Invasive Fusobacterium nucleatum may play a role in the carcinogenesis of proximal colon cancer through the serrated neoplasia pathway

Abstract

The prevalence of invasive Fusobacterium nucleatum (Fn) within the serrated neoplasia pathway of the proximal colon has seldom been investigated. We examined the invasive Fn and bacterial biofilms in 35 proximal hyperplastic polyps (HPs), 33 sessile serrated adenomas (SSAs), 48 proximal colorectal cancers (CRCs) and 10 matched metastatic lymph nodes using 16S rRNA fluorescence in situ hybridization (FISH). Samples of normal mucosa, traditional adenomas (TAs), distal HPs, distal CRCs and matched lymph nodes with or without metastases were used as controls. The prevalence of invasive Fn within proximal HPs (65.7%) and SSAs (78.8%) were significantly higher than that of proximal TAs (28.9%) and distal TAs (24.4%; p < 0.05). Invasive Fn was detected in markedly more proximal CRCs (89.6%) than in distal CRCs (42.2%; p < 0.05). Moreover, invasive Fn was detected in a significantly higher proportion of matched metastatic lymph nodes (100%) than that within nonmetastatic lymph nodes (40.0%; p < 0.001). Bacterial biofilms were found on 52.1% of proximal CRCs, 55.6% of distal CRCs and 48.5% of SSAs. Biofilms were positive for Fn in 47.9% of proximal CRCs, 48.9% of distal CRCs and 27.3% of SSAs. However, the presence of Fn in biofilms was not related to invasive Fn within colorectal tissues (p 5 0.415). Invasive Fn may play a role in the carcinogenesis of proximal colon developing via the serrated neoplasia pathway, but might have a less important role in the TA-carcinoma sequence. Bacterial biofilms may not contribute to the invasion of Fn into tumor tissues.The human gut is populated by hundreds of different bacterial species, some of which contribute toward the pathogenesis of a range of human diseases.1 Recently, Fusobacterium nucleatum (Fn) has been recognized as an opportunistic pathogen implicated in inflammatory diseases of the gut, including appendicitis and inflammatory bowel diseases. 2,3Current microbiome surveys of human tumors revealed an enrichment of Fn in colorectal cancer (CRC). 4-8 Moreover,accumulating evidence suggest that Fn may play a role in modulating CRC development. 4,9Many of these observations, however, were studies of the traditional adenoma (TA)-carcinoma sequence. In recent years, it's believed that up to 20% of all CRCs arise through an alternative, serrated neoplasia pathway.

Bacterial Biofilm and its Role in the Pathogenesis of Disease

“…Tomkovich et al recently reported that human colon mucosal biofilms were carcinogenic in murine CRC-models, whether the biofilm associated microbiota were from CRC-patients or healthy individuals [104]. Yu et al detected biofilms associated with CRC, adenomas, and polyps by SEM, FISH, and fluorescence microscopy and found that the prevalence of F. nucleatum was significantly higher in biofilms from CRC than the other sample groups [105]. Although a connection between the composition of the colorectal microbiota and CRC is becoming increasingly evident, more research is needed to determine the exact role of the microbial community of the biofilm and its constituting species in carcinogenesis.…”

The role of microbiota in the development of colorectal cancer

“…The unique FadA adhesin of F. nucleatum can bins to E-cadherin, which activates β-catenin signaling, inducing oncogenic responses in CRC cells. 93 This is accompanied by increasing expression of transcription factors, oncogenes, Wnt, and inflammatory genes, together with growth promotion of CRC cells. 94 By releasing RNA into the host cell and activating NF-κB, F. nucleatum induced inflammation.…”

Fusobacterium nucleatum promotes colorectal cancer by inducing Wnt/β‐catenin modulator Annexin A1

“…Numerous recent studies have reported that the anaerobic Gram-negative oral commensal bacterium, Fusobacterium nucleatum, plays a significant role in colorectal carcinogenesis [8][9][10][11][12][13][14]. F. nucleatum has been detected iñ 10-90% CRC tissues, with higher prevalence in the proximal than distal colon [15][16][17]. It is often associated with advanced disease, chemo-resistance, metastasis, and poor prognosis [14,[18][19][20].…”