Association between oral microflora and gastrointestinal tumors (Review)

  • Authors:
    • Xiaoxiao Li
    • Sibo Zhu
    • Tiejun Zhang
    • Xingdong Chen
  • View Affiliations

  • Published online on: June 10, 2021     https://doi.org/10.3892/or.2021.8111
  • Article Number: 160
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The oral cavity contains the highest density and the most species of microorganisms compared with other parts of the body. Recent studies have determined that the species and abundance of oral microflora are closely associated with the development of upper gastrointestinal tumors, including oral, esophageal and gastric cancer. Additionally, differential abundant microbiota in patients with cancer and abnormal microorganisms inside the tumor tissue have been identified as critical markers of tumorigenesis. There is evidence to suggest that certain genera, including Firmicutes, along with various species, such as Porphyromonas, can increase the risk of oral cancer. Furthermore, Porphyromonas gingivalis is a risk factor for esophageal carcinoma, while Helicobacter pylori infections are a main cause of gastric cancer. Currently, as far as carcinogenic mechanisms of oral microorganisms are concerned, it has been hypothesized that the production of carcinogenic substances, chronic inflammation and altered cell metabolisms may be mechanisms by which oral microorganisms influence the development of upper gastrointestinal cancer. Certain phrases, including ‘oral microbes’, ‘oral microorganism’, ‘oral microbiology’, ‘oral microflora’, ‘oral cancer’, ‘oral carcinoma’, ‘carcinoma of mouth’, ‘esophagus cancer’, ‘esophageal cancer’, ‘esophageal carcinoma’, ‘carcinoma of esophagus’, ‘gastric cancer’, ‘gastric carcinoma’, ‘stomach cancer’, ‘cancer of the stomach’, ‘carcinogenic mechanism’ and ‘carcinogenesis’, were searched as key words in PubMed and Web of Science for articles published between 1975 to 2020. A total of 1,512 studies were obtained. After further searching the abstracts for key words, such as oral microorganisms, oral cancer, esophagus cancer, gastric cancer and carcinogenic mechanisms, 137 studies were selected. The current review systematically and comprehensively summarized the association between the oral microbiota and oral, esophageal and gastric cancer. Additionally, the current review described the carcinogenic mechanisms of oral microbes and attempted to identify common molecular mechanisms among different types of tumor. The association between upper gastrointestinal cancer therapy and oral microflora was also assessed. The present review may be used as a reference for future diagnosis and therapeutics for upper gastrointestinal tumors.

Introduction

The incidence and mortality rates of upper gastrointestinal cancer are high, particularly in gastric and esophageal cancer (1). According to statistics produced by the World Health Organization (WHO), cancer is the first or second leading cause of death among individuals <70 years old in 91 countries, ranking third or fourth in an additional 22 countries (1). Most types of cancer have clear causes, such as smoking for lung cancer (2) and alcohol consumption (3) or occupational hazards (4) for upper gastrointestinal cancer. The human mouth is colonized by a set of microorganisms, including bacteria, archaea, fungi and viruses (5). Additionally, the bacterial colonies of the oral cavity are significantly less variable and more diverse than all other environments of the body, including the gut or skin (6). Currently, a large number of studies have demonstrated that oral microorganisms are closely associated with gastrointestinal tumors (7,8). Mechanisms of carcinogenesis mediated by oral microorganisms may include the production of carcinogenic substances, chronic inflammation and altered cell metabolisms (9). The current review summarized the association between the oral microbiota and oral, esophageal and gastric cancer, providing discussion regarding the carcinogenic mechanisms of oral microbes and attempting to identify common molecular mechanisms among different tumors. The regulation of the oral microbiota from the perspective of diet, probiotics and prebiotics was also assessed to improve gastrointestinal cancer prevention and treatment.

