McAllister S C, Moses A V
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA.
Curr Top Microbiol Immunol. 2007;312:211-44. doi: 10.1007/978-3-540-34344-8_8.
Kaposi sarcoma (KS), the most common AIDS-associated malignancy, is a multifocal 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.
卡波西肉瘤（KS）是最常见的与艾滋病相关的恶性肿瘤，是一种多灶性肿瘤，其特征为血管生成失调、梭形细胞增殖以及炎性细胞和红细胞外渗。卡波西肉瘤相关疱疹病毒（KSHV；也称为人类疱疹病毒8型）与KS的所有临床形式都有关联。内皮细胞（EC）在体内携带KSHV基因组，在体外对病毒感染具有易感性，并且被认为是KS梭形细胞的前体。梭形细胞在早期斑块期KS病变中很少见，但在后期斑块期和结节期病变中成为主要细胞类型。因此，促进增殖和存活的内皮/梭形细胞生理学改变被认为在疾病进展中很重要，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、防止细胞凋亡以及对抗宿主免疫反应的基因。这些基因的综合作用被认为驱动了受感染梭形细胞的增殖和存活，并影响病变微环境。大规模基因表达分析表明，KSHV感染还会诱导EC转录组的显著重编程。细胞基因表达的这些变化可能有助于KS病变的发展。除了KS，KSHV还存在于包括原发性渗出性淋巴瘤和多中心Castleman病在内的B细胞肿瘤中。类似地，病毒和病毒诱导的宿主因子的组合被认为有助于这些恶性肿瘤的发生和发展。已经开发了许多基于淋巴细胞和EC的系统，这些系统为了解KSHV促进宿主细胞恶性转化的方式提供了一些见解。虽然KSHV在体外培养的PEL细胞中能很好地维持，但移植的梭形细胞会迅速丢失病毒附加体。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影响的基于内皮细胞的系统需要对原代或寿命延长的EC进行体外感染。本章包括对这些体外细胞培养系统的综述，认识到它们的优点和缺点，并阐述每种系统如何有助于我们理解复杂的KS病变环境。此外，我们根据从这些模型中收集的发现以及KS化疗的最新临床进展，提出了一个KS病变进展模型。因此，这个统一模型通过汇集多种KS进展理论来描述我们目前对KS发病机制的理解，而这些理论本身无法解释肿瘤发展的复杂性。
