Leukemia-promoting effects of microbiota

 描述(申请人提供)：逆转录病毒通过在脊椎动物中引起广泛的肿瘤而声名狼藉。虽然一些逆转录病毒在其基因组中携带癌基因，但绝大多数逆转录病毒并不编码这些元件，因此必须整合近细胞的原癌基因并上调它们才能诱发肿瘤。许多参与肿瘤发生的细胞基因最初被鉴定为病毒癌基因(v-onc)或逆转录病毒插入时上调的基因。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-oncs上调细胞原癌基因是肿瘤诱导的必要步骤。然而，单靠癌基因的上调是不足以诱导肿瘤发生的，肿瘤的发生还需要其他事件。因此，与其他病因的肿瘤相似，逆转录病毒诱导的肿瘤是一个多步骤的过程，因此，代表了一个有价值的系统来解决与癌症诱导和促进机制相关的问题。最初，我们着手解决共生细菌(微生物群)在小鼠白血病病毒(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，我们将易感的BALB/CJ小鼠重新衍生为无菌(GF，无菌)，并发现这些动物能够传播传染性病毒。然而，令我们惊讶的是，感染了GF的小鼠从未患上由病毒引起的疾病--淋巴瘤或白血病。GF小鼠与一组确定的共生细菌(改变的舍德勒菌群或ASF)和一种单一的痤疮丙酸杆菌(痤疮丙酸杆菌)相关联，但不与类似于大肠杆菌和志贺氏菌的变形杆菌(SECS)相关联，逆转了肿瘤耐药表型，确立了白血病发生过程中对特定微生物输入的要求。基因表达分析表明，白血病进展的微生物依赖机制可能由促炎细胞因子，特别是白细胞介素6(IL6)和粒细胞巨噬细胞集落刺激因子(GM-CSF)介导。虽然肠道微生物区系与结肠癌和肝癌的发展有关，但肠道微生物区系对白血病发展的需求是一个新的发现。因此，我们的模型是识别由共生细菌激活的白血病诱发途径的有力工具。慢性炎症导致多种癌症。由于炎症通常与微生物产品有关，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.