Basic features and oral microflora characteristics of three types of tumor

Stomach cancer

Stomach cancer (gastric cancer) is one of the most common malignancies as indicated by International Agency for Research on Cancer data collected in 2018 (1). The incidence of stomach cancer was 5.7% worldwide, ranking fifth among all types of cancer in the same year (1). Additionally, the mortality rate was 8.2%, ranking third worldwide (1). In China, stomach cancer is one of the most common types of malignancy. A 2017 survey revealed that the incidence and mortality rates of stomach cancer among the Chinese population was 1.5 times higher than those of the world standard population who died of stomach cancer (10). As a result, stomach cancer has been the focus of national cancer prevention and treatment (10).

The human stomach has a pH of 1–2, whereas the gastric mucus layer establishes a pH gradient from 6–7 at the surface of the mucosa (11). The stomach can therefore support a bacterial community with hundreds of phylotypes (12). Additionally, pH values <4 prevent bacterial overgrowth, which is important as the acidic milieu is not capable of sterilizing the stomach (13). However, Helicobacter (H.) pylori influences gastric colonization dynamics (14). During the development of chronic gastric disease, pH values increase, resulting in bacterial overgrowth, particularly of Gram-negative bacilli in diarrheic infants (15).

There is an association between the development of gastric cancer and the oral microbiota. The first gastric tumor-associated bacteria to be identified was Streptococcus salivarius (16). Yamamura et al (17) revealed that Fusobacterium (F.) nucleatum in the oral cavity may be involved in the development of esophageal and gastric cancer. Additionally, Lactobacillus colonization increases during the process from gastritis to gastric cancer (18). In the saliva or plaque of patients with gastric cancer, the relative abundance of certain bacteria (Veillonella, Prevotella, Aggregatibacter and Megasphaera) increases, while that of others (Leptotrichia, Rothia, Capnocytophaga, Campylobacter, Tannerella and Granulicatella) decreases (19). Compared with healthy controls with no gastric diseases, the coating of patient tongues has a higher relative abundance of Firmicutes and a lower relative abundance of Bacteroidetes at the phylum level (20). Additionally, higher Streptococcus and lower Neisseria, Prevotella, Prevotella and Porphyromonas levels have been demonstrated at the genus level (20). Sun et al (21) revealed that the increased colonization of periodontal pathogens in the oral cavities of patients with gastric cancer, specifically Treponema denticola, Tannerella forsythia and Actinobacillus actinomycetemcomitans, decreased bacterial diversity in dental plaques. Furthermore, not regularly flossing teeth has been identified as a significant predictor of increased risk of precancerous lesions in gastric cancer (21). Therefore, importance should be placed on daily cleaning for the purposes of oral hygiene. The occurrence of gastric cancer may also be associated with certain viruses, such as the Epstein-Barr virus (22).

Esophageal cancer

The incidence rate of esophageal cancer is the 7th highest in the world (1). Additionally, it is one of the deadliest tumors, with the 6th highest mortality rate of any type of cancer worldwide (1). In China, esophageal cancer is the fourth most common cause of cancer-associated death (23). It is also the most highly publicized and researched type of cancer in China, indicating that it causes serious harm to human health (24). Esophageal cancer is regionally aggregated in China, demonstrating a high incidence in Linxian (Henan province) (25), Cixian and Shexian (Hebei province) (26) and Taixing (Jiangsu Province) (27). In total, >90% of esophageal cancer cases are of the esophageal squamous cell cancer (ESCC) and esophageal adenocarcinoma (EAC) type (28). Esophageal cancer is a genetically diverse disease with a high frequency of somatic copy number alterations in oncogenic driver genes due to large-scale rearrangements (29). The development of esophageal cancer also involves various external factors, such as drinking excessive quantities of hot tea (30), smoking, alcohol consumption (31) and the interaction between alcohol intake and genetic polymorphisms (32). The prognosis of patients with esophageal cancer is dependent on their pathological stage and the treatment available, as early detection and suitable therapy can significantly improve the prognosis of individuals (33). Li et al (34) demonstrated that CD147 was an important prognostic factor that was highly expressed in patients with esophageal cancer, which was associated with decreased patient survival.

