Characterization of the Oral and Esophageal Microbiota in Esophageal Precancerous Lesions and Squamous Cell Carcinoma.
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ABSTRACT:
SUBMITTER: Li Z
PROVIDER: S-EPMC8479167 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Precancerous lesions of the oral mucosa, especially those accompanied by moderate to severe dysplasia, contribute to the initiation of oral squamous cell carcinoma (OSCC). However, the cellular compositions and spatial organization of the precancerous stage and how these factors promote human OSCC initiation remain unclear. Here, we built a single-cell transcriptome atlas and a spatial transcriptome map after obtaining data from pairwise human oral mucosal biopsies of 9 individuals consisting of very early-stage OSCC, adjacent precancerous lesions with moderate to severe dysplasia, as well as a matched normal region. An altered epithelial gene-expression profile was identified which favored OSCC initiation. This observation was coupled with distinct fibroblast, monocytic, and regulatory T-cell subclusters involved in reshaping the microenvironment. In particular, a unique immune-inhibitory monocyte subtype and spatial-switching regulation of VEGF signaling were observed surrounding precancerous lesions, concertedly strengthening activities in promoting cancer initiation. Collectively, our work elucidated the cellular landscapes and roles of precancerous lesions underlying OSCC initiation, which is essential for understanding the entire OSCC initiation process and helps inform therapeutic strategies for cancer intervention.
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Project description:Microbial imbalances have been well elucidated in esophageal adenocarcinoma. However, few studies address the microbiota in esophageal squamous cell carcinoma (ESCC) and esophagitis (ES). We aimed to explore the association of esophageal microbiota with these patients. Esophageal tissues were obtained from healthy controls and ES and ESCC patients undergoing upper endoscopy. 16S rRNA gene sequencing was applied to analyze the microbiome. The α and β diversity differences were tested by Tukey test and partial least squares-discriminant analysis (PLS-DA), respectively. Linear discriminant analysis effect size (LEfSe) analysis was performed to assess taxonomic differences between groups. A total of 68 individuals were enrolled (control = 21, ES = 15, ESCC = 32). Microbial diversity was significantly different between the ESCC patients and healthy controls by Chao1 index, Shannon index, and PLS-DA. Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, and Fusobacteria were the five dominant bacterial phyla among the three groups. Megamonas, Collinsella, Roseburia, and Ruminococcus_2 showed a significantly continuous decreasing trend from the control group to the ESCC group at the genus level. When compared with the control group, decreased Fusobacteria at phylum level and Faecalibacterium, Bacteroides, Curvibacter, and Blautia at genus level were detected. ESCC samples also displayed a striking reduction of Bacteroidetes, Faecalibacterium, Bacteroides, and Blautia in comparison with the ES patients. LEfSe analysis indicated a greater abundance of Streptococcus, Actinobacillus, Peptostreptococcus, Fusobacterium, and Prevotella in the ESCC group. Our study suggests a potential association between esophageal microbiome dysbiosis and ESCC and provides insights into potential screening markers for esophageal cancer.
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Project description:Saliva is an easy-to access body fluid with high diagnostic potential. The utilization of saliva for oral cancer diagnosis can be an attractive possibility. Besides the oral cancer, it is important to better understand the precancerous lesions such as oral lichen planus (OLP) and leukoplakia (OLK). In order to examine the changes of salivary proteins in controls, patients with oral cancer, and patients with precancerous conditions, proximity extension assay was utilized. Some proteins and functions were characteristic to the examined groups and can serve as a starting point for further biomarker studies. The different nature of OLK and OLP was demonstrated, showing the malignant transformation and the inflammation as the prominent biological processes in the OLK and OLP, respectively. The salivary level of IL6 was verified using quantitative ELISA and the mRNA level was also studied. Elevated IL6 levels could be detected in precancerous groups compared to controls.
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Project description:Important evidence indicates the microbiota plays a key role in esophageal squamous cell carcinoma (ESCC). The esophageal microbiota was prospectively investigated in 18 patients with ESCC and 11 patients with physiological normal (PN) esophagus by 16S rRNA gene profiling, using next-generation sequencing. The microbiota composition in tumor tissues of ESCC patients were significantly different from that of patients with PN tissues. The ESCC microbiota was characterized by reduced microbial diversity, by decreased abundance of Bacteroidetes, Fusobacteria, and Spirochaetes. Employing these taxa into a microbial dysbiosis index demonstrated that dysbiosis microbiota had good capacity to discriminate between ESCC and PN esophagus. Functional analysis characterized that ESCC microbiota had altered nitrate reductase and nitrite reductase functions compared with PN group. These results suggest that specific microbes and the microbiota may drive or mitigate ESCC carcinogenesis, and this study will facilitate assigning causal roles in ESCC development to certain microbes and microbiota.
