Leukemia-promoting effects of microbiota

微生物群的白血病促进作用

• 批准号: 9110906
• 负责人: Tatyana V Golovkina
• 金额: $ 17.18万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110906
• 关键词: Address; Animal Model; Animals; Antibiotics; BALB/cJ Mouse; Bacteria; Blood-Borne Pathogens; Cell physiology; Cells; Chronic; Colon Carcinoma; Communities; Data; Development; Disease; Elements; Epigenetic Process; Escherichia coli; Etiology; Event; Gene Expression Profiling; Genes; Genome; Germ-Free; Gnotobiotic; Goals; Gram-Positive Bacteria; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Hematopoietic stem cells; Human; Inflammation; Inflammatory; Insertional Mutagenesis; Interleukin-6; Link; Lymphoma; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Microbe; Modeling; Murine leukemia virus; Mus; Mutation; Oncogenes; Oral; Pathway interactions; Phenotype; Predisposition; Process; Property; Propionibacterium acnes; Proteobacteria; Proto-Oncogenes; Resistance; Retroviridae; Role; Series; Shigella; Signal Pathway; Somatic Mutation; Spleen; Staging; Sterility; System; TLR2 gene; Testing; Thinking; Up-Regulation; Vertebrates; Viral Oncogene; Virus; acrosome stabilizing factor; cancer prevention; cancer therapy; carcinogenesis; commensal microbes; cytokine; genetic approach; germ free condition; gut microbiota; high reward; high risk; insight; leukemia; leukemogenesis; microbial; microbiota; reconstitution; tool; transcriptome sequencing; transmission process; tumor; tumorigenesis

 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.

 描述（由适用提供）：逆转录病毒通过在脊椎动物中引起广泛的肿瘤赢得了臭名昭著。尽管某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此类元素，因此，必须整合在细胞原始癌基因附近并上调它们以诱导肿瘤。首先将许多参与肿瘤发生的细胞基因被鉴定为病毒癌基因（V-ONC）或逆转录病毒插入后上调的基因。现在众所周知，它们参与了人类的各种赞助肿瘤。通过插入诱变或插入V-oncs的细胞原始基因上调是肿瘤诱导的必要步骤。但是，仅癌基因的上调不足以诱导肿瘤，并且需要其他事件才能进行肿瘤的发育。因此，与其他病因的肿瘤类似，逆转录病毒诱导的肿瘤是一种多步过程，因此代表了一个有价值的系统，用于解决与癌症诱导和促进机制有关的问题。最初，我们着手解决共生细菌（Microbiota）在鼠白血病病毒（MULV）传播中的作用，这些病毒（MULV）与其他逆转录病毒不同，这些病毒可以像口服和血源性病原体一样高效地传播。据此，我们将易感的BALB/CJ小鼠重新衍生为无菌（GF，无菌），发现这些动物能够传播传染病。然而，令我们惊讶的是，感染的GF小鼠从未患有病毒诱发的疾病 - 淋巴瘤或白血病。 GF小鼠与一组定义的共生细菌（改变的Schaedler Flora或ASF）以及单一的丙酸杆菌（P. acnes）的关联，但没有与蛋白质细菌“类似于大肠杆菌和志贺氏菌”（SECS）（SECS）（SECS），使Tumor抗抗菌的现象与Gut Microbiot的相互作用，并在gut colon中建立了IMPRERETION，该现象一直在进步。癌症，肠道菌群对白血病开发的需求是一个新发现。因此，我们的模型是识别由共生细菌激活的白血病诱导的途径的强大工具。慢性感染有助于多种癌症。由于感染通常与微生物产品有关，因此我们认为我们的发现将为预防癌症和治疗提供宝贵的新见解。