From the perspective of the microbiota, the development of esophageal cancer is also associated with oral microorganisms. Peters et al (35) revealed that the periodontal pathogen, Tannerella forsythia, was associated with an increased risk of EAC, and that the depletion of the commensal genus Neisseria, as well as the species Streptococcus pneumoniae, was associated with decreased EAC risk. Finally, the abundance of Porphyromonas (P.) gingivalis in the oral cavity has been associated with an increased risk of ESCC (35), which is in agreement with another study (36). Treponema denticola, Streptococcus mitis and Streptococcus anginosus may have significant roles in the carcinogenic process of esophageal cancer by causing inflammation and by promoting the carcinogenic process (37). Eradication of these bacteria may therefore decrease the risk of recurrence (37). Chen et al (38) demonstrated that patients with ESCC exhibited significantly decreased microbial diversity and a significant decrease in Lautropia, Bulleidia, Catonella, Corynebacterium, Moryella, Peptococcus and Cardiobacterium abundance compared with those of healthy controls and patients with dysplasia. In terms of fungi, the participation of nitrosamine compounds produced by chronic Candida infections has been revealed to be a risk factor for esophageal cancer (39), which is consistent with the fact that oral Candida colonization is significantly more common in patients with esophageal cancer than in healthy controls (40). Professional dental care, such as teeth and tongue cleaning, may reduce ‘bad’ microbiota abundance in the oral cavity, thereby decreasing the risk of esophageal cancer (41,42).

Oral cancer

Oral cancer is a general term for tumors of the oral cavity, and is one of the most common malignancies of the head and neck. The 5-year overall survival rate of patients with oral cancer is 68%, and the 5-year disease-specific survival rate is 78%, and the cancer stage and invasion depth are important factors affecting prognosis (43). The latest global cancer statistics report revealed that new cases and deaths associated with oral cancer were ranked 18th and 15th, respectively, among all tumors in 2018 (1). According to the WHO definition, >80% of oral cancer cases are squamous cell carcinoma, followed by glandular carcinoma, basal cell carcinoma, undifferentiated carcinoma and lymphatic carcinoma (ICD-10 rubrics C01-C06) (44). Oral cancer treatment strategies include surgery (45), radiation therapy (45), chemotherapy (46) and traditional Chinese medicine (47). Additionally, oral cancer may be treated via diet therapy. Lee et al (48) determined that a diet low in n-6/n-3 polyunsaturated fatty acids may prevent oral cancer.

The development of oral cancer is closely associated with oral microorganisms. Takahashi et al (49), Schmidt et al (50) and Zhao et al (51) reported significantly greater bacterial diversity in oral cancer samples than in normal samples. However, other studies have indicated that bacterial diversity is decreased in oral cancer (5254). Patients with oral cancer have an increased richness of Peptostreptococcus, Fusobacterium, Alloprevotella and Capnocytophaga, whilst also demonstrating a lower richness of Rothia and Haemophilus (49). This is consistent with the conclusion of Yost et al (55), which indicated that Fusobacteria contained a significantly higher number of transcripts in patients with cancer than in healthy controls at tumor sites and tumor-adjacent sites. Three species of periodontopathogenic bacteria, including Prevotella tannerae, F. nucleatum and Prevotella intermedia, have been associated with an increased risk of oral squamous cell carcinoma (OSCC) (56). Experiments in mice have revealed that P. gingivalis infection-induced periodontitis increases the tongue lesion size and multiplicity of each mouse, promoting oral cancer development (57). In particular, a group of periodontitis-associated taxa, including Fusobacterium, Dialister, Peptostreptococcus, Filifactor, Peptococcus, Catonella and Parvimonas, are significantly enriched in OSCC samples (51). Additionally, a case-control study in Mexico has revealed that the prevalence of human papillomavirus (HPV) infection is significantly increased in patients with oral cancer, indicating that without risk factors such as smoking and alcohol consumption, high risk-HPV may be a risk factor for oral mucosa carcinogenesis (58) (Table I).

Table I.

Characteristics of the oral flora in patients with upper gastrointestinal tumors compared with in healthy controls.

Table I.

Characteristics of the oral flora in patients with upper gastrointestinal tumors compared with in healthy controls.

