of tumor endothelial c-Met also induces extracellular matrix degradation, tubule formation, and angiogenesis in vivo. SF/HGF induces brain tumor angiogenesis directly through partly known mechanisms and indirectly by regulating other angiogenic pathways such as VEGF. Different approaches to inhibiting SF/HGF and c-Met have been recently developed. These include receptor antagonism with SF/HGF fragments such as NK4, SF/HGF, and c-Met expression inhibition with UlsnRNA/ribozymes; competitive ligand binding with soluble Met receptors; neutralizing antibodies to SF/HGF; and small molecular tyrosine kinase inhibitors. Use of these inhibitors in experimental tumor models leads to inhibition of tumor growth and angiogenesis. In this review, we summarize current knowledge of how the SF/HGF:c-Met pathway contributes to brain tumor malignancy with a focus on glioma angiogenesis.