Virally-induced tumorigenesis controlled by the microbiota

摘要 逆转录病毒在脊椎动物中诱导广泛的肿瘤。虽然有些逆转录病毒携带 尽管逆转录病毒在其基因组中含有致癌基因，但绝大多数逆转录病毒不编码这些元件，因此，它们的 诱导肿瘤的能力取决于细胞原癌基因附近的整合。然而，癌基因 单独的活化不足以诱导肿瘤，肿瘤发展需要额外的事件。 小鼠白血病病毒（MuLV），可以作为口腔和血液传播的病原体传播， 擅长引发白血病有趣的是，同一品系的感染小鼠的肿瘤发病率不同 在不同的设施之间。在研究实验室之间可能存在差异的环境因素中， 因此，我们试图确定微生物群是否有助于 病毒诱导的白血病因此，我们在无菌（GF，无菌） 和无特定病原体（SPF）的常规饲养的BALB/cJ小鼠。尽管MuLV复制和 在没有微生物群的情况下，GF小鼠的传播没有受到影响，GF小鼠对微生物群的抵抗力明显更强。 SPF小鼠的白血病。用确定的一组肠道细菌（Altered Schaedler's）定殖GF小鼠 植物群），或与单一细菌如鼠乳杆菌（Lactobacillus murinus），但不与Parabacteroides distasonis或类似物 与大肠大肠杆菌和志贺氏菌（SECS）没有改变病毒复制，但消除了肿瘤的耐药表型， 这表明某些肠道微生物具有促肿瘤特性。与此同时，GF 缺乏适应性免疫系统（T和B淋巴细胞）的小鼠发生白血病的几率很高，这表明 肠道微生物通过抵消适应性免疫反应来促进白血病的发生。基因-- 白血病前脾的表达分析揭示了由细胞因子诱导的几种负调节因子。 微生物群在这些基因中，已知的V-set和含有IG结构域的4（VSig 4）基因是V-set的负调节因子。 T细胞反应引起了我们的兴趣，因为它被发现在各种人类癌症中上调。 肠道微生物群与结肠癌和肝癌（“局部”）的进展有关。 影响），以及通过增强抗癌免疫疗法的效果而在全身抗癌效果中。 还有一个暗示，微生物环境可以影响非病毒诱导的发育， 淋巴瘤为了确定肠道微生物群促进白血病的机制，我们将使用我们的 病毒学、哺乳动物遗传学和微生物技术方面的专门知识（芝加哥大学Golovkina博士） 以及细菌遗传学和代谢组学方面的专业知识（Fischbach博士，斯坦福大学）。的目标 建议是：确定微生物调节的VSig 4在病毒诱导的白血病发生中的作用; 表征导致病毒诱导白血病发展的细菌化合物;以确定 肠道微生物群是否影响非病毒癌症模型中白血病的发展。

Abstract Retroviruses induce a broad range of tumors in vertebrates. Although some retroviruses carry oncogenes in their genome, the vast majority of retroviruses do not encode such elements and thus, their capacity to induce tumors depends on integration near cellular proto-oncogenes. However, oncogene activation alone is not sufficient for tumor induction and additional events are required for tumor development. Murine Leukemia Virus (MuLV), which can spread as an oral and as a blood-borne pathogen, is highly proficient in causing leukemia. Intriguingly, tumor incidence within the same strain of infected mice varies between different facilities. Among environmental factors that may differ between the research labs, the variation in gut microbiota stands out.Thus, we sought to determine whether the microbiota contributes to virally-induced leukemogenesis. Accordingly, we monitored virally-induced leukemia in germ-free (GF, sterile) and specific pathogen free (SPF) conventionally raised BALB/cJ mice. Even though MuLV replication and spread were not affected in the absence of the microbiota, GF mice were significantly more resistant to the leukemia than SPF mice. Colonizing GF mice with a defined group of commensal bacteria (Altered Schaedler’s Flora), or with a single bacterium such as Lactobacillus murinus but not Parabacteroides distasonis or similar to E. coli and shigella (SECS) did not change virus replication but abolished the tumor-resistant phenotype of the colonized mice, indicating that some gut microbes have tumor-promoting properties. At the same time, GF mice lacking adaptive immune system (T and B lymphocytes) developed leukemia at a high rate suggesting that the gut microbes facilitate leukemia promotion by counteracting the adaptive immune response. Gene- expression analysis of the pre-leukemic spleens revealed several negative regulators induced by the microbiota. Among those, the ‘V-set and Ig domain-containing 4’ (VSig4) gene, a known negative regulator of T-cell responses attracted our interest because it was found upregulated in various human cancers. The gut microbiota has been implicated in both progression of cancers of colon and liver (‘local’ influence), as well as in systemic anti-cancer effect by enhancing the effect of anti-cancer immunotherapy. There is also a hint that the microbial environment can influence development of non-virally induced lymphomas. To identify the mechanism(s) by which the gut microbiota promotes leukemia, we will use our expertise in virology, mammalian genetics and gnotobiotic technologies (Dr. Golovkina, University of Chicago) and expertise in bacterial genetics and metabolomics (Dr. Fischbach, Stanford University). The goals of the proposal are: to determine the role of microbially regulated-VSig4 in virally-induced leukemogenesis; to characterize the bacterial compound(s) responsible for virally-induced leukemia development; to determine whether the gut microbiota influences leukemia development in a non-viral model of cancer.