Type of cancerDiversity of oral bacteriaEnriched oral bacteriaReduced oral bacteriaOther enriched microorganisms in the oral cavity
Stomach cancer↓ (21)Veillonella, Prevotella, Aggregatibacter, Megasphaera and other 25 types of bacteria (19); Actinobacteria (125); Firmicutes, Streptococcus (20); Treponema denticola, Tannerella forsythia and Actinobacillus actinomycetemcomitans (21)Leptotrichia, Rothia, Capnocytophaga, Campylobacter, Tannerella and Granulicatella (19); Proteobacteria, Fusobacterium, Haemophilus, Porphyromonas (125); Neisseria (20,57,125), Prevotella, Bacteroidetes (20)Epstein-Barr virus (22)
Esophageal cancer↓ (38)Tannerella forsythia, Porphyromonas gingivalis (35,36); Treponema denticola, Streptococcus mitis, Streptococcus anginosus (37)Neisseria and Streptococcus pneumoniae (35), Lautropia, Bulleidia, Catonella, Corynebacterium, Moryella, Peptococcus, and Cardiobacterium (38)Chronic candidiasis (39,40)
Oral cancer↑ (4951) ↓ (52,54) Alloprevotella, and Capnocytophaga (49); Prevotella tannerae and Prevotella intermedia (56); Porphyromonas gingivalis (57); Peptostreptococcus (49,51), Fusobacterium (49,51,55,56), Dialister, Filifactor, Peptococcus, Catonella (51); Fusobacteria (55), Firmicutes, Lactobacillus, Streptococcus, Staphylococcus and Parvimonas (52)Rothia (49) and Haemophilus (49,52), Bacteroidetes, Proteobacteria, Aggregatibacter, Lautropia, Leptotricha, Neisseria, Gemellaceae (52)High-risk-human papillomavirus (58)

[i] The arrows (↓ and ↑) indicate decrease and increase of oral bacteria diversity, respectively.

In summary, a decrease in diversity of oral bacteria and Neisseria abundance occurs in all of the three aforementioned types of cancer. Rothia, Proteobacteria, Haemophilus and Bacteroidetes diversity is decreased in stomach and oral cancer, while the diversity of Treponema denticola and Tannerella forsythia increases in stomach and esophageal cancer. Furthermore, Prevotella and Firmicutes diversity is enriched in stomach and oral cancer, while P. gingivalis is enriched in esophageal and oral cancer.

The differences between the cancer and normal paracancer tissues of the same patients with oral, esophageal and gastric cancer were compared in the current review (Table II). Compared with normal tissues, an enriched microflora was identified in oral cancer tissues, exhibiting bacteria such as Veillonella, Fusobacterium, Prevotella, Porphyromonas, Actinomyces and Clostridium (anaerobes); Haemophilus, Enterobacteriaceae and Streptococcus (aerobes); Candida albicans (59); Streptococcus species, Staphylococcus species, Moraxella species, Enterococcus faecalis, aerobic spore formers, Klebsiella species, Citrobacter species, Proteus species and Pseudomonas species (60). Similar patterns were observed in esophageal and gastric cancer (Table II).

Table II.

Microorganism composition of tumor tissues compared with normal tissues.

Table II.

Microorganism composition of tumor tissues compared with normal tissues.

Type of cancerDiversityEnriched bacteriaReduced bacteria
Stomach cancer↑ (117) ↓ (126)Streptococcus salivarius (16), Fusobacterium nucleatum (17), Peptostreptococcus, Streptococcus (117)Lactic acid-producing bacteria, such as
(Serum-derived samples) Lactococcus lactis and Lactobacillus brevis (117)
Esophageal cancer↓ (127) (Esophageal disease)Porphyromonas gingivalis (36), Enterobacteriaceae (83), chronic candida (39,40)NA
Oral cancerNAVeillonella, Fusobacterium, Prevotella, Porphyromonas, Actinomyces and Clostridium (anaerobes), and Haemophilus, Enterobacteriaceae (59), Streptococcus species (aerobes), Candida albicans (59,60), Staphylococcus species, Moraxella species, Enterococcus feacalis, aerobic spore bearers, Klebsiella species, Citrobacter species, Proteus species, Pseudomonas species (60)NA

[i] The arrows (↓ and ↑) indicate decrease and increase of oral bacteria diversity, respectively. NA, not applicable.

