ANGIOGENIC FACTORS AND THEIR EXPRESSION/REGULATION IN KS

卡波西肉瘤是一种肿瘤，其中病变主要包括 异常血管增生 肿瘤组织或KS衍生的纺锤体 细胞，当放置在裸鼠皮下时，诱导血管生成。 类似卡波西肉瘤的病变，并且是小鼠组织来源的。 此外，病变显示延迟（12小时）的血管 高渗透性反应 因此，该肿瘤提供了一个极好的模型， 系统不仅要了解更多关于肿瘤本身，而且还要了解 参与血管生成的信号，并研究可以 后来被用于治疗各种疾病，包括血管疾病， 疾病、恶性肿瘤和炎性疾病。 血管生成的主要介质包括：（i）成纤维细胞生长因子， 碱性和酸性，两者都缺乏信号肽，因此不是 分泌的，和（ii）血管内皮细胞生长因子或血管内皮细胞生长因子 血管通透性因子（VDGF/VPF）是一种具有信号肽的分泌型血管通透性因子。 VEGF/VPF和FGF由卡波西肉瘤衍生的梭形细胞产生。 血管生成的次级介质（如TNF、TFG-α和β， 血管生成素等）仅在体内诱导血管生成损伤。 因此这些 因素必须通过诱导初级 调解员 KS衍生的梭形细胞产生许多这些细胞因子 （TGF-β、IL-1和IL-6）。 此外，类固醇激素调节细胞因子的表达， 调节血管生成因子。 或者，类固醇激素可 直接调节血管生成因子。 我们还表明， 糖皮质激素反常地增强IL-6的表达， 上调VEGF/VPF。 基于上述情况，我们建议研究 使用血管内皮细胞和血管平滑肌 细胞作为对照： (1)已知的血管生成的主要介质的表达， KS来源的梭形细胞及其受类固醇激素和 （ii）进一步定义新的细胞因子的存在或不存在。 由KS衍生的梭形细胞表达的血管生成因子;（iii）研究 IL-6和VEGF/VPF的转导途径;（iv）确定 糖皮质激素对KS细胞中IL-6的矛盾上调 梭形细胞，并与其他细胞类型进行比较。

Kaposi's sarcoma is a tumor in which the lesion predominantly consists of aberrant vascular proliferation. The tumor tissue, or KS-derived spindle cells, when placed subcutaneously in the nude mouse, induces a vascular lesion resembling Kaposi's sarcoma and is of mouse tissue origin. Further, the lesion demonstrates a delayed (12 hr) vascular hyperpermeability response. Thus, this tumor provides an excellent model system to not only understand more about the tumor itself, but also the signals involved in angiogenesis, and to study inhibitors that could later be used for therapy of a variety of diseases, including vascular diseases, malignancy and inflammatory disease. Primary mediators of angiogenesis include: (i) fibroblast growth factors, basic and acidic, both of which lack signal peptide and thus are not secreted, and (ii) vascular endothelial cell growth factor or vascular permeability factor (VDGF/VPF) which has signal peptide and is secreted. VEGF/VPF and FGFs are produced by Kaposi's sarcoma derived spindle cells. Secondary mediators of angiogenesis (such as TNF, TFG-alpha and beta, angiogenin etc) induce angiogenic lesions only in vivo. Thus, these factors must exert their response through the induction of primary mediators. KS derived spindle cells produces many of these cytokines (TGF-beta, IL-1 and IL-6). Further, steroid hormones regulate cytokine expression which in turn regulates angiogenic factors. Alternatively steroid hormones may directly regulate angiogenic factors. We have also shown that glucocorticoids pardoxically enhance IL-6 expression, which in turn upregulates VEGF/VPF. Based on the above, we propose to study the following using vascular endothelial cells and vascular smooth muscle cells as controls: (1) The expression of known primary mediators of angiogenesis in KS-derived spindle cells and their regulation by steroid hormones and cytokines; (ii) Define further the presence or absence of a novel angiogenic factor expressed by KS-derived spindle cells; (iii) Study the transduction pathway of IL-6 and VEGF/VPF; (iv) Define the mechanism of the paradoxical upregulation of IL-6 with glucocorticoids in KS derived spindle cells and compare to other cell types.