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Clinical significance of Fusobacterium nucleatum, epithelial-mesenchymal transition, and cancer stem cell markers in stage III/IV colorectal cancer patients.

ABSTRACT: Colorectal cancer (CRC) is a common digestive malignancy and emerging studies have closely linked its initiation and development with gut microbiota changes. Fusobacterium nucleatum (Fn) has been recently identified as a pathogenic bacteria for CRC; however, its prognostic significance for patients is poorly investigated and is less for patients within late stage. Therefore, in this study, we made efforts to analyze its level and prognostic significance in a retrospective cohort of 280 stage III/IV CRC patients. We found that the Fn level was abnormally high in tumor tissues and correlated with tumor invasion, lymph node metastasis status, and distant metastasis. We also identified it as an independent adverse prognostic factor for cancer-specific survival (CSS) and disease-free survival (DFS). The following subgroup analysis indicated that Fn level could stratify CSS and DFS in stage IIIB/C and IV patients but failed in stage IIIA patients. In addition, stage III/IV patients with low Fn level were found to benefit more from adjuvant chemotherapy than those with high Fn level, in terms of DFS. Finally, we analyzed the expression and clinical significance of epithelial-to-mesenchymal transition (EMT) markers (E-cadherin and N-cadherin) and cancer stem cell (CSC) markers (Nanog, Oct-4, and Sox-2) in CRC tissues. The results indicated that N-cadherin, Nanog, Oct-4, and Sox-2 were adverse prognostic factors in these patients, while the opposite was true for E-cadherin. More importantly, expression of E-cadherin, N-cadherin, and Nanog was significantly correlated with Fn level in tumor tissues, suggesting the potential involvement of Fn in EMT-CSC cross talk during CRC progression. Taken together, these findings indicate that Fn is a novel predictive biomarker for clinical management in stage III/IV patients, and targeting Fn may be an effective adjuvant approach for preventing CRC metastasis and chemotherapy resistance.

SUBMITTER: Yan X

PROVIDER: S-EPMC5652912 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aspirin is a chemopreventive agent for colorectal adenoma and cancer (CRC) that, like many drugs inclusive of chemotherapeutics, has been investigated for its effects on bacterial growth and virulence gene expression. Given the evolving recognition of the roles for bacteria in CRC, in this work, we investigate the effects of aspirin with a focus on one oncomicrobe-Fusobacterium nucleatum We show that aspirin and its primary metabolite salicylic acid alter F. nucleatum strain Fn7-1 growth in culture and that aspirin can effectively kill both actively growing and stationary Fn7-1. We also demonstrate that, at levels that do not inhibit growth, aspirin influences Fn7-1 gene expression. To assess whether aspirin modulation of F. nucleatum may be relevant in vivo, we use the ApcMin/+ mouse intestinal tumor model in which Fn7-1 is orally inoculated daily to reveal that aspirin-supplemented chow is sufficient to inhibit F. nucleatum-potentiated colonic tumorigenesis. We expand our characterization of aspirin sensitivity across other F. nucleatum strains, including those isolated from human CRC tissues, as well as other CRC-associated microbes, enterotoxigenic Bacteroides fragilis, and colibactin-producing Escherichia coli Finally, we determine that individuals who use aspirin daily have lower fusobacterial abundance in colon adenoma tissues, as determined by quantitative PCR performed on adenoma DNA. Together, our data support that aspirin has direct antibiotic activity against F. nucleatum strains and suggest that consideration of the potential effects of aspirin on the microbiome holds promise in optimizing risk-benefit assessments for use of aspirin in CRC prevention and management.IMPORTANCE There is an increasing understanding of the clinical correlations and potential mechanistic roles of specific members of the gut and tumoral microbiota in colorectal cancer (CRC) initiation, progression, and survival. However, we have yet to parlay this knowledge into better CRC outcomes through microbially informed diagnostic, preventive, or therapeutic approaches. Here, we demonstrate that aspirin, an established CRC chemopreventive, exhibits specific effects on the CRC-associated Fusobacterium nucleatum in culture, an animal model of intestinal tumorigenesis, and in human colonic adenoma tissues. Our work proposes a potential role for aspirin in influencing CRC-associated bacteria to prevent colorectal adenomas and cancer, beyond aspirin's canonical anti-inflammatory role targeting host tissues. Future research, such as studies investigating the effects of aspirin on fusobacterial load in patients, will help further elucidate the prospect of using aspirin to modulate F. nucleatumin vivo for improving CRC outcomes.

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Clinical significance of Fusobacterium nucleatum, epithelial-mesenchymal transition, and cancer stem cell markers in stage III/IV colorectal cancer patients.

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