Possible mechanisms of oral microorganisms affecting the three types of gastrointestinal tumors

Gastrointestinal tumors may affect the density and diversity of oral microorganisms. For patients with cancer exhibiting low immunities, harmful microbes may take advantage and disrupt the normal distribution of human oral flora. Conversely, alterations in oral microorganisms may also be a risk or protective factor for the tumorigenesis of various types of cancer, including gastrointestinal cancer. The possible mechanisms by which this occurs are described in the current review. Currently, the carcinogenic mechanisms of oral microorganisms include the production of carcinogenic substances, chronic inflammation (61) and altered cell metabolism, through which oral microorganisms influence the development of upper gastrointestinal cancer (62).

Carcinogenic substances

Carcinogens produced by oral microorganisms in the process of upper digestive tract tumor development include acetaldehyde, reactive oxygen species (ROS), organic acids and n-nitrotrimethylamine (6365).

Oral cancer may develop from certain Gram-negative bacteria, such as Stomatococcus, which convert ethanol into acetaldehyde via alcohol dehydrogenase (66). Among bacteria, the genus Neisseria exhibits extremely high alcohol dehydrogenase activity and can produce a large quantity of acetaldehyde (100 times that of other strains) when cocultured with ethanol in vitro, promoting the development of upper aerodigestive tract tumors (63). Carcinogenic substances are produced after long-term alcohol consumption (67). Furthermore, drinking alcohol affects the distribution of oral bacteria, leading to an increased abundance of Neisseria, which further leads to an increase in carcinogen production (63). This interaction suggests that Neisseria may be a primary source of the oral carcinogen, acetaldehyde, and that oral microbial disorders may serve an important role in the occurrence of upper gastrointestinal tumors induced by drinking alcohol (63). The concentration of acetaldehyde in the oral cavity of healthy adults is positively correlated with the abundance and diversity of lingual dorsal bacteria and the relative abundance of Gemella sanguinis, Veillonella parvula and Neisseria flavescens (64).

Oral bacteria, such as streptococci, are involved in the formation of certain ROS, including peroxide (68). ROS participate in cell metabolism and serve an important role in the occurrence and development of eukaryotic periodontitis by participating in signal transduction, cell differentiation and apoptosis (69). Additionally, ROS can damage DNA, serving an important role in carcinogenesis (69).

Compared with non-tumor oral tissues, bacteria isolated from oral squamous cell carcinoma tissue demonstrate acid resistance (65). Additionally, various oral bacteria, such as Streptococcus mutans, can ferment nutrients to produce lactic acid, among other organic acids (70). Therefore, these oral microorganisms may cause oral cancer by producing organic acids. Furthermore, specific Candida fungi can produce N-nitrosobenzylmethylamine (NBMA), a potent carcinogen (39).

Therefore, oral microorganisms may cause esophageal cancer by producing carcinogens. Bacteria that colonize the dorsum of the tongue convert ~30% of dietary nitrate to nitrite (71), which can be converted into carcinogenic N-nitroso-compounds in the acidic environment of the distal esophagus, resulting in gastroesophageal reflux disease and potentially cancer (72). Professional oral care can reduce the amount of acetaldehyde in the oral cavity and decrease the risk of esophageal cancer by reducing the density of certain microorganisms (41).

Causing chronic inflammation

Chronic irritation and inflammation are important factors in tumorigenesis. Various important cytokines serve key roles in the development of chronic inflammation, including TNF-α, IL-6, IL-1, IL-17 and IL-23 (73). Additionally, IL-6 activates numerous important immune cells, including macrophages and T cells (74), serving an important role in the acute inflammatory response. Moreover, IL-1 mediates a key inflammatory pathway in rare genetic syndromes and gout, which is a chronic inflammatory disease (75).

