Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels.
Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels.
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DOI：
10.1084/jem.174.5.1275
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发表时间：
1991-11-01
期刊：
影响因子：
--
通讯作者：
Senger DR
中科院分区：
文献类型：
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作者：
Dvorak HF;Sioussat TM;Brown LF;Berse B;Nagy JA;Sotrel A;Manseau EJ;Van de Water L;Senger DR
血管通透性因子（Vascular permeability factor， VPF）是一种高度保守的34-42-kD蛋白，由许多肿瘤细胞分泌。在已知的最有效的血管通透性增强因子中，VPF也是一种选择性血管内皮细胞有丝分裂原，因此被称为血管内皮细胞生长因子（VEGF）。我们的目标是确定VPF （VEGF）在体内肿瘤中合成和积累的细胞位点。免疫组织化学研究在实体和腹水豚鼠1号线和10号线胆管癌上进行，使用抗体直接针对合成的代表nh2末端和VPF内部序列的肽。这些抗体染色肿瘤细胞，并均匀且最强烈地染色直接邻近血管的内皮，包括先前存在的和由肿瘤血管生成新诱导的血管。在人原发性淋巴瘤中也观察到类似的VPF染色模式。原位杂交显示VPF mRNA几乎存在于所有的10号系肿瘤细胞中，但不存在于肿瘤血管中，这表明用VPF肽抗体对肿瘤血管进行免疫组化标记反映了VPF的摄取，而不是内源性合成。早在肿瘤移植后5小时，邻近的预先存在的小静脉和小静脉就出现了VPF蛋白染色，在新诱导的肿瘤血管中，VPF蛋白染色在大约5天后达到了最高水平。VPF染色的血管也对大分子具有高透性，这可以通过它们积累循环胶体碳的能力来判断。相比之下，距离肿瘤约0.5 mm以上的血管没有高透性，也没有VPF的免疫组织化学染色。血管染色在肿瘤排斥反应24-48小时内消失。这些研究表明，VPF在体内由肿瘤细胞合成，并在其作用靶点附近的血管中积累。由于肿瘤血管渗漏引发一系列事件，包括血浆外渗并最终导致血管生成和肿瘤间质形成，VPF可能在促进肿瘤生长中起关键作用。此外，VPF免疫染色为肿瘤血管提供了一种新的标记物，可用于肿瘤成像或治疗。
Vascular permeability factor (VPF) is a highly conserved 34-42-kD protein secreted by many tumor cells. Among the most potent vascular permeability-enhancing factors known, VPF is also a selective vascular endothelial cell mitogen, and therefore has been called vascular endothelial cell growth factor (VEGF). Our goal was to define the cellular sites of VPF (VEGF) synthesis and accumulation in tumors in vivo. Immunohistochemical studies were performed on solid and ascites guinea pig line 1 and line 10 bile duct carcinomas using antibodies directed against peptides synthesized to represent the NH2-terminal and internal sequences of VPF. These antibodies stained tumor cells and, uniformly and most intensely, the endothelium of immediately adjacent blood vessels, both preexisting and those newly induced by tumor angiogenesis. A similar pattern of VPF staining was observed in autochthonous human lymphoma. In situ hybridization demonstrated VPF mRNA in nearly all line 10 tumor cells but not in tumor blood vessels, indicating that immunohistochemical labeling of tumor vessels with antibodies to VPF peptides reflects uptake of VPF, not endogenous synthesis. VPF protein staining was evident in adjacent preexisting venules and small veins as early as 5 h after tumor transplant and plateaued at maximally intense levels in newly induced tumor vessels by approximately 5 d. VPF-stained vessels were also hyperpermeable to macromolecules as judged by their capacity to accumulate circulating colloidal carbon. In contrast, vessels more than approximately 0.5 mm distant from tumors were not hyperpermeable and did not exhibit immunohistochemical staining for VPF. Vessel staining disappeared within 24-48 h of tumor rejection. These studies indicate that VPF is synthesized by tumor cells in vivo and accumulates in nearby blood vessels, its target of action. Because leaky tumor vessels initiate a cascade of events, which include plasma extravasation and which lead ultimately to angiogenesis and tumor stroma formation, VPF may have a pivotal role in promoting tumor growth. Also, VPF immunostaining provides a new marker for tumor blood vessels that may be exploitable for tumor imaging or therapy.