Vascular Endothelial Growth Factor (VEGF), VEGF Receptors and Their Inhibitors for Antiangiogenic Tumor Therapy
Vascular Endothelial Growth Factor (VEGF), VEGF Receptors and Their Inhibitors for Antiangiogenic Tumor Therapy
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DOI：
10.1248/bpb.34.1785
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发表时间：
2011-12-01
影响因子：
2
通讯作者：
Takahashi, Satoru
中科院分区：
文献类型：
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作者：
Takahashi, Satoru
血管内皮生长因子（VEGF）及其受体（VEGFRs）在生理和病理性血管生成中起重要作用。VEGF家族由VEGF-A（通常称为VEGF）、VEGF-B、VEGF-C、VEGF-D和胎盘生长因子（PIG F）组成。这些肽对VEGFR亚型显示不同的亲和力。VEGFR以VEGFR-1、VEGFR-2和VEGFR-3三种亚型存在，并且在结构上与血小板衍生生长因子受体相关。所有亚型在细胞外区域具有七个免疫球蛋白样结构域，在细胞内区域具有一个酪氨酸激酶结构域。VEGF-A激活VEGFR-1和VEGFR-2，而VEGF-B和PlGF仅结合VEFGR-1。VEGF-C和VEGF-D仅与VEGFR-3结合。VEGFR-1（fms样酪氨酸激酶-1，Flt-1）负调节胚胎血管发生，并通过激活单核细胞和巨噬细胞参与肿瘤血管生成。VEGFR-2（人的KDR或小鼠的Flk-1）主要负责胚胎血管发生和肿瘤血管生成。相比之下，VEGFR-3（Flt-4）调节淋巴管生成。因此，VEGF-A和VEGFR-2是目前抗血管生成治疗的主要靶点。贝伐珠单抗是一种抗VEGF-A的人源化单克隆抗体，阿柏西普（VEGF-Trap）是VEGFR-1和VEGFR-2的细胞外结构域与免疫球蛋白G（IgG）Fc区的可溶性融合蛋白。它们中和VEGF-A，从而防止肿瘤血管生成。VEGFR酪氨酸激酶抑制剂如舒尼替尼和索拉非尼通过抑制VEGFR信号传导在抗血管生成肿瘤治疗中也是有效的。抗VEGF药物是一种有前途的治疗癌症患者。
Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) have crucial roles in both physiological and pathological angiogenesis. The VEGF family consists of VEGF-A (generally called VEGF), VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PIG F). These peptides show different affinities for VEGFR subtypes. VEGFR exists as three subtypes, VEGFR-1, VEGFR-2, and VEGFR-3, and is structurally related to platelet-derived growth factor receptors. All subtypes possess seven immunoglobulin-like domains in the extracellular region and a tyrosine kinase domain in the intracellular region. VEGF-A activates VEGFR-1 and VEGFR-2, whereas VEGF-B and PIGF bind to only VEFGR-1. VEGF-C and VEGF-D only bind to VEGFR-3. VEGFR-1 (fms-like tyrosine kinase-1, Flt-1) negatively regulates embryonic vasculogenesis and is involved in tumor angiogenesis via activation of monocytes and macrophages. VEGFR-2 (KDR in humans or Flk-1 in mice) is predominantly responsible for both embryonic vasculogenesis and tumor angiogenesis. In contrast, VEGFR-3 (Flt-4) regulates lymphangiogenesis. Consequently, VEGF-A and VEGFR-2 are currently the main targets for antiangiogenic therapy. Bevacizumab is a humanized monoclonal antibody against VEGF-A, and aflibercept (VEGF-Trap) is a soluble fusion protein of the extracelluar domain of VEGFR-1 and VEGFR-2 and the Fc region of immunoglobulin G (IgG). They neutralize VEGF-A, resulting in prevention of tumor angiogenesis. VEGFR tyrosine kinase inhibitors such as sunitinib and sorafenib are also effective in antiangiogenic tumor therapy by inhibiting VEGFR signaling. Anti-VEGF drugs are a promising therapy for cancer patients.