Colorectal cancer (CRC) is the third most prevalent cancer and second in terms of mortality. Over 95% of CRC are adenocarcinomas, and the majority develop via the adenoma-carcinoma sequence. Several risk factors are associated with CRC, such as genetic mutations on tumor suppressor genes and oncogenes,older age,diet,and chronic inflammation. In addition to these established risk factors, increasing evidence has linked CRC with some bacterial species in the gastrointestinal tract such as Fusobacterium nucleatum.

Malignant tumors are complex communities of oncogenically transformed cells with aberrant genomes, associated nonneoplastic cells including immune and stromal cells, and sometimes microbes, including bacteria and viruses.

The only alignments we obtained that were markedly disproportionate between tumor and control were to the genome of Fusobacterium nucleatum subsp. nucleatum (American Type Culture Collection [ATCC] 25586), a Gram-negative anaerobe. F. nucleatum was the organism with the highest number of hits overall (21% of all alignments), and nine of the 11 subjects showed at least twofold higher read counts in tumor relative to corresponding control tissue.

Colorectal tumorigenesis is associated with significant genetic disorders (mutations in suppressor genes and oncogenes) resulting in the transformation of normal intestinal epithelium toward malignant neoplasm. The development of CRC is commonly initiated by mutations in the Adenomatous Polyposis Coli (APC) tumor suppressor gen.

The distinguishing characteristic of the colon is the relative abundance of the resident microbiota. Microbial communities present elsewhere in the GI tract are much smaller and show lower diversity.

There is the qualitative and quantitative difference of commensal bacteria bet ween the right and left colon cancer, which induces epigenetic changes in the intestinal epithelial cells and in the resident immune population. The differences of the genetic features of cancer cells in the right and left colon cancer, induce on the immunological difference between right and left colon cancer is the different mutational load.

Intestinal epithelial cells play a key role in the maintenance of intestinal homeostasis. The first cells entering the lesion site after damage to the intestinal epithelial barrier are innate immune cells. The initial inflammatory response is characterized by the activation of the NF-kB, MAPK/extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 pathways. Genes within the NF-kB family of transcription factors are responsible for the regulation of inflammation and apoptosis.

Chronic inflammation of the intestinal mucosa might induce genetic mutations, promote angiogenesis, stimulate proliferation, and inhibit apoptosis.

The primitive part of the immune system are pattern recognition receptors, which have the ability to identify microflora by molecular structures. These receptors include TLRs, a class of proteins expressed on antigen-presenting cells, macrophages, and dendritic cells (DCs).In the situation of the intestinal barrier damage by microorganisms, cells that present the antigen recognize these microorganisms through TLR receptors, causing the secretion of some cytokines activating the immune response.

Its has been proven that TLR2 and TLR4 binding plays an important role in the carcinogenesis of colorectal cancer by inducing the proliferation,invasion,and migration of tumor cells,and by loss of immunospecificity and the development of resistant to chemotherapy.

Fusobacterium is a genus of the Fusobacteriaceae family, containing bacterial species isolated from both human and animal sources. Its an oral Gram-negative anaerobe, with a spindle-rod shape, non-motile, and non-spore forming. Fusobacterium nucleatum is associated with periodontitis. Fusobacterium nucleatum, a gram-negative anaerobic bacterium, is one of the commensal microbes which is found naturally in the microflora of mouth and gastrointestinal tract in healthy humans. It is also associated with the periodontal and endodontal illnesses. Higher-density Fusobacterium was found in CRC patients comparing to the health through quantitative PCR and bacteria 16S rDNA sequence analysis, including tumor tissues and faeces.

Carcinogenesis

Initiation of the CRC:

As contributors to carcinogenesis, the gut microbiota have emerged into the research field during recent years. Chronic inflammation is regarded as one of the main causes of digestion system cancer.It has been report that Fusobacterium could induce gingivitis, periodontitis, and oral ulcerations. There is also a potential link between Fusobacterium and inflammatory bowel disease.A  more interesting phenomenon is that Fusobacterium stimulates human CRC cell proliferation, without any impact on the noncancerous cells in vitro.

