Leung Kam
National Center for Biotechnology Information, NLM, NIH
The vascular endothelial growth factor (VEGF) family is composed of five VEGF glycoproteins (VEGF-A, VEGF-B, VEGF-C, VEGF-D, and VEGF-E) and consists of at least six isoforms of various numbers of amino acids (121, 145, 165, 183, 189, and 206 amino acids) produced through alternative splicing (1). VEGF-A is composed of VEGF, VEGF, and VEGF isoforms, which are secreted by most cell types and are active as homodimers linked by disulfide bonds. VEGF does not bind to heparin like other VEGF polypeptides do (2). VEGF is a potent angiogenic factor that induces proliferation, sprouting, migration, and tube formation of endothelial cells. There are three high-affinity tyrosine kinase VEGF receptors (VEGFR-1, Flt-1; VEGFR-2, KDR/Flt-1; and VEGFR-3, Flt-4) on endothelial cells. Several types of non-endothelial cells, such as hematopoietic stem cells, melanoma cells, monocytes, osteoblasts, and pancreatic β cells, also express VEGFRs (1). VEGF is overexpressed in various tumor cells and tumor-associated endothelial cells (3). Among the at least seven isoforms of VEGF-A, VEGF is freely soluble while all VEGF is bound to the cell membrane or extracellular matrix (ECM). VEGF exhibits an intermediary behavior (i.e. partly diffusible and partly bound). Inhibition of VEGFR function has been shown to inhibit pathological angiogenesis as well as tumor growth and metastasis (4, 5). Radiolabeled VEGF has been developed as a single-photon emission computed tomography tracer for imaging solid tumors and angiogenesis in humans (6-8). However, several studies have shown that cancer treatments (photodynamic therapy, radiotherapy, and chemotherapy) can lead to increased tumor VEGF expression and subsequently to more aggressive disease (9, 10). Therefore, it is important to measure VEGF levels in the tumors to design better anticancer treatment protocols. Bevacizumab (Bev) is a humanized antibody against VEGF-A (11) that binds to all VEGF-A isoforms, and it is approved for clinical use in metastatic colon carcinoma and non-small cell lung cancer (12). VEGFR-2 has been shown to mediate most of the VEGF-A activation in tumor endothelial cells (13, 14). Zhang et al. (15) prepared Cu-1,4,7-triazacyclononane-1,4,7-triacetic acid--isothiocyanatobenzyl-bevacizumab-IRDye 800CW (Cu-NOTA-Bev-800CW) for positron emission tomography (PET) and near-infrared fluorescence (NIR) multimodal imaging of VEGF expression in nude mice bearing U87MG human glioblastoma xenografts. U87MG cells express all three isoforms of VEGF-A (VEGF VEGF and VEGF).
血管内皮生长因子（VEGF）家族由五种VEGF糖蛋白（VEGF-A、VEGF-B、VEGF-C、VEGF-D和VEGF-E）组成，通过可变剪接产生至少六种不同氨基酸数量（121、145、165、183、189和206个氨基酸）的异构体（1）。VEGF-A由VEGF、VEGF和VEGF异构体组成，这些异构体由大多数细胞类型分泌，以通过二硫键连接的同二聚体形式具有活性。VEGF不像其他VEGF多肽那样与肝素结合（2）。VEGF是一种强效血管生成因子，可诱导内皮细胞增殖、发芽、迁移和管形成。内皮细胞上有三种高亲和力酪氨酸激酶VEGF受体（VEGFR-1，Flt-1；VEGFR-2，KDR/Flt-1；和VEGFR-3，Flt-4）。几种非内皮细胞类型，如造血干细胞、黑色素瘤细胞、单核细胞、成骨细胞和胰腺β细胞，也表达VEGFRs（1）。VEGF在各种肿瘤细胞和肿瘤相关内皮细胞中过度表达（3）。在VEGF-A的至少七种异构体中，VEGF是可自由溶解的，而所有VEGF都与细胞膜或细胞外基质（ECM）结合。VEGF表现出中间行为（即部分可扩散和部分结合）。已证明抑制VEGFR功能可抑制病理性血管生成以及肿瘤生长和转移（4,5）。放射性标记的VEGF已被开发为用于人类实体瘤和血管生成成像的单光子发射计算机断层扫描示踪剂（6-8）。然而，几项研究表明，癌症治疗（光动力疗法、放射疗法和化学疗法）可导致肿瘤VEGF表达增加，随后导致疾病更具侵袭性（9,10）。因此，测量肿瘤中的VEGF水平对于设计更好的抗癌治疗方案很重要。贝伐单抗（Bev）是一种针对VEGF-A的人源化抗体（11），可与所有VEGF-A异构体结合，已被批准用于转移性结肠癌和非小细胞肺癌的临床治疗（12）。已证明VEGFR-2介导肿瘤内皮细胞中大多数VEGF-A的激活（13,14）。Zhang等人（15）制备了用于携带U87MG人胶质母细胞瘤异种移植裸鼠中VEGF表达的正电子发射断层扫描（PET）和近红外荧光（NIR）多模态成像的Cu-1,4,7-三氮杂环壬烷-1,4,7-三乙酸-异硫氰酸苄基-贝伐单抗-IRDye 800CW（Cu-NOTA-Bev-800CW）。U87MG细胞表达VEGF-A的所有三种异构体（VEGF VEGF和VEGF）。
