Berkman R A, Merrill M J, Reinhold W C, Monacci W T, Saxena A, Clark W C, Robertson J T, Ali I U, Oldfield E H
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
J Clin Invest. 1993 Jan;91(1):153-9. doi: 10.1172/JCI116165.
Expression of the vascular permeability factor/vascular endothelial growth factor (VEGPF) gene was investigated in human central nervous system (CNS) neoplasms and normal brain. Adsorption of capillary permeability activity from human glioblastoma multiforme (GBM) cell conditioned medium and GBM cyst fluids by anti-VEGPF antibodies demonstrated that VEGPF is secreted by GBM cells and is present in sufficient quantities in vivo to induce vascular permeability. Cloning and sequencing of polymerase chain reaction-amplified GBM and normal brain cDNA demonstrated three forms of the VEGPF coding region (567, 495, and 363 nucleotides), corresponding to mature polypeptides of 189, 165, and 121 amino acids, respectively. VEGPF mRNA levels in CNS tumors vs. normal brain were investigated by the RNase protection assay. Significant elevation of VEGPF gene expression was observed in 81% (22/27) of the highly vascular and edema-associated CNS neoplasms (6/8 GBM, 8/8 capillary hemangioblastomas, 6/7 meningiomas, and 2/4 cerebral metastases). In contrast, only 13% (2/15) of those CNS tumors that are not commonly associated with significant neovascularity or cerebral edema (2/10 pituitary adenomas and 0/5 nonastrocytic gliomas) had significantly increased levels of VEGPF mRNA. The relative abundance of the forms of VEGPF mRNA was consistent in tumor and normal brain: VEGPF495 > VEGPF363 > VEGPF567. In situ hybridization confirmed the presence of VEGPF mRNA in tumor cells and its increased abundance in capillary hemangioblastomas. Our results suggest a significant role for VEGPF in the development of CNS tumor neovascularity and peritumoral edema.
在人类中枢神经系统（CNS）肿瘤和正常脑组织中研究了血管通透性因子/血管内皮生长因子（VEGPF）基因的表达。抗VEGPF抗体对人多形性胶质母细胞瘤（GBM）细胞条件培养基和GBM囊肿液中毛细血管通透性活性的吸附表明，VEGPF由GBM细胞分泌，且在体内含量足以诱导血管通透性。对聚合酶链反应扩增的GBM和正常脑cDNA进行克隆和测序，发现VEGPF编码区有三种形式（567、495和363个核苷酸），分别对应189、165和121个氨基酸的成熟多肽。采用核糖核酸酶保护试验研究了中枢神经系统肿瘤与正常脑组织中VEGPF mRNA水平。在81%（22/27）的高血管化且与水肿相关的中枢神经系统肿瘤（6/8 GBM、8/8毛细血管性成血管细胞瘤、6/7脑膜瘤和2/4脑转移瘤）中观察到VEGPF基因表达显著升高。相比之下，在那些通常与显著新生血管形成或脑水肿无关的中枢神经系统肿瘤中，只有13%（2/15）（2/10垂体腺瘤和0/5非星形细胞胶质瘤）的VEGPF mRNA水平显著升高。肿瘤和正常脑组织中VEGPF mRNA各形式的相对丰度一致：VEGPF495 > VEGPF363 > VEGPF567。原位杂交证实肿瘤细胞中存在VEGPF mRNA，且在毛细血管性成血管细胞瘤中其丰度增加。我们的结果表明VEGPF在中枢神经系统肿瘤新生血管形成和瘤周水肿的发生发展中起重要作用。