Fusobacterium genus abundance in feces was found to be strongly associated with presence of CRC, but not with presence of advance or non-advance adenoma.It is, however, still under debate whether Fusobacterium is a passenger taking advantage of the conditions caused by the tumor or if the bacterium has a causative role in CRC development.

Proliferation and metastasis of CRC:

Invasion is a vital property of Fusobacterium. Ohkusa et al found that Fusobacterium could penetrate tumors cells and cause proinflammatory cytokine secretion. The elevation of IL-8, TNF-alpha, monocyte chemotactic protein 1 (MCP-1) and IL-6 are known to be a benefit for the proliferation of tumor. In the CRC progress, the typical characteristics of Epithelial-mesenchymal transition include the loss of epithelial E-cadherin which mediates calcium-dependent cell-cell adhesion and restrains cell mobility (metastasis of CRC cells). Fusobacterium nucleatum  enriched colorectal adenocarcinoma tissue, altered the lumen microbial structures, and also promoted tumorigenesis by increasing tumor-immune cytokine secretion of IL-17 and protein expression of phospho signal transducer and activator of transcription 3 (p-STAT3), p-STAT5 and phosphor-extracellular regulated protein kinases (p-ERK). Some researchers concluded that CRC patients associated with the enrichment of F. nucleatum  showed shorter survival duration and were linked with recurrence post-chemotherapy. Fusobacterium  nucleatum induced the expression of autophagic proteins, ULK1, ATG7 which caused Fusobacterium nucleatum to be resistant to 5-FU and oxaliplatin. These finding also indicated that the high amount of Fusobacterium is a risk factor for CRC recurrence. Some studies also reported that Fusobacterium also mediated CRC metastases. Fusobacterium nucleatum load,cancer cell proliferation, and overall tumor growth were reduced by antibiotic metronidazole treatment.

Proinflammatory Cytokine secretion:

Fusobacterium nucleatum and molecular alterations:

Colorectal cancers with high frequency microsatellite instability (MSI-H) show a favorable clinical outcome. A recent study has demonstrated a controversial result that CRCs with more Fusobacterium infection is associated with MSI-H but with poor prognosis.

Fusobacterium is responsible for the drug resistant of CRC:

You et al found that Fusobacterium aimed at TLR4 and MYD88 innating immune response and non-coding RNAs to arouse autophagy pathways and also contribute to CRC chemotherapeutic drug-response.

Premalignant colorectal lesions:

Premalignant colorectal neoplastic lesions appear to be important precursor lesions in the pathogenesis of CRC. In particular, the serrated neoplasia pathway has attracted considerable attention as an alternative pathway of CRC development and serrated lesions exhibit unique clinicopathological and molecular features.

A better understanding of the role of F. nucleatum present in the tumor at the early stage of colorectal tumorigenesis may help to elucidate the pathogenesis of CRC and may provide new possibilities for diagnostic and therapeutic approaches to the disease. Fusobacterium nucleatum is present in all histological types of premalignant colorectal lesions and may play a role in the early stage of tumorigenesis. In this study, the frequency of F. nucleatum positivity in sessile serrated adenomas (SSA) increased gradually from the sigmoid colon to the ascending colon and cecum. To the best of our knowledge, this is the first report describing an association between F. nucleatum positivity and the colorectal continuum concept in the serrated pathway. The crypts of SSA are distorted, particularly at the base where the crypt becomes branched and dilated forming an anchor or “L” shape. The base shows hyper-serration with mature goblet and mucinous cells leading to excessive mucus production, which is seen as a mucus cap on endoscopic examination. These mucus enrichments may explain the high frequency of F. nucleatum positivity in SSAs of the ascending colon and cecum because mucus caps are frequently seen on the surface of right-sided colon SSAs. The mucus cap may help the microbiota to survive, by coating the surface of the neoplastic lesion. Further investigation is needed to clarify the association between F. nucleatum positivity and mucus caps in SSAs.