Periodontitis is characterized by a chronic inflammation produced in response to a disease-associated multispecies bacterial community in the subgingival region. Although the inflammatory processes occur locally in the oral cavity, several studies have determined that inflammatory mediators produced during periodontitis, as well as subgingival species and bacterial components, can disseminate from the oral cavity, contributing therefore, to various extraoral diseases like cancer. Interestingly, carcinogenesis associated with periodontal species has been observed in both the oral cavity and in extra oral sites. In this review, several studies were summarized showing a strong association between orodigestive cancers and poor oral health, presence of periodontitis-associated bacteria, tooth loss, and clinical signs of periodontitis. Proinflammatory pathways were also summarized. Such pathways are activated either by mono- or polymicrobial infections, resulting in an increase in the expression of proinflammatory molecules such as IL-6, IL-8, IL-1β, and TNF-α. In addition, it has been shown that several periodontitis-associated species induce the expression of genes related to cell proliferation, cell cycle, apoptosis, transport, and immune and inflammatory responses. Intriguingly, many of these pathways are linked to carcinogenesis. Among them, the activation of Toll-like receptors (TLRs) and antiapoptotic pathways (such as the PI3K/Akt, JAK/STAT, and MAPK pathways), the reduction of proapoptotic protein expression, the increase in cell migration and invasion, and the enhancement in metastasis are addressed. Considering that periodontitis is a polymicrobial disease, it is likely that mixed species promote carcinogenesis both in the oral cavity and in extra oral tissues and probably—as observed in periodontitis—synergistic and/or antagonistic interactions occur between microbes in the community. To date, a good amount of studies has allowed us to understand how monospecies infections activate pathways involved in tumorigenesis; however, more studies are needed to determine the combined effect of oral species in carcinogenesis.

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Chronic Inflammation as a Link between Periodontitis and Carcinogenesis.

Colorectal cancer (CRC) is a leading cause of cancer death worldwide. It includes different subtypes that differ in their clinical and prognostic features. In the past decade, in addition to the conventional adenoma-carcinoma model, an alternative multistep mechanism of carcinogenesis, namely the “serrated pathway”, has been described. Approximately, 15 to 30% of all CRCs arise from neoplastic serrated polyps, a heterogeneous group of lesions that are histologically classified into three morphologic categories: hyperplastic polyps, sessile serrated adenomas/polyps, and the traditional serrated adenomas/polyps. Serrated polyps are characterized by genetic (BRAF or KRAS mutations) and epigenetic (CpG island methylator phenotype (CIMP)) alterations that cooperate to initiate and drive malignant transformation from normal colon mucosa to polyps, and then to CRC. The high heterogeneity of the serrated lesions renders their diagnostic and pathological interpretation difficult. Hence, novel genetic and epigenetic biomarkers are required for better classification and management of CRCs. To date, several molecular alterations have been associated with the serrated polyp-CRC sequence. In addition, the gut microbiota is emerging as a contributor to/modulator of the serrated pathway. This review summarizes the state of the art of the genetic, epigenetic and microbiota signatures associated with serrated CRCs, together with their clinical implications.

https://www.mdpi.com/2072-6694/11/7/1017/pdf

The Molecular Hallmarks of the Serrated Pathway in Colorectal Cancer

Human guts harbor abundant microbes that regulate many aspects of host physiology. However, bacterial imbalance or dysbiosis in the gut due to the dietary or environmental changes may cause colorectal cancer (CRC). Increasing studies show that gut microbiota plays an important role in the occurrence and development of CRC, as a result of virulence factors, bacterial metabolites, or inflammatory pathways. In the future, probiotics or targeting the microbiota will probably be a powerful weapon in the battle against CRC. This review seeks to outline the relationship between gut microbiota and the development of CRC as well as the potential mechanisms of microbiota involved in treatment of CRC, so as to provide some references for research on the development, prevention, and treatment of this disease.

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Role of Gut Microbiota in the Development and Treatment of Colorectal Cancer.