Generally, oral microorganisms may cause oral cancer by inducing chronic inflammation and periodontal disease, which is harmful to parenchymal cells (9). These cells influence the concentration of various cytokines, including TNF-α, leading to tumor development (9). For example, P. gingivalis infections can induce periodontitis in mice, increasing the area and type of oral lesions and promoting the occurrence and development of oral cancer (57).

Chronic inflammation has been revealed to promote genetic and epigenetic abnormalities that result in cancer (76). In the process of inflammation leading to cancer, the NF-κB family of transcription factors are important for the mediation of inflammation, cell proliferation, differentiation and cell death (77). NF-κB cooperates with several other signaling pathways to regulate a large number of target genes and produce a complex feedback loop, serving a vital role in inflammation and innate immunity, and certain Gram-negative bacteria can activate NF-κB, and thereby interfere with the Toll-like receptor 4 (TLR4) signaling pathway, causing carcinogenesis in the colon, liver, pancreas and skin (77). In view of the role of NF-κB in the development of cancer, the NF-κB signaling pathway may be an effective target for clinical intervention (78). In addition, inflammatory cells and cytokines, such as TNF-α, have been found to decrease the number of fibroblasts and osteoblasts in the tumor microenvironment during bacterial-associated chronic inflammation (79), which can also lead to the production of ROS and nitrogen, inducing DNA mutations that lead to cancer (80,81). In terms of viruses, infection with HPV can cause p53 inactivation, immunodeficiency or suppression of the immune response, increased DNA fragility and increased sensitivity to carcinogens (82).

Oral microorganisms may potentially cause esophageal cancer by inducing chronic mild inflammation. Distal esophageal colonies are composed of oral bacteria, in which Gram-negative bacterial-specific antigens, such as lipopolysaccharides, promote tissue inflammation (83). In addition, oral esophageal bacteria are altered in Barrett's esophagus and reflux esophagitis, and the known risk factors, combined with the chronic mild inflammation or direct carcinogenesis caused by the altered microbiota, promote Barrett's esophagus metaplasia, progressing to EAC (83).

Oral microorganisms may cause gastric cancer through distal effects. For example, they can cause periodontal disease, and periodontal infection can lead to systemic chronic inflammation, which is a risk factor for gastric cancer (19,84).

Regulation of host cell metabolism

Through murine experiments, Wu et al (57) revealed that P. gingivalis infection enhanced the carcinogenesis induced by 4-nitroquinoline-1-oxide. Additionally, immunohistochemical analysis and reverse transcription-quantitative PCR results revealed that the expression levels of fatty acid synthase and acetyl-CoA carboxylase I in the tongue and liver tissues of mice increased after animals were infected with P. gingivalis, indicating that the fatty acid synthesis pathway may be activated during oral carcinogenesis, and that the pathway may be further upregulated by P. gingivalis infection (57). The possible mechanism by which this may occur is via P. gingivalis infection significantly increasing the level of free fatty acids in the mouse tongue and serum, therefore changing the fatty acid spectrum, aggravating fatty acid metabolism disorder and eventually promoting oral carcinogenesis (57). Oral bacteria may also secrete bacterial effector proteins through type three or type four secretory systems, directly affecting the development of cancer (85), while normal tissues are still regulated by oral microorganisms after they become cancerous. Cho et al (86) determined that P. gingivalis inhibited the proliferation of oral cancer cells by blocking the G1 phase of the cell cycle. The results also demonstrated that compared with uninfected control cells, the expression levels of cyclin D1 and CDK4 in oral cancer cells were decreased, while the expression levels of the CDK inhibitor p21 were increased after infection with P. gingivalis, suggesting that autophagy was significantly enhanced in infected cells, aiding the inhibition of proliferation (86). Yamamura et al (17) first detected the oral microorganism F. nucleatum in esophageal and gastric cancer. It was determined that the involvement of F. nucleatum in the formation of gastrointestinal tumors may be associated with nucleation (17). H. pylori, commonly found in the oral cavity, is a strong inducer of gastric cancer and precancerous lesions (87). Increased PI3K/AKT/GSK3β mRNA and protein expression in gastric cancer tissues may indicate that H. pylori infection can activate the PI3K/AKT/GSK3β signaling pathway in gastric cancer (88), promoting the proliferation of tumor cells (89).

