TUMOR-SECRETED VASCULAR PERMEABILITY FACTOR

肿瘤分泌的血管通透性因子

• 批准号: 3186470
• 负责人: DONALD R SENGER
• 金额: $ 14.73万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-01-01 至 1990-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3186470
• 关键词: affinity chromatography; antibody neutralization test; deficient growth media; gene expression; guinea pigs; high performance liquid chromatography; histamine release; human tissue; immunologic techniques; inflammation; laboratory mouse; laboratory rabbit; malignant ascites; monoclonal antibody; neoplastic cell; neoplastic growth; neoplastic transformation; osteosarcoma; pleural neoplasms; protein sequence; protein structure; proteins; tissue /cell culture; vascular endothelium; vascular endothelium permeability

A variety of tumor cells of both rodent and human origin secrete in vitro and in vivo, a novel vascular permeability factor with an approximate molecular weight of 38,000. This permeability factor (VPF) causes a rapid and completely reversible increase in microvascular permeability without causing endothelial cell damage or exciting an inflammatory cell infiltrate. Furthermore, VPF is active in the species from which it is derived (e.g., guinea pig tumor-secreted VPF is active on guinea pig vessels), and it does not appear to mediate its effects through histamine release, kinin generation, or prostaglandin synthesis. VPF is abundantly present in animal tumor ascites fluids but is not detectable in normal serum or plasma, and furthermore, while it is secreted by a variety of tumor cell lines (carcinomas and sarcomas), it is apparently not secreted by normal epithelial cells or fibroblasts. Direct comparisons between non-tumorigenic human cell lines and their tumorigenic derivatives suggest that expression of VPF is closely linked to neoplastic transformation, and taken together, out data suggest that tumor-secreted VPF is responsible, at least in part and perhaps to a large extent, for the fluid accumulation and increased vessel permeability commonly associated with tumor growth. A major goal is to purify this permeability factor to homogeneity and to obtain a panel of monoclonal antibodies specific for this protein. In addition, the purified protein will be subjected to amino acid sequence analysis; partial amino acid sequence and highly-specific antibodies will greatly facilitate efforts at cloning cDNA encoding VPF (not within the scope of the present proposal). A second major goal is to continue our study of the biology of VPF. Specific antibodies to VPF will be employed in immunoassays to investigate further the apparent correlation between expression of VPF and neoplastic transformation. In addition, blocking antibodies will be employed in animal models to ascertain the potential significance of VPF for tumor growth and fluid accumulation. Finally, experiments will be undertaken to identify non-malignant situations in which VPF might be expressed; and in particular the possibility that inflammatory cells secrete this protein will be examined.

多种啮齿动物和人类来源的肿瘤细胞在体外分泌 在体内，一种新型血管通透性因子的近似值 分子量38,000。 该渗透系数 (VPF) 会导致快速 和完全可逆的微血管通透性增加，而无需 引起内皮细胞损伤或刺激炎症细胞 浸润。此外，VPF 在其来源的物种中具有活性 衍生的（例如，豚鼠肿瘤分泌的 VPF 对豚鼠有活性） 血管），并且它似乎不通过组胺介导其作用 释放、激肽生成或前列腺素合成。 VPF 丰富 存在于动物肿瘤腹水中，但在正常人中检测不到 血清或血浆，此外，虽然它是由多种细胞分泌的 肿瘤细胞系（癌和肉瘤），它显然不分泌 由正常上皮细胞或成纤维细胞产生。 之间的直接比较 非致瘤人类细胞系及其致瘤衍生物表明 VPF 的表达与肿瘤转化密切相关，并且 综合起来，我们的数据表明肿瘤分泌的 VPF 是造成这种情况的原因 至少部分地，或许在很大程度上，是为了流体的积累和 血管通透性增加通常与肿瘤生长相关。 一个主要目标是纯化该渗透系数使其均匀并 获得一组针对该蛋白质的单克隆抗体。 在 另外，纯化后的蛋白质将进行氨基酸序列分析 分析;部分氨基酸序列和高度特异性的抗体将 极大地促进了克隆编码 VPF 的 cDNA 的工作（不在 本提案的范围）。 第二个主要目标是继续我们对 VPF 生物学的研究。 VPF 特异性抗体将用于免疫分析中进行研究 进一步证实了 VPF 表达与肿瘤之间的明显相关性 转变。 此外，阻断抗体将用于 动物模型以确定 VPF 对肿瘤的潜在意义 生长和体液积累。 最后，将进行实验 确定 VPF 可能表达的非恶性情况；并在 特别是炎症细胞分泌这种蛋白质的可能性 将接受检查。