Shibuya Masabumi
Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan, and Jobu University, Isesaki, Japan.
Genes Cancer. 2010 Nov;1(11):1119-23. doi: 10.1177/1947601910392987.
Ligands and their tyrosine kinase (TK) receptors regulate a variety of biological systems in animals. Vascular endothelial growth factor (VEGF) and its receptor (Flt/VEGFR family) system play a crucial role not only in physiological but also in most parts of pathological angiogenesis including cancer. Flt-1/VEGFR-1 and KDR/VEGFR-2 bind VEGF-A but have different functions on angiogenesis at early embryogenesis: Flt-1 has a negative role by trapping ligands, whereas KDR (Flk1 in mice) exerts a strong positive signal, resulting in a balance in blood vessel formation. At adult stages, however, both VEGFRs contribute to pathological angiogenesis either directly or through stimulation of migration/activation of macrophage lineage cells and stimulate tumor growth, metastasis, and inflammation. VEGFRs activate downstream signaling of the phospholipase Cγ-protein kinase C-MAP kinase pathway but not Ras pathway for cell proliferation. The VEGF-C/D and Flt-4/VEGFR-3 system regulates lymphangiogenesis. Thus, VEGFs as well as these receptor TKs are attractive targets for suppressing pathological angiogenesis.
配体及其酪氨酸激酶（TK）受体调节动物体内多种生物系统。血管内皮生长因子（VEGF）及其受体（Flt/VEGFR家族）系统不仅在生理过程中，而且在包括癌症在内的大多数病理性血管生成过程中都起着至关重要的作用。Flt-1/VEGFR-1和KDR/VEGFR-2可结合VEGF-A，但在胚胎早期发育阶段对血管生成具有不同功能：Flt-1通过捕获配体发挥负性作用，而KDR（小鼠中的Flk1）则发出强烈的正性信号，从而在血管形成中实现平衡。然而，在成年阶段，两种VEGFRs均可直接或通过刺激巨噬细胞系细胞的迁移/激活来促进病理性血管生成，并刺激肿瘤生长、转移和炎症。VEGFRs激活磷脂酶Cγ-蛋白激酶C-MAP激酶途径的下游信号，但不激活细胞增殖的Ras途径。VEGF-C/D和Flt-4/VEGFR-3系统调节淋巴管生成。因此，VEGF以及这些受体酪氨酸激酶是抑制病理性血管生成的有吸引力的靶点。