The aforementioned carcinogenic mechanisms are summarized in Fig. 1, representing the three main carcinogenic mechanisms of oral cancer caused by oral microorganisms. In the first carcinogenic mechanism, oral microorganisms contribute to the formation of acetaldehyde, ROS, organic acids, N-NBMA, nitrite and other carcinogenic substances in the body to promote cancer cell proliferation. In addition, after the conversion of nitrate to nitrite, nitrite is further converted into the carcinogens N-nitroso-compounds in the acidic environment of the distal esophagus and stomach cardia, resulting in gastroesophageal reflux disease and potentially cancer. In the second carcinogenic mechanism, microorganisms directly or indirectly cause chronic inflammation, which leads to DNA mutations or causes cell carcinogenesis through TLR4 and other metabolic pathways. Additionally, oral microorganisms can induce periodontitis and chronic inflammation of the esophagus and stomach, which encourages Barrett's esophagus and Reflux esophagitis to esophageal and gastric cancer. In the third carcinogenic mechanism, microorganisms regulate host cell metabolism to induce metabolic disorders that lead to cell carcinogenesis and proliferation. H. pylori infection can activate the PI3K/AKT/GSK3β signaling pathway in gastric cancer, promoting the proliferation of tumor cells.

Association between therapy and microflora

Thus far, the association between oral microbes and three types of upper gastrointestinal cancer has been described in the present review, as well as their related mechanisms. As a result, from the perspective of regulating oral microorganisms, upper gastrointestinal cancer types may be protected in the future. There are numerous ways to regulate oral microorganisms: Physical removal, antibiotic use, diet control, probiotics and prebiotics (90). More novel interventions, such as diet, probiotics and prebiotics, will be discussed henceforth.

There is sufficient evidence to indicate that diet affects numerous types of cancer (91). For example, a pro-inflammatory diet may be a risk factor for oral cancer (92). One of the reasons why diet is relevant to cancer may be that diet can affect the composition of oral microbes (93). Diet can also affect the gut microbiota, serving a fundamental role in the prevention of gastric (94) and colorectal cancer (95,96). Therefore, it may be possible to effectively prevent oral and other types of cancer by controlling certain dietary aspects, such as eating more fruit and vegetables, and less meat and animal products (97).

Prebiotics are ingredients capable of stimulating the growth of beneficial gut microorganisms, while probiotics provide benefits to the host when taken in sufficient quantities (98,99). The probiotic E. coli Nissle 1917 can be used as a targeting vector to transfer P53 and the tum5 protein to the tumor region, enhancing targeted therapeutic effects and reducing tumor volume (100). Propionibacterium freudenreichii is able to induce tumor cell death in the human colon and stomach (101). Moreover, Lactobacillus acidophilus and Lactobacillus casei can enhance 5-fluorouracil-induced apoptosis in colon cancer cells (102), improving the efficacy of chemotherapy. Furthermore, probiotics and prebiotics have chemoprophylactic effects on colon cancer (103). Research has demonstrated that gut microbes can influence the efficacy of chemotherapy for pancreatic cancer (104). For melanoma, probiotics enhance immunity and the antitumor immune response by increasing antigen presentation and improving T cell function (105). In a previous study assessing lung cancer, tumor volumes increased and survival rates were significantly decreased when patients were treated with cisplatin and a combination of antibiotics compared with those that received cisplatin alone (106). This indicated that a balanced commensal flora improved anticancer chemotherapy. Additionally, the flora of the human body can affect the efficacy of radiotherapy, gene therapy, immunotherapy and other tumor treatments (106).

Prebiotics (107) and probiotics (108,109) enhance the immunity of the body through the intestinal flora, reducing gastrointestinal inflammation and preventing cancer (110). For example, Guglielmetti et al (111) demonstrated that certain types of oral Streptococci exhibited good adaptability to the host and had potential immune regulatory and anti-inflammatory effects, making them potential candidates for pharyngeal probiotics. Conversely, probiotics can also affect oral microorganisms. Cortes-Dorantes et al (112) revealed that probiotics can decrease the levels of Streptococcus mutans.

