Cornali E, Zietz C, Benelli R, Weninger W, Masiello L, Breier G, Tschachler E, Albini A, Stürzl M
Abeilung Virusforschung, Max-Planck-Institut für Biochemie, Martinsried, Germany.
Am J Pathol. 1996 Dec;149(6):1851-69.
Abundant vasculature with increased permeability is a prominent histological feature of Kaposi's sarcoma (KS), a multifocal, cytokine-regulated tumor. Here we report on the role of vascular endothelial growth factor (VEGF) in AIDS-KS angiogenesis and vascular permeability. We demonstrate that different cytokines, which were previously shown to be active in KS development, modulate VEGF expression in KS spindle cells and cooperate with VEGF on the functional level. Northern blot analysis as well as studies on single cells using in situ hybridization revealed that VEGF expression in cultivated AIDS-KS spindle cells is up-regulated by platelet-derived growth factor-B and interleukin-1 beta. Western blot and enzyme-linked immunosorbent assay analysis of cell culture supernatants demonstrated that the VEGF protein is secreted by stimulated AIDS-KS spindle cells in sufficiently high amounts to activate proliferation of human dermal microvascular endothelial cells. Basic fibroblast growth factor did not increase VEGF expression but acted synergistically with VEGF in the induction of angiogenic KS-like lesions in a mouse model in vivo. Angiogenesis and cellularity of KS-like lesions were clearly increased when both factors were injected simultaneously into the flanks of mice, compared with separate injection of each factor. A comparable angiogenic reaction as obtained by simultaneous injection of basic fibroblast growth factor and VEGF was observed when cell culture supernatants of AIDS-KS spindle cells were used for these experiments. Finally, analysis of primary human AIDS-KS lesions revealed that high amounts of VEGF mRNA and protein were present in KS spindle cells in vivo. These data provide evidence that VEGF, in concert with platelet-derived growth factor-B, interleukin-1 beta, and basic fibroblast growth factor, is a key mediator of angiogenesis and vascular permeability in KS lesions in vivo.
血管丰富且通透性增加是卡波西肉瘤（KS）的一个显著组织学特征，KS是一种多灶性、细胞因子调节的肿瘤。在此，我们报告血管内皮生长因子（VEGF）在艾滋病相关KS血管生成和血管通透性中的作用。我们证明，先前显示在KS发展中起作用的不同细胞因子，可调节KS梭形细胞中VEGF的表达，并在功能水平上与VEGF协同作用。Northern印迹分析以及使用原位杂交对单细胞的研究表明，培养的艾滋病相关KS梭形细胞中VEGF的表达受血小板衍生生长因子-B和白细胞介素-1β上调。对细胞培养上清液的蛋白质印迹和酶联免疫吸附测定分析表明，受刺激的艾滋病相关KS梭形细胞分泌的VEGF蛋白量足以激活人真皮微血管内皮细胞的增殖。碱性成纤维细胞生长因子不会增加VEGF的表达，但在体内小鼠模型中诱导血管生成性KS样病变时与VEGF协同作用。与分别注射每种因子相比，当将这两种因子同时注射到小鼠侧腹时，KS样病变的血管生成和细胞密度明显增加。当使用艾滋病相关KS梭形细胞的细胞培养上清液进行这些实验时，观察到与同时注射碱性成纤维细胞生长因子和VEGF所获得的类似血管生成反应。最后，对原发性人类艾滋病相关KS病变的分析表明，体内KS梭形细胞中存在大量VEGF mRNA和蛋白。这些数据提供了证据，表明VEGF与血小板衍生生长因子-B、白细胞介素-1β和碱性成纤维细胞生长因子协同作用，是体内KS病变血管生成和血管通透性的关键介质。
