ANGIOGENIC FACTORS AND THEIR EXPRESSION/REGULATION IN KS

卡波西肉瘤是一种肿瘤，其病变主要由 异常的血管增殖。肿瘤组织，或KS来源的纺锤体 当细胞被放置在裸鼠的皮下时，可以诱导血管 类似卡波西氏肉瘤的病变，起源于小鼠组织。 此外，病变显示血管延迟(12小时)。 高渗透反应。因此，这个肿瘤提供了一个很好的模型。 系统不仅对肿瘤本身有更多的了解，而且 参与血管生成的信号，并研究可以 后来被用来治疗各种疾病，包括血管 疾病、恶性肿瘤和炎症性疾病。 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 通透性因子(VDGF/VPF)，具有信号肽，可分泌。 血管内皮生长因子/血管内皮生长因子和成纤维细胞生长因子由卡波西肉瘤来源的梭形细胞产生。 血管生成的二级介质(如肿瘤坏死因子、肿瘤坏死因子-α和β-干扰素、 血管生成素等)仅在体内诱导血管新生损伤。因此，这些 因素必须通过诱导原发来发挥它们的反应 调解人。KS来源的梭形细胞产生许多这样的细胞因子 (转化生长因子-β、IL-1和IL-6)。 此外，类固醇激素调节细胞因子的表达，进而 调节血管生成因子。或者，类固醇激素可以 直接调节血管生成因子。我们还表明， 糖皮质激素可过度增强IL-6的表达，进而 上调血管内皮生长因子/血管内皮生长因子。基于以上原因，我们建议研究 后续使用血管内皮细胞和血管平滑肌 作为控件的单元格： (1)已知的血管生成主要介质在血管生成中的表达 KS来源的梭形细胞及其类固醇激素和激素的调节 细胞因子；(2)进一步定义小说的存在或不存在 KS来源的梭形细胞表达血管生成因子；(Iii)研究 IL-6和血管内皮细胞生长因子/血管内皮生长因子的信号转导途径； 糖皮质激素对KS细胞IL-6的反常上调作用 纺锤形细胞并与其他类型的细胞进行比较。

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.