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Project description:Poor oral health has been linked with an increased risk of esophageal squamous cell carcinoma (ESCC). We investigated whether alteration of oral microbiota is associated with ESCC risk. Fasting saliva samples were collected from 87 incident and histopathologicallly diagnosed ESCC cases, 63 subjects with dysplasia and 85 healthy controls. All subjects were also interviewed with a questionnaire. V3-V4 region of 16S rRNA was amplified and sequenced by 454-pyrosequencing platform. Carriage of each genus was compared by means of multivariate-adjusted odds ratios derived from logistic regression model. Relative abundance was compared using Metastats method. Beta diversity was estimated using Unifrac and weighted Unifrac distances. Principal coordinate analysis (PCoA) was applied to ordinate dissimilarity matrices. Multinomial logistic regression was used to compare the coordinates between different groups. ESCC subjects had an overall decreased microbial diversity compared to control and dysplasia subjects (P<0.001). Decreased carriage of genera Lautropia, Bulleidia, Catonella, Corynebacterium, Moryella, Peptococcus and Cardiobacterium were found in ESCC subjects compared to non-ESCC subjects. Multinomial logistic regression analyses on PCoA coordinates also revealed that ESCC subjects had significantly different levels for several coordinates compared to non-ESCC subjects. In conclusion, we observed a correlation between altered salivary bacterial microbiota and ESCC risk. The results of our study on the saliva microbiome are of particular interest as it reflects the shift in microbial communities. Further studies are warranted to verify this finding, and if being verified, to explore the underlying mechanisms.
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Project description:Infection with specific pathogens and alterations in tissue commensal microbial composition are intricately associated with the development of many human cancers. Likewise, dysbiosis of oral microbiome was also shown to play critical role in the initiation as well as progression of oral cancer. However, there are no reports portraying changes in oral microbial community in the patients of Indian subcontinent, which has the highest incidence of oral cancer per year, globally. To establish the association of bacterial dysbiosis and oral squamous cell carcinoma (OSCC) among the Indian population, malignant lesions and anatomically matched adjacent normal tissues were obtained from fifty well-differentiated OSCC patients and analyzed using 16S rRNA V3-V4 amplicon based sequencing on the MiSeq platform. Interestingly, in contrast to the previous studies, a significantly lower bacterial diversity was observed in the malignant samples as compared to the normal counterpart. Overall our study identified Prevotella, Corynebacterium, Pseudomonas, Deinococcus and Noviherbaspirillum as significantly enriched genera, whereas genera including Actinomyces, Sutterella, Stenotrophomonas, Anoxybacillus, and Serratia were notably decreased in the OSCC lesions. Moreover, we demonstrated HPV-16 but not HPV-18 was significantly associated with the OSCC development. In future, with additional validation, this panel could directly be applied into clinical diagnostic and prognostic workflows for OSCC in Indian scenario.
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Project description:Oral squamous cell carcinoma (OSCC) is a highly aggressive cancer and the fourth leading malignancy among males in Taiwan. Some pathogenic bacteria are associated with periodontitis and oral cancer. However, the comprehensive profile of the oral microbiome during the cancer's progression from the early stage to the late stage is still unclear. We profiled the oral microbiota and identified bacteria biomarkers associated with OSCC. The microbiota of an oral rinse from 51 healthy individuals and 197 OSCC patients at different stages were investigated using 16S rRNA V3V4 amplicon sequencing, followed by bioinformatics and statistical analyses. The oral microbiota communities from stage 4 patients showed significantly higher complexity than those from healthy controls. The populations also dynamically changed with the cancer's progression from stage 1 to stage 4. The predominant phyla in the oral samples showed variation in the relative abundance of Fusobacteria, Bacteroidetes, and Actinobacteria. The abundance of Fusobacteria increased significantly with the progression of oral cancer from the healthy controls (2.98%) to OSCC stage 1 (4.35%) through stage 4 (7.92%). At the genus level, the abundance of Fusobacterium increased, while the number of Streptococcus, Haemophilus, Porphyromonas, and Actinomyces decreased with cancer progression. Fusobacterium periodonticum, Parvimonas micra, Streptococcus constellatus, Haemophilus influenza, and Filifactor alocis were associated with OSCC, and they progressively increased in abundance from stage 1 to stage 4. The abundances of Streptococcus mitis, Haemophilus parainfluenzae, and Porphyromonas pasteri were inversely associated with OSCC progression. We selected a bacterial marker panel of three bacteria (upregulated F. periodonticum, down-regulated S. mitis, and P. pasteri), which had an AUC of 0.956 (95% CI = 0.925-0.986) in discriminating OSCC stage 4 from the healthy controls. Furthermore, the functional prediction of oral bacterial communities showed that genes involved in carbohydrate-related metabolism, such as methane metabolism, and energy-metabolism-related parameters, such as oxidative phosphorylation and carbon fixation in photosynthetic organisms, were enriched in late-stage OSCC, while those responsible for amino acid metabolism, such as folate biosynthesis and valine, leucine, and isoleucine biosynthesis, were significantly associated with the healthy controls. In conclusion, our results provided evidence of oral bacteria community changes during oral cancer progression and suggested the possibility of using bacteria as OSCC diagnostic markers.