In terms of the oral cavity, increasing numbers of studies have demonstrated that probiotics can decrease the incidence of dental caries (113), oral inflammation and periodontal disease when properly applied (90). Krasse et al (114) determined that the probiotic Lactobacillus reuteri can decrease gingivitis and gum bleeding. Therefore, it can be assumed that probiotics or prebiotics can be used to control periodontal disease and oral inflammation to prevent and treat oral cancer. Xie et al (115) and Zheng et al (110) hypothesized that probiotics can regulate intestinal microorganisms by increasing the number of beneficial bacteria, such as Bacteroides, Faecalibacterium and Akkermansia, decreasing the density of harmful bacteria, such as Streptococcus, and finally reducing the degree of inflammation and enhancing the immunity of patients with gastric cancer. Faecalibacterium and Akkermansia are highly abundant human gut microbes in healthy people, and their decreased levels are associated with inflammation and alterations of metabolic processes (116). At the genus level, the probiotic combination treatment greatly enhances the richness of Faecalibacterium (6.50 vs. 0.32%, richness with probiotic combination treatment versus richness without probiotic combination treatment) and Akkermansia (2.42 vs. 0.01%, richness with probiotic combination treatment versus richness without probiotic combination treatment), indicating an improved balance of the intestinal microflora, thereby decreasing the severity of physiological and microbial disorders, and as a result, impeding the development and progression of gastric cancer (110). Although the mechanism by which oral microorganisms cause oral cancer has been relatively well-studied, the mechanism by which oral microorganisms cause gastric and esophageal cancer has not been fully elucidated. Therefore, further studies are required.

Summary and outlook

The current review summarized the association between oral, esophageal and gastric cancer and oral microbial abundance and diversity. It also compared the microbial differences between cancer tissues of patients with upper gastrointestinal tumors and normal adjacent tissues. The analysis revealed that certain microorganisms are enriched in the oral cavity and in tumor tissues. For example, Streptococcus is enriched in the stomach and oral cavity of patients with gastric cancer (20,117). Therefore, the present review suggested that the high abundance of Streptococcus and other microorganisms in the oral cavity may be important to promote the occurrence and development of gastric, esophageal and oral cancer.

The possible mechanisms of oral microbial carcinogenesis can be roughly divided into three types. First, oral microorganisms participate in material metabolism to produce carcinogens (66) or greatly increase the production of carcinogenic substances (63). Second, oral bacteria can cause periodontitis (57), esophageal (83) or gastric inflammation by producing distal effects (84). Third, oral microorganisms regulate host metabolism, participating in important signaling pathways and even directly interacting with parenchymal cells (57). As a result, the incidence of cancer may be inhibited and decreased by regulating the distribution of oral microorganisms through physical removal, antibiotics, specific diet, prebiotics and probiotics (90).

Previous studies have focused on 16S ribosomal RNA (rRNA) (118,119). Although 16S rRNA profiling is an effective and straightforward technique to study microbial communities, it only provides the taxonomic composition. Due to complex variations among oral microbiota, characterization at the species level may not be sufficient to evaluate their pathogenic potential. Metagenomic whole-genome shotgun sequencing data can provide taxonomy information and determine the biological functional profiles of microbial communities (120). Furthermore, as bacteria contain plasmids, there may be cross-species conjugation and transfer (from one bacterium to another), which cannot be determined via 16S rRNA evaluation. The recent discovery that genotoxic polyketide-non-ribosomal peptide synthase operon (also referred to as clb) E. coli promotes colorectal cancer may suggest that genes are dominant and that bacteria are only a vehicle (121). The function of the bacterial spectrum may be considered the resting state, while genomics involves counting and quantification. Metatranscriptomic (122) and metaproteomic (123) techniques can further describe the promotive function of bacterial spectrums on esophageal cancer.

Probiotics may decrease inflammation in gastrointestinal illness and oral cancer. Bacteriotