Leukemia-promoting effects of microbiota

 描述（由申请人提供）：逆转录病毒因在脊椎动物中诱导广泛的肿瘤而声名狼借。尽管一些逆转录病毒在其基因组中携带致癌基因，但绝大多数逆转录病毒不编码这些元件，因此必须整合近细胞原癌基因并上调它们以诱导肿瘤。许多参与肿瘤发生的细胞基因首先被鉴定为病毒癌基因（v-onc）或在逆转录病毒插入后上调的基因。现在已知它们与人类各种类型的自发性肿瘤有关。通过插入突变或插入v-onc上调细胞原癌基因是肿瘤诱导的必要步骤。然而，单独的癌基因的上调不足以诱导肿瘤，并且肿瘤发展需要其他事件。因此，类似于其他病因的肿瘤，逆转录病毒诱导的肿瘤是作为一个多步骤的过程，因此，代表了一个有价值的系统，以解决与癌症诱导和促进机制有关的问题。 最初，我们着手解决肠道细菌（微生物群）在鼠白血病病毒（MuLV）传播中的作用，与其他逆转录病毒不同，MuLV可以作为口腔和血液传播的病原体高效传播。因此，我们将易感BALB/cJ小鼠重新衍生为无菌（GF，无菌）小鼠，发现这些动物能够传播感染性病毒。然而，令我们惊讶的是，受感染的GF小鼠从未发生病毒诱导的疾病-淋巴瘤或白血病。将GF小鼠与一组确定的痤疮细菌（Altered Schaedler植物群或ASF）和单一痤疮丙酸杆菌（P. acnes）结合，但不与类似于E.大肠杆菌和志贺氏菌（SECS）逆转了肿瘤抗性表型，确立了白血病发展中对特定微生物输入的需求。基因表达分析表明，白血病进展的微生物群依赖性机制可以由促炎细胞因子，特别是白细胞介素6（IL 6）和粒细胞巨噬细胞集落刺激因子（GM-CSF）介导。虽然肠道微生物群与结肠癌和肝癌的进展有关，但肠道微生物群对白血病发展的需求是一个新发现。因此，我们的模型是一个强大的工具，用于识别白血病诱导途径激活的大肠杆菌。 慢性炎症导致多种癌症。由于炎症通常与微生物产物有关，我们认为我们的发现将为癌症预防和治疗提供有价值的新见解。

 DESCRIPTION (provided by applicant): Retroviruses earned their notoriety by inducing a broad range of tumors in vertebrates. Whereas some retroviruses carry oncogenes in their genome, the vast majority of retroviruses do not encode such elements and thus, must integrate near cellular proto-oncogenes and up-regulate them to induce tumors. Many cellular genes involved in tumorigenesis were first identified as viral oncogenes (v-onc) or genes up-regulated upon retroviral insertion. They are now known to be involved in various types of spontaneous tumors in humans. Up-regulation of cellular protooncogenes via insertional mutagenesis or insertion of v-oncs constitutes a necessary step for tumor induction. However, up-regulation of an oncogene alone is not sufficient for tumor induction and other events are required for tumor development. Therefore, similarly to tumors of other etiologies, retrovirally-induced tumors are developed as a multistep process and thus, represent a valuable system to address questions related to mechanisms of cancer induction and promotion. Initially, we set out to address the role of commensal bacteria (microbiota) in transmission of Murine Leukemia Virus (MuLV) which unlike other retroviruses can spread highly efficiently as an oral and as a blood- borne pathogen. Accordingly, we re-derived susceptible BALB/cJ mice as germ-free (GF, sterile) and found that these animals were capable of transmitting infectious virus. However, to our surprise, infected GF mice never developed virally-induced disease - lymphoma or leukemia. Association of the GF mice with a defined group of commensal bacteria (Altered Schaedler Flora or ASF) and with a single Propionibacterium acnes (P. acnes) but not with proteobacterium `similar to E. coli and Shigella' (SECS) reversed the tumor- resistant phenotype, establishing the requirement for specific microbial input in leukemia development. Gene- expression analysis suggested that microbiota-dependent mechanism of leukemia progression could be mediated by pro-inflammatory cytokines, in particular interleukin 6 (IL6) and granulocyte macrophage colony- stimulating factor (GM-CSF). Although the gut microbiota has been implicated in the progression of colon and liver cancers, the requirement of the gut microbiota for leukemia development is a new discovery. Therefore, our model is a powerful tool for identifying leukemia-inducing pathways activated by commensal bacteria. Chronic inflammation contributes to a multitude of cancers. As inflammation is often associated with microbial products, we think that our findings will provide valuable new insights into cancer prevention and treatment.