Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor vascular permeability factor antibody
Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor vascular permeability factor antibody
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DOI：
10.1073/pnas.93.25.14765
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发表时间：
1996-12-10
影响因子：
11.1
通讯作者：
Jain, RK
中科院分区：
文献类型：
--
作者：
Yuan, F;Chen, Y;Jain, RK
与正常血管相比，肿瘤血管对大分子物质的高通透性可能是由于肿瘤细胞和/或宿主细胞释放的血管内皮生长因子/血管通透性因子（VEGF/VPF）所致。此外，VEGF/VPF是一种强有力的血管生成因子，去除这种生长因子可降低通透性，抑制肿瘤血管生成。为了验证这些假设，我们将人胶质母细胞瘤（U87）、人结肠腺癌（LS 174 T）和人黑色素瘤（P-MEL）移植到免疫缺陷小鼠的两个位置：颅窗和背皮褶腔，携带血管化肿瘤的小鼠用推注治疗，（0.2 ml）抗VEGF/VPF的中和抗体（A4.6.1）（492 μ g/ml）或PBS（对照）。我们发现，抗体治疗组的肿瘤血管对白蛋白的渗透性低于匹配对照组，并且抗体的作用是时间依赖性的，并受注射方式的影响。肿瘤血管渗透性直到治疗后4天才对腹腔注射抗体产生反应，然而，在静脉注射等量抗体后6小时内渗透性降低，除了血管渗透性的降低之外，在抗体注射后，肿瘤血管的直径变得更小并且弯曲度更小，并且在U87肿瘤中连续四次治疗后最终从表面消失，这些结果表明，肿瘤血管通透性可以通过中和内源性VEGF/VEGF受体而降低。VPF和表明，血管生成和肿瘤血管的完整性的维持需要VEGF/VPF在组织微环境中的存在。后一个发现揭示了肿瘤血管消退的新机制，即，在实体瘤中阻断VEGF/VPF与内皮细胞之间的相互作用或抑制VEGF/VPF的合成会导致血管直径显著减小，这可能会阻断血液成分的通过，从而导致血管退化。
The hyperpermeability of tumor vessels to macromolecules, compared with normal vessels, is presumably due to vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) released by neoplastic and/or host cells, In addition, VEGF/VPF is a potent angiogenic factor, Removal of this growth factor may reduce the permeability and inhibit tumor angiogenesis. To test these hypotheses, we transplanted a human glioblastoma (U87), a human colon adenocarcinoma (LS174T), and a human melanoma (P-MEL) into two locations in immunodeficient mice: the cranial window and the dorsal skinfold chamber, The mice bearing vascularized tumors were treated with a bolus (0.2 ml) of either a neutralizing antibody (A4.6.1) (492 mu g/ml) against VEGF/VPF or PBS (control). We found that tumor vascular permeability to albumin in antibody-treated groups was lower than in the matched controls and that the effect of the antibody was time-dependent and influenced by the mode of injection, Tumor vascular permeability did not respond to i.p. injection of the antibody until 4 days posttreatment, However, the permeability was reduced within 6 h after i.v. injection of the same amount of antibody, In addition to the reduction in vascular permeability, the tumor vessels became smaller in diameter and less tortuous after antibody injections and eventually disappeared from the surface after four consecutive treatments in U87 tumors, These results demonstrate that tumor vascular permeability can be reduced by neutralization of endogenous VEGF/VPF and suggest that angiogenesis and the maintenance of integrity of tumor vessels require the presence of VEGF/VPF in the tissue microenvironment. The latter finding reveals a new mechanism of tumor vessel regression-i.e., blocking the interactions between VEGF/VPF and endothelial cells or inhibiting VEGF/VPF synthesis in solid tumors causes dramatic reduction in vessel diameter, which mag block the passage of blood elements and thus lead to vascular regression.