Viral G protein-coupled receptor and Kaposi's sarcoma: a model of paracrine neoplasia?
Viral G protein-coupled receptor and Kaposi's sarcoma: a model of paracrine neoplasia?
复制标题
DOI：
10.1084/jem.191.3.417
复制
发表时间：
2000-02-07
期刊：
影响因子：
--
通讯作者：
Gershengorn MC
中科院分区：
文献类型：
--
作者：
Cesarman E;Mesri EA;Gershengorn MC
最近发现的人类疱疹病毒，卡波西肉瘤（KS）相关疱疹病毒（KSHV）或人类疱疹病毒8（HHV-8），已被发现是所有形式KS的必要病原体，尽管可能不是充分病原体（1，2）。这种病毒也总是存在于一种罕见的恶性淋巴瘤亚组，原发性渗出性淋巴瘤（PEL），以及相当大比例的多中心Castleman病患者中，这是一种血管淋巴增生性疾病（3，4）。KS和PEL都更频繁地发生在HIV感染者中，但不是唯一的，所有HIV相关的多中心Castleman病病例都感染了KSHV。这些研究结果表明，免疫抑制和HIV感染在KSHV介导的发病机制中起重要作用。尽管KS是否为恶性肿瘤仍存在争议，但KS病变可能从反应性、炎症/血管增生过程演变为真正的克隆性癌症。因此，KS通常被认为是一种恶性肿瘤，特别是因为其频繁的多灶性和侵袭性行为。鉴于KSHV与两种不同的人类恶性肿瘤的明确关联，将KSHV视为人类致癌病毒并不困难。KSHV是一种γ疱疹病毒，其分别与人和猿猴病毒EBV和疱疹病毒saimiri（HVS）同源，其能够在培养物中转化淋巴细胞并在某些情况下引起恶性淋巴瘤。基因组测序显示，KSHV含有几个可能具有致癌相关功能的基因，这些基因破坏了参与细胞活化、增殖、分化和存活的途径。这些基因中的许多是细胞基因的病毒同源物，包括编码病毒细胞周期蛋白D、IFN调节因子（IRF）、病毒IL-6（vIL-6）、BCL-2、FLICE抑制蛋白（FLIP）、三种趋化因子（病毒巨噬细胞炎性蛋白[vMIP]-I、-II和-III）以及最后但并非最不重要的G蛋白偶联受体（KSHV GPCR）的那些。在小鼠成纤维细胞试验中发现这些基因中的三个（vIRF、KSHV GPCR和vIL-6）转化，并且两个与细胞癌基因同源（vBCL-2和v-细胞周期蛋白D）。另外两种没有直接细胞对应物的病毒基因，即由开放阅读框K1（含有基于免疫受体酪氨酸的激活基序[ITAM]）和K12编码的基因，也已在某些实验测定中发现转化。因此，KSHV有资格成为迄今为止鉴定出的具有最多推定致癌基因的病毒。因此，出现了以下困境：尽管在西方国家KSHV感染的血清阳性率至少为5%，但为什么KSHV相关肿瘤在普通人群中如此罕见？为什么KSHV在感染培养细胞后转化率很低？这可以部分解释为KSHV介导的发病机制将由病毒基因表达的特定模式和这些基因表达的特定细胞背景决定，这两者都高度依赖于宿主因素（5，6）。大多数发现或怀疑转化的基因是裂解基因，其仅在KS病变和PEL中的细胞亚群中转录。然而，在Yang等人的文章中，这样稀疏表达的单个基因产物的致病潜力被优雅地证明了。Yang等人的报告提供了第一个使用单个KSHV基因（趋化因子受体KSHV GPCR）的KS转基因小鼠模型。在这项研究中，发现KSHV GPCR在转基因小鼠造血细胞中的表达导致血管增生性病变，表现出KS的大部分特征。这个病毒
The most recently identified human herpesvirus, Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8), has been found to be a necessary, although perhaps not sufficient, etiologic agent for all forms of KS (1, 2). This virus is also invariably present in a rare subset of malignant lymphomas, primary effusion lymphomas (PELs), and in a significant percentage of patients with multicentric Castleman’s disease, an angiolymphoproliferative disorder (3, 4). Both KS and PEL occur more frequently, but not exclusively, in HIV-infected individuals, and all cases of HIV-related multicentric Castleman’s disease are infected with KSHV. These findings suggest an important role of immunosuppression and HIV infection in KSHV-mediated pathogenesis. Although it remains controversial whether KS is a malignant neoplasm, KS lesions probably evolve from a reactive, inflammatory/angioproliferative process into true clonal cancers. Thus, KS is generally considered a malignancy, especially because of its frequent multifocal and aggressive behavior. Given the definitive association of KSHV with two different human malignancies, it is not difficult to consider KSHV to be a human oncogenic virus. KSHV is a gammaherpesvirus that is homologous to EBV and herpesvirus saimiri (HVS), human and simian viruses, respectively, that are able to transform lymphoid cells in culture and cause malignant lymphomas in some circumstances. Genomic sequencing has revealed that KSHV contains several genes with likely oncogenesis-related functions that subvert pathways involved in cellular activation, proliferation, differentiation, and survival. Many of these genes are viral homologues of cellular genes, including those encoding viral cyclin D, IFN regulatory factors (IRFs), viral IL-6 (vIL-6), BCL-2, FLICE-inhibitory protein (FLIP), three chemokines (viral macrophage inflammatory protein [vMIP]-I,-II, and-III) and last, but not least, a G protein–coupled receptor (KSHV GPCR). Three of these genes have been found to be transforming in mouse fibroblast assays (vIRF, KSHV GPCR, and vIL-6), and two are homologous to cellular oncogenes (vBCL-2 and v-cyclin D). Two additional viral genes having no direct cellular counterpart, those encoded by open reading frame K1 (containing an immunoreceptor tyrosine-based activation motif [ITAM]) and K12, have also been found to be transforming in certain experimental assays. Therefore, KSHV qualifies as the virus with the most putative oncogenes identified to date. Thus, the following dilemma: why are KSHV-associated neoplasms so rare in the general population in spite of a seroprevalence of KSHV infections of at least 5% in Western countries? Why is KSHV only poorly transforming after infecting cells in culture? This may be partially explained by the concept that KSHV-mediated pathogenesis will be determined by the specific pattern of viral gene expression and the specific cellular background in which these genes are expressed, both of which are highly dependent on host factors (5, 6). Most of the genes found or suspected to be transforming are lytic genes, which are only transcribed in a subset of cells in KS lesions and PEL. However, the pathogenic potential of a single gene product thus sparsely expressed is elegantly demonstrated in the article by Yang et al. in this issue (7). The report by Yang et al. provides the first transgenic mouse model for KS using a single KSHV gene, the chemokine receptor KSHV GPCR. In this study, it was found that expression of KSHV GPCR in hematopoietic cells of transgenic mice leads to angioproliferative lesions that exhibit most of the characteristics of KS. This viral …
登录
查看更多内容
影响因子：
15.3
作者：
Endres, MJ;Garlisi, CG;Hedrick, JA
通讯作者：
Hedrick, JA
DOI：
10.1006/bbrc.1998.9557
发表时间：
1998-12-30
影响因子：
3.1
作者：
Geras-Raaka, E;Varma, A;Gershengorn, MC
通讯作者：
Gershengorn, MC
影响因子：
5.4
作者：
Isegawa, Y;Ping, Z;Yamanishi, K
通讯作者：
Yamanishi, K
DOI：
10.1084/jem.188.5.855
发表时间：
1998-09-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bodaghi B;Jones TR;Zipeto D;Vita C;Sun L;Laurent L;Arenzana-Seisdedos F;Virelizier JL;Michelson S
通讯作者：
Michelson S
影响因子：
4.8
作者：
Dairaghi, DJ;Fan, PA;Schall, TJ
通讯作者：
Schall, TJ