The development of colorectal cancer, responsible for 9% of cancer-related deaths, is favored by a combination of genetic and environmental factors. The modification of diet and lifestyle may modify the risk of colorectal cancer (CRC) and prevent neoplasia in up to 50% of cases. The Western diet, characterized by a high intake of fat, red meat and processed meat has emerged as an important contributor. Conversely, a high intake of dietary fiber partially counteracts the unfavorable effects of meat through multiple mechanisms, including reduced intestinal transit time and dilution of carcinogenic compounds. Providing antioxidants (e.g., vitamins C and E) and leading to increased intraluminal production of protective fermentation products, like butyrate, represent other beneficial and useful effects of a fiber-rich diet. Protective effects on the risk of developing colorectal cancer have been also advocated for some specific micronutrients like vitamin D, selenium, and calcium. Diet-induced modifications of the gut microbiota modulate colonic epithelial cell homeostasis and carcinogenesis. This can have, under different conditions, opposite effects on the risk of CRC, through the production of mutagenic and carcinogenic agents or, conversely, of protective compounds. The aim of this review is to summarize the most recent evidence on the role of diet as a potential risk factor for the development of colorectal malignancies, as well as providing possible prevention dietary strategies.

Dietary Factors Modulating Colorectal Carcinogenesis.

Globally, colorectal cancer (CRC) affects more than 1 million people each year. In addition to non-modifiable and other environmental risk factors, Fusobacterium nucleatum infection has been linked to CRC recently. In this study, we explored mechanisms underlying the role of Fusobacterium nucleatum infection in the progression of CRC in a mouse model. C57BL/6 J-Adenomatous polyposis coli (APC) Min/J mice [APC (Min/+)] were treated with Fusobacterium nucleatum (109 cfu/mL, 0.2 mL/time/day, i.g., 12 weeks), saline, or FadA knockout (FadA−/−) Fusobacterium nucleatum. The number, size, and weight of CRC tumors were determined in isolated tumor masses. The human CRC cell lines HCT29 and HT116 were treated with lentiviral vectors overexpressing chk2 or silencing β-catenin. DNA damage was determined by Comet assay and γH2AX immunofluorescence assay and flow cytometry. The mRNA expression of chk2 was determined by RT-qPCR. Protein expression of FadA, E-cadherin, β-catenin, and chk2 were determined by Western blot analysis. Fusobacterium nucleatum treatment promoted DNA damage in CRC in APC (Min/+) mice. Fusobacterium nucleatum also increased the number of CRC cells that were in the S phase of the cell cycle. FadA−/− reduced tumor number, size, and burden in vivo. FadA−/− also reduced DNA damage, cell proliferation, expression of E-cadherin and chk2, and cells in the S phase. Chk2 overexpression elevated DNA damage and tumor growth in APC (Min/+) mice. In conclusion, this study provided evidence that Fusobacterium nucleatum induced DNA damage and cell growth in CRC through FadA-dependent activation of the E-cadherin/β-catenin pathway, leading to up-regulation of chk2.

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FadA promotes DNA damage and progression of Fusobacterium nucleatum -induced colorectal cancer through up-regulation of chk2

Increasing evidence suggests that Fusobacterium nucleatum is involved in colorectal carcinogenesis. Previous studies have explored whether F. nucleatum may trigger colonic epithelial-mesenchymal transition. The results of the present study demonstrated that F. nucleatum enhances the proliferation and invasion of NCM460 cells compared with that of normal control and DH5α cells. Furthermore, F. nucleatum significantly increased the phosphorylation of p65 (a subunit of nuclear factor-κB), as well as the expression of interleukin (IL)-6, IL-1β and matrix metalloproteinase (MMP)-13. Additionally, F. nucleatum infection did not affect the expression levels of epithelial (E-)cadherin and β-catenin. E-cadherin knockdown in NCM460 cells did not induce the activation of inflammatory responses in response to F. nucleatum infection, whereas it increased inflammation in response to β-catenin silencing. F. nucleatum infection could not increase the proportion of cells at S phase when E-cadherin was silenced. Nevertheless, F. nucleatum infection enhanced the proportion of NCM460 cells at S phase when transfected with small interfering RNAs to knock down β-catenin expression. In conclusion, the results of the present study demonstrated that F. nucleatum infection interacted with E-cadherin instead of β-catenin, which in turn enhances the malignant phenotype of colorectal cancer cells.

/pdf/fusobacterium-nucleatum-promotes-the-progression-of-3sdsa61k6g.pdf

Chun‑Ting Ma

Papers

Fusobacterium nucleatum promotes the progression of colorectal cancer by interacting with E‑cadherin