## 2 Esophageal Cancers
### Microbiota in Esophagus Cancer

Table 2: Oral microbiota composition differences between esophageal squamous cell carcinoma and esophagus adenocarcinoma (distribution of clones at the genus and species levels). healthy controls amplification of V3-V4 region of 16S rRNA and sequencing by 454-pyrosequencing platform [21]; 325 esophageal cancer biopsy, quantification of _F. nucleation_ DNA [22]. It has been demonstrated that the prevalence of _Actinomyces_ is greater in EAC. _Actinomyces_ is a common genus residing on the surfaces of the oral mucosa and has also been found in the human pharynx; however, in the case of tissue injury, their presence might lead to endogenous infection known as actinomycosis [23]. Actinomycosis causes the development of chronic inflammation in soft tissues, leading to necrosis and the formation of yellowish sulphur granules [24]. _Tannerella forysthia_, a Gram negative, anaerobic bacterium, strongly induces pro-inflammatory cytokines such as interleukin (IL)-18 and IL-6 by CD4 (cluster of different 4) + T helper cells and tumor necrosis factor (TNF-\(\alpha\)). Moreover, multiple virulence factors such as trypsin-like proteases and cysteine-like proteases can cause the degradation of protein components within infected tissues, which facilitates tissue colonization by other pathogens [25]. EAC microbiota have also been shown to be enriched with bacteria related to periodontal disease, that is, _Veillonella_[26]_Selenomonas_, and _Treponema denticola_[27]. _T. denticola_ has been mostly associated with severe periodontitis; however, it has been suggested that bacterial virulence factors, especially chymotrypsin-like proteinase (Td-CTLP), might contribute to cancer development. [PERSON] et al. reported that Td-CTLP exhibit regulatory activity on proteins critical for the regulation of tumour microenvironment and inflammation [27]. Interestingly, an increase in _T. denticola_ abundance has also been linked to pancreatic cancer. Both EAC and ESCC were enriched in _Streptococcus_ genera, and it has been found that enrichment in _Streptococcus_ might lead to cancer development, as these bacteria strongly activate the immune system of the host. [PERSON] et al. reported that _Streptococcus mitis_ and _Streptococcus anginos_ increase the expression of IL-8, a strong chemotactic factor for immune cells, and growth-regulated protein \(\alpha\) (GRO\(\alpha\)), a chemokine involved in inflammation and tumorigenesis [18; 28]. The microflora of ESCC patients has also been reported to be enriched in bacterial genera linked to periodontitis and inflammation, that is, _Porphyromonas_, _Treponema_, _Streptococcus_, and _Prevotella_. _Prevotella_ is a member of commensal human microflora, so its presence seems explicable in the microflora of ESCC cancer patients; however, it is also linked to periodontitis, rheumatoid arthritis, and low-grade systemic inflammation. It might contribute to cancer development by stimulating epithelial cells to produce proinflammatory cytokines, that is, IL-8, IL-6 and CCL20, a chemokine linked directly to cancer development [29]. Considerable interest has been focused on a possible link between the presence of _Porphyromonas_ and the development of oral, gastrointestinal, and pancreatic cancers. [PERSON] et al. (model exposing human immortalized oral epithelial cells to _P. gingivalis_ at a low multiplicity of infection for 5-23 weeks) and [PERSON] et al. (murine model of periodontitis-associated oral tumorigenesis) note that Porphyromonas _gingivalis_ robustly induces inflammatory response and promotes the proliferation of cyclin D1, matrix metalloproteinase-9 (MMP-9), and heparinase [30; 31]. Moreover, long-term exposure to _P. gingivalis_ stimulates cell migration and invasion abilities [31]. In both types of esophageal cancers, a strong decrease in commensal microflora can be observed, which may be associated with changes occurring in tissues undergoing carcinogenic transformation.