KSHV immortalization of human lymphatic endothelial cells

摘要： 机会性感染是艾滋病患者发病和死亡的主要原因 国家和艾滋病患者容易患上由机会性感染引起的多种癌症。 卡波西肉瘤(KS)是艾滋病患者最常见的肿瘤，也是报道最多的肿瘤 非洲部分地区的总体肿瘤。KS的病原体是卡波西肉瘤相关疱疹病毒 (KSHV或HHV-8)。KSHV总是存在于主要的KS肿瘤细胞、梭形细胞、 内皮细胞起源，病毒主要以潜伏状态存在。梭形细胞表达 淋巴管内皮细胞的标志物，似乎与这种内皮细胞最接近 打字。虽然KSHV显然是一种致癌病毒，但人们对KSHV如何早期步骤知之甚少 血管内皮细胞感染会导致肿瘤。人们普遍认为，早期的步骤之一是 肿瘤的形成是细胞的永生化。人类细胞永生有两个主要步骤， 衰老和危机。虽然已经有研究检验了KSHV诱导的永生 目前还没有明确、易处理和可靠的相关人体细胞系统。我们 新近发现KSHV感染原代新生淋巴管内皮细胞导致旁路 衰老，永生的第一步。这项建议将进一步分析KSHV调解的 绕过衰老，并确定KSHV是否可以驱动完全永生，或者其他遗传步骤是否 这是必要的。KSHV介导淋巴管永生化的细胞和病毒机制 内皮细胞也将被阐明。这些研究为分析KSHV提供了一个可靠的系统 介导与KS主要肿瘤细胞--梭形细胞关系最密切的细胞类型永生化。 更深入地了解KSHV如何诱导永生的最早步骤将有助于确定如何 KSHV改变内皮细胞成为梭形细胞，最终成为KS肿瘤，并潜在地提供 治疗KS细胞增殖的新途径。

Abstract: Opportunistic infections are a major cause of morbidity and mortality of AIDS patients in developing countries and AIDS patients are susceptible to a number of cancers caused by opportunistic infections. Kaposi's Sarcoma (KS) is the most common tumor of AIDS patients and is the most commonly reported tumor overall in parts of Africa. The etiologic agent of KS is Kaposi's Sarcoma-associated herpesvirus (KSHV or HHV-8). KSHV is invariably found in the main KS tumor cell, the spindle cell, a cell of endothelial origin, where the virus is present predominantly in the latent state. Spindle cells express markers of lymphatic endothelial cells and appear to be most closely aligned with this endothelial cells type. While KSHV is clearly an oncogenic virus, little is known about the early steps of how KSHV infection of endothelial cells leads to tumors. It is generally recognized that one of the early steps of tumor formation is immortalization of cells. There are two main steps in immortalization of human cells, senescence and crisis. While there have been studies that have examined KSHV Induced immortalization and transformation, no clear tractable and reliable relevant human cell system has be identified. We recently found that KSHV infection of primary neonatal lymphatic endothelial cells leads to bypass of senescence, the first step in immortalization. This proposal will further analyze the KSHV mediated bypass of senescence and determine if KSHV can drive full immortalization or if other genetic steps are necessary. Both the cellular and viral mechanism of KSHV mediated immortalization of lymphatic endothelial cells will also be elucidated. These studies provide a robust system for analyzing KSHV mediated immortalization of the cell type most closely related to the main KS tumor cell, the spindle cell. A deeper understanding of how KSHV induces the earliest steps in immortalization will help identify how KSHV alters endothelial cells to become spindle cells and ultimately KS tumors and potentially provides novel therapeutic avenues for KS cell proliferation.