The role of XMRV, a newly discovered human retrovirus, in cancer pathogenesis

描述（由申请人提供）：前列腺癌是美国男性最常见的非皮肤癌(1)。在美国，一生中患前列腺癌的风险约为六分之一(2)。由于寿命延长，前列腺癌的发病率和死亡率可能会进一步增加。流行病学研究表明，感染和炎症可能在前列腺癌的发展中发挥作用（3,4）。最近对前列腺癌组织中病毒核酸的研究导致在大约10%的前列腺癌检测中发现了一种新的逆转录病毒——异嗜性小鼠白血病病毒相关病毒（XMRV）(5)。通过序列分析，XMRV是一种γ -逆转录病毒。虽然病毒在动物中具有明显的致癌作用，但尚未显示它们会导致人类癌症。初步结果表明，XMRV确实是一种伽玛逆转录病毒，其蛋白质组成和颗粒超微结构与另一种伽玛逆转录病毒Moloney小鼠白血病病毒（MoMLV）高度相似。我们使用定量PCR和抗xmrv特异性抗血清免疫组化分析了334例连续前列腺切除术标本。我们在27%的前列腺癌和6%的非癌症对照中发现了XMRV，首次显示了XMRV与前列腺癌的关联。XMRV蛋白主要在恶性上皮细胞中表达，提示逆转录病毒感染可能与肿瘤发生直接相关。XMRV的存在与高级别前列腺癌相关。我们发现XMRV感染与RNASEL基因的常见多态性无关，这与之前的报道不同。这增加了XMRV感染的风险人群，从只有那些纯合子的RNASEL变体，到所有个体。我们的目标是进一步了解XMRV的发病机制，确定这种病毒是否导致前列腺癌，并描述可能的肿瘤发生机制。我们还将开展流行病学研究，研究这一新的重要病毒的流行和倾向。我们的具体目标是：目标1：表征XMRV在细胞培养中的复制；肿瘤发生机制测试：我们将使用我们组装的XMRV全长复制能力DNA克隆，以及我们生成的XMRV特异性多克隆抗血清来表征病毒生命周期的不同步骤。目的2：进一步表征XMRV在人类前列腺癌中的感染。我们将继续对大量未鉴定的人类前列腺癌进行分析。我们将进一步表征XMRV在不同级别、分期和组织学亚型的癌症中的存在和定位，以及它与前列腺癌不同预后特征的关系。目的3：流行病学研究，寻找XMRV在一般人群中的流行情况：在血液中，以及在前列腺以外的组织中。我们的研究可以将XMRV与致癌联系起来，并为癌症预防和治疗提供新的模式。

DESCRIPTION (provided by applicant): Prostate cancer is the most common form of non-skin cancer in US men (1). The lifetime risk for developing prostate cancer is approximately one in six in the US (2). Morbidity and mortality due to prostate cancer are likely to grow further given increasing longevity. Epidemiologic studies indicate that infection and inflammation may play a role in the development of prostate cancer (3, 4). A recent search for viral nucleic acids in prostate cancer tissues led to the identification of a novel retrovirus, Xenotropic murine leukemia virus-related virus (XMRV) in approximately 10% of prostate cancers tested (5). XMRV, by sequence analysis, is a gammaretrovirus. While gammaretroviruses have well- characterized oncogenic effects in animals, they have not been shown to cause human cancers. Our preliminary results show that XMRV is indeed a gammaretrovirus with protein composition and particle ultrastructure highly similar to another gammaretrovirus, Moloney murine leukemia virus (MoMLV). We analyzed 334 consecutive prostate resection specimens using a quantitative PCR assay and immunohistochemistry with an anti-XMRV specific antiserum. We found XMRV in 27% of prostate cancers and in only 6% of non-cancer controls, showing for the first time an association of XMRV with prostate cancer. XMRV proteins were expressed primarily in malignant epithelial cells, suggesting that retroviral infection may be directly linked to tumorigenesis. The presence of XMRV correlated with higher-grades of prostate cancers. We found XMRV infection to be unrelated to a common polymorphism in the RNASEL gene, unlike previously reported. This increases the population at risk for XMRV infection from only those homozygous for the RNASEL variant, to all individuals. Our goal is to further understand pathogenesis by XMRV, to determine if this virus causes prostate cancer, and delineate possible mechanisms for oncogenesis. We will also carry out epidemiological studies to study the prevalence and tropism of this new and important virus. Our specific aims are: Aim 1: Characterization of XMRV replication in cell culture; testing mechanisms of oncogenesis: We will use the full- length replication-competent DNA clone of XMRV that we have assembled, and the polyclonal XMRV-specific antisera we have generated to characterize different steps in the viral life cycle. Aim 2: Further characterization of XMRV infection in human prostate cancers. We will continue our analysis of large numbers of de-identified human prostate cancers. We will further characterize the presence and localization of XMRV within cancers of different grades, stages and histologic subtypes and its association with different prognostic features of prostate cancer. Aim 3: Epidemiological studies to look for prevalence of XMRV in the general population: in blood, and in tissues other than prostate. Our studies could causally link XMRV to carcinogenesis and lead to novel modalities for cancer prevention and treatment. PUBLIC HEALTH RELEVANCE: XMRV is a new retrovirus that was recently identified from human prostate cancers. This study will attempt to understand the replication of this virus in vitro and its association with cancer. We will explore mechanisms of oncogenesis in cells, in tumors, as well as in animal models, and carry out epidemiological studies to estimate prevalence of viral infection in the general population.