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Project description:Observational studies revealed a relationship between changes in gastric mucosa and risk of esophageal squamous cell carcinoma (ESCC) which suggested a possible role for gastric microbiota in ESCC carcinogenesis. In this study we aimed to compare pattern of gastric corpus microbiota in ESCC with normal esophagus. Cases were included subjects with early ESCC (stage I-II) and esophageal squamous dysplasia (ESD) as the cancer precursor. Control groups included age and sex-matched subjects with mid-esophagus esophagitis (diseased-control), and histologically normal esophagus (healthy-control). DNA was extracted from snap-frozen gastric corpus tissues and 16S rRNA was sequenced on GS-FLX Titanium. After noise removal, an average of 3004 reads per sample was obtained from 93 subjects. We applied principal coordinate analysis to ordinate distances from beta diversity data. Pattern of gastric microbiota using Unifrac (p = 0.004) and weighted Unifrac distances (p = 0.018) statistically varied between cases and healthy controls. Sequences were aligned to SILVA database and Clostridiales and Erysipelotrichales orders were more abundant among cases after controling for multiple testing (p = 0.011). No such difference was observed between mid-esophagitis and healthy controls. This study is the first to show that composition of gastric corpus mucosal microbiota differs in early ESCC and ESD from healthy esophagus.
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Project description:Background:Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent malignancies and a major cause of cancer related death worldwide, especially in China. Cell lines are widely used disease models for basic medical research, however, well characterized ESCC cell models from China were seldom reported. Misidentifying and cross-contaminations of cell lines also hamper the way of producing solid and reproductive data. Methods:CSEC216 was originated from a 45-year-old male ESCC patient from Chaoshan littoral, China. Specimens were minced into fragments and seeded in T-25 flask for primary culture. Immunoflourescence staining was performed for identifying the origination and proliferation activity. In vitro migration and invasion abilities was tested by transwell assay. DNA Short Tandem Repeats profiling was implemented for cell authorization. Karyotype was investigated by spectrum karyotyping. Whole genome sequencing was utilized to investigate genomic alterations. Background information and genomic mutation data of published ESCC cell lines were obtained from online databases. Results:CSEC216 was an uncontaminated cell line, exhibited epithelial cell features with polygonal morphology and adherent growth as monolayer. Immuno staining demonstrated its epithelial origination and high proliferation rate. The Population Doubling time was 29.7 h. The karyotype demonstrated tumor cell patterns with aneuploidy and complex chromosomal aberrations. Mutation signatures, genes with SNA or CNA of CSEC216 and published ESCC cell lines were similar with the mutation spectrum of original ESCC tumors. Conclusions:ESCC cell line CSEC216 from high incidence region in China was established with no cross-contamination. Biological features were studied. Genomic mutation features of CSEC216 and 28 ESCC cell lines were characterized which provided thorough cytogenetic background that facilitated future usage.
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Project description:Esophageal squamous cell carcinoma (ESCC) is prevalent worldwide and particularly common in certain regions of Asia. Here we report the whole-exome or targeted deep sequencing of 139 paired ESCC cases, and analysis of somatic copy number variations (SCNV) of over 180 ESCCs. We identified previously uncharacterized mutated genes such as FAT1, FAT2, ZNF750 and KMT2D, in addition to those already known (TP53, PIK3CA and NOTCH1). Further SCNV evaluation, immunohistochemistry and biological analysis suggested their functional relevance in ESCC. Notably, RTK-MAPK-PI3K pathways, cell cycle and epigenetic regulation are frequently dysregulated by multiple molecular mechanisms in this cancer. Our approaches also uncovered many druggable candidates, and XPO1 was further explored as a therapeutic target because it showed both gene mutation and protein overexpression. Our integrated study unmasks a number of novel genetic lesions in ESCC and provides an important molecular foundation for understanding esophageal tumors and developing therapeutic targets.
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