Endothelial cell- and lymphocyte-based in vitro systems for understanding KSHV biology.
Endothelial cell- and lymphocyte-based in vitro systems for understanding KSHV biology.
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DOI：
10.1007/978-3-540-34344-8_8
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发表时间：
2007
影响因子：
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通讯作者：
S. McAllister;A. Moses
中科院分区：
文献类型：
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作者：
S. McAllister;A. Moses
卡波西肉瘤（Kaposi sarcoma，KS）是一种多灶性肿瘤，以血管生成失调、梭形细胞增生、炎性细胞和红细胞外渗为特征。卡波西肉瘤相关疱疹病毒（KSHV;也是人疱疹病毒-8）涉及所有临床形式的KS。内皮细胞（EC）在体内携带KSHV基因组，在体外允许病毒感染，并且被认为是KS梭形细胞的前体。梭形细胞是罕见的早期斑块阶段KS病变，但成为主要的细胞类型，在后期斑块和结节阶段的病变。因此，促进增殖和存活的内皮/梭形细胞生理学的改变被认为在疾病进展中是重要的，并且可能代表潜在的治疗靶点。KSHV编码刺激细胞增殖和迁移、防止细胞凋亡和对抗宿主免疫应答的基因。这些基因的联合作用被认为是驱动受感染梭形细胞的增殖和存活，并影响病变微环境。大规模的基因表达分析表明，KSHV感染也诱导EC转录组的显着重编程。细胞基因表达的这些变化可能有助于KS病变的发展。除KS外，KSHV还存在于B细胞瘤形成中，包括原发性渗出性淋巴瘤和多中心Castleman病。病毒和病毒诱导的宿主因子的组合同样被认为有助于这些恶性肿瘤的建立和进展。已经开发了许多基于淋巴细胞和EC的系统，这些系统提供了对KSHV促成宿主细胞恶性转化的手段的一些了解。尽管KSHV在体外培养的PEL细胞中保持良好，但接种的梭形细胞迅速失去病毒附加体。因此，用于研究KSHV基因表达和功能以及感染对宿主细胞生理学的影响的基于内皮细胞的系统需要体外感染原发性或寿命延长的EC。本章包括这些在体外细胞培养系统的审查，承认他们的长处和短处，并把每个角度如何有助于我们了解复杂的KS病变环境。此外，我们提出了一个模型的KS病变进展的基础上，从这些模型以及KS化疗的最新临床进展。因此，这个统一的模型描述了我们目前对KS发病机制的理解，将KS进展的多种理论结合在一起，这些理论本身不能解释肿瘤发展的复杂性。
Kaposi sarcoma (KS), the most common AIDS-associated malignancy, is amultifocal tumor characterized by deregulated angiogenesis, proliferation of spindle cells, and extravasation of inflammatory cells and erythrocytes. Kaposi sarcoma-associated herpesvirus (KSHV; also human herpesvirus-8) is implicated in all clinical forms of KS. Endothelial cells (EC) harbor the KSHV genome in vivo, are permissive for virus infection in vitro, and are thought to be the precursors of KS spindle cells. Spindle cells are rare in early patch-stage KS lesions but become the predominant cell type in later plaque- and nodular-stage lesions. Alterations in endothelial/spindle cell physiology that promote proliferation and survival are thus thought to be important in disease progression and may represent potential therapeutic targets. KSHV encodes genes that stimulate cellular proliferation and migration, prevent apoptosis, and counter the host immune response. The combined effect of these genes is thought to drive the proliferation and survival of infected spindle cells and influence the lesional microenvironment. Large-scale gene expression analyses have revealed that KSHV infection also induces dramatic reprogramming of the EC transcriptome. These changes in cellular gene expression likely contribute to the development of the KS lesion. In addition to KS, KSHV is also present in B cell neoplasias including primary effusion lymphoma and multicentric Castleman disease. A combination of virus and virus-induced host factors are similarly thought to contribute to establishment and progression of these malignancies. A number of lymphocyte- and EC-based systems have been developed that afford some insight into the means by which KSHV contributes to malignant transformation of host cells. Whereas KSHV is well maintained in PEL cells cultured in vitro, explanted spindle cells rapidly lose the viral episome. Thus, endothelial cell-based systems for studying KSHV gene expression and function, as well as the effect of infection on host cell physiology, have required in vitro infection of primary or life-extended EC. This chapter includes a review of these in vitro cell culture systems, acknowledging their strengths and weaknesses and putting into perspective how each has contributed to our understanding of the complex KS lesional environment. In addition, we present a model of KS lesion progression based on findings culled from these models as well as recent clinical advances in KS chemotherapy. Thus this unifying model describes our current understanding of KS pathogenesis by drawing together multiple theories of KS progression that by themselves cannot account for the complexities of tumor development.