KSHV Induction of Angiogenic and Lympliangiogenic Phenotypes

卡波西肉瘤（Kaposi 'sSarcoma，KS）是艾滋病患者最常见的口腔恶性肿瘤，发病率和死亡率都很高。KS的主要肿瘤细胞是梭形细胞，一种内皮源性细胞。KS的病原体是卡波西肉瘤相关疱疹病毒（KSHV），并发现在所有KS肿瘤的梭形细胞。该提案旨在了解潜伏的KSHV如何通过血管生成和淋巴管生成途径激活内皮细胞，以诱导口腔环境中的KS肿瘤。潜在的KSHV感染增加血管生成和淋巴管生成受体在内皮细胞的表达，这个建议将检查KSHV如何激活血管生成和淋巴管生成表型。 整合素在血管生成中起关键作用，并且在第一个目的中，将检查KSHV诱导的整合素在潜伏期期间诱导血管生成表型中的作用。许多整联蛋白抑制剂正在进行临床试验，这些研究将确定这些抑制剂治疗KS肿瘤的潜力。 KSHV还诱导血液内皮细胞分化为淋巴管内皮细胞。KS肿瘤中的梭形细胞表达淋巴管内皮的标志物，特别是VEGF受体3，其是诱导淋巴管生成的关键受体。目的2探讨KSHV诱导血淋巴细胞增殖的机制 将检查内皮细胞分化，并分析参与该过程的新因素，以确定KSHV诱导的淋巴管内皮重编程的机制。最后，在目标3中，我们将确定目标1中描述的整合素是否在口腔KS肿瘤中高度表达。还将在KS组织中检查先前未确定的对KSHV诱导的血液向淋巴管内皮细胞分化至关重要的细胞因子的表达。KSHV诱导血管生成和淋巴管生成受体和表型，更好地理解KSHV如何通过这些受体和表型激活内皮细胞， 这将为KSHV和KS肿瘤带来新的更好的治疗选择。

Kaposi's Sarcoma (KS) is the most common oral malignancy of AIDS patients and causes significant morbidity and mortality. The main tumor cell of KS is the spindle cell, a cell of endothelial origin. The etiologic agent of KS is Kaposi's Sarcoma-associated herpesvirus (KSHV) and is found in the spindle cells of all KS tumors. This proposal seeks to understand how latent KSHV activates endothelial cells through angiogenic and lymphangiogenic pathways to induce KS tumors in the oral environment. Latent KSHV infection increases the expression of both angiogenic and lymphangiogenic receptors in endothelial cells and this proposal will examine how KSHV activates both angiogenic and lymphangiogenic phenotypes. Integrins play a critical role in angiogenesis and in the first Aim, the role of KSHV induced integrins in the induction of angiogenic phenotypes during latency will be examined. A number of integrin inhibitors are in clinical trials and these studies will determine the potential of these inhibitors for treatment of KS tumors. KSHV also induces the differentiation of blood endothelial cells to lymphatic endothelial cells. Spindle cells in the KS tumor express markers of lymphatic endothelium and in particular VEGF receptor3 a key receptor in the induction of lymphangiogenesis. In Aim 2 the mechanism of KSHV induced blood to lymphatic endothelial cell differentiation will be examined and new factors involved in this process will be analyzed to determine the mechanism of KSHV induced reprogramming to lymphatic endothelium. Finally, in Aim 3 we will determine if the integrins described in Aim 1 are highly expressed in oral KS tumors. The expression of previously undefined cellular factors critical for KSHV induced blood to lymphatic endothelial cell differentiation will also be examined in KS tissue. KSHV induces both angiogenic and lymphangiogenic receptors and phenotypes and a better understanding of how KSHV activates endothelial cells through these pathways will lead to new and better treatment options for KSHV and KS tumors.