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（由申请人提供）：逆转录病毒因在脊椎动物中诱导多种肿瘤而声名狼藉。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不编码这些元件，因此必须整合到细胞原癌基因附近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。通过插入诱变或插入 v-oncs 上调细胞原癌基因是诱导肿瘤的必要步骤。然而，仅癌基因的上调不足以诱导肿瘤，肿瘤的发展需要其他事件。因此，与其他病因学的肿瘤类似，逆转录病毒诱导的肿瘤是作为一个多步骤过程而发展的，因此代表了解决与癌症诱导和促进机制相关的问题的有价值的系统。 最初，我们着手解决共生细菌（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 可以作为口腔和血源性病原体高效传播。因此，我们重新衍生出无菌（GF，无菌）易感 BALB/cJ 小鼠，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，受感染的 GF 小鼠从未患上病毒诱发的疾病 - 淋巴瘤或白血病。 GF小鼠与一组确定的共生细菌（改变的谢德勒菌群或ASF）和单个痤疮丙酸杆菌（P.acnes）的关联，但不与“类似于大肠杆菌和志贺氏菌”的变形菌（SECS）的关联，逆转了肿瘤抗性表型，建立了白血病发展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是由促炎细胞因子介导的，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）。尽管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要求是一个新发现。因此，我们的模型是识别共生细菌激活的白血病诱导途径的强大工具。 慢性炎症会导致多种癌症。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。