Stashenko Philip, Yost Susan, Choi Yoonhee, Danciu Theodora, Chen Tsute, Yoganathan Subbiah, Kressirer Christine, Ruiz-Tourrella Montserrat, Das Bikul, Kokaras Alexis, Frias-Lopez Jorge
Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA.
Forsyth Institute, Cambridge, Massachusetts, USA.
mSystems. 2019 Aug 6;4(4):e00323-19. doi: 10.1128/mSystems.00323-19.
Oral squamous cell carcinoma (OSCC) is the most common malignancy of the head and neck worldwide. Dysbiosis of the microbiome has increasingly been linked to the development of different kinds of cancer. Applying 16S rRNA gene sequence analysis and metatranscriptomic analyses, we characterized the longitudinal changes in the profiles and the function of the oral microbiome in a 4-nitroquinoline-1-oxide (4-NQO)-induced model of OSCC in gnotobiotic mice. We characterized the dynamics of the oral microbiome in this model using two different microbiome inocula: one from healthy mice and the other from mice bearing a 4-NQO-induced tumor. Mice colonized with different oral microbiomes and exposed to 4-NQO had increased tumor numbers and sizes compared to controls exposed to 4-NQO but lacking a microbiome. We observed an overall increase in diversity in the tumorigenic samples compared to that in the nontumor group not exposed to 4-NQO. Despite the variability in community dynamics, specific patterns emerged during the progression of the disease. In the two groups that were inoculated with the OSCC-associated microbiome, we observed opposite profiles of abundance in and While the percentage of bacteria decreased in the control group, it increased in the OSCC group, and the opposite was observed for The metatranscriptomic analysis revealed overexpression of the same metabolic signatures associated with OSCC regardless of the community profile. These included nitrogen transport, response to stress, interspecies interactions, Wnt pathway modulation, and amino acid and lipid biosynthesis. Thus, these results seem to suggest that certain collective physiological activities are critical for microbiome-mediated OSCC progression. There is growing evidence that changes in the microbiome are associated with carcinogenesis. To date, no consistent oral microbiome composition associated with OSCC has been identified. Longitudinal and functional studies like the study presented here should yield a better understanding of the role that the oral microbiome plays in OSCC. Our findings, obtained using a germ-free mouse model, indicate that the presence of different oral microbiomes enhances tumorigenesis and increases the final number of tumors in mice. By studying community-wide expression profiles, we found that regardless of the phylogenetic composition of the microbiome, the same metabolic activities were consistently associated with OSCC. Therefore, due to the functional redundancy of the microbiome, the critical element in explaining the contribution of the microbiota in OSCC is the collective physiological activity of the community, thus accounting for the previous inability to identify a consensus community profile or etiologic agents for OSCC.
口腔鳞状细胞癌（OSCC）是全球范围内头颈部最常见的恶性肿瘤。微生物群失调与各类癌症的发生发展之间的关联日益受到关注。我们运用16S rRNA基因序列分析和宏转录组分析方法，对无菌小鼠中4-硝基喹啉-1-氧化物（4-NQO）诱导的OSCC模型中口腔微生物群的组成和功能的纵向变化进行了表征。我们使用两种不同的微生物群接种物来表征该模型中口腔微生物群的动态变化：一种来自健康小鼠，另一种来自携带4-NQO诱导肿瘤的小鼠。与暴露于4-NQO但没有微生物群的对照组相比，接种不同口腔微生物群并暴露于4-NQO的小鼠肿瘤数量和大小增加。与未暴露于4-NQO的非肿瘤组相比，我们观察到致瘤样本中的多样性总体增加。尽管群落动态存在差异，但在疾病进展过程中出现了特定模式。在接种了与OSCC相关微生物群的两组中，我们观察到 和 的丰度分布相反。在对照组中， 细菌的百分比下降，而在OSCC组中则增加， 细菌的情况则相反。宏转录组分析显示，无论群落组成如何，与OSCC相关的相同代谢特征均有过表达。这些特征包括氮转运、应激反应、种间相互作用、Wnt信号通路调节以及氨基酸和脂质生物合成。因此，这些结果似乎表明某些集体生理活动对于微生物群介导的OSCC进展至关重要。越来越多的证据表明微生物群的变化与致癌作用有关。迄今为止，尚未确定与OSCC相关的一致的口腔微生物群组成。像本文所呈现的这种纵向和功能研究应该能更好地理解口腔微生物群在OSCC中所起的作用。我们使用无菌小鼠模型获得的研究结果表明，不同口腔微生物群的存在会增强小鼠的肿瘤发生并增加最终肿瘤数量。通过研究全群落表达谱，我们发现无论微生物群的系统发育组成如何，相同的代谢活动始终与OSCC相关。因此，由于微生物群的功能冗余，解释微生物群在OSCC中作用的关键因素是群落的集体生理活动，这也解释了先前无法确定OSCC一致的群落组成或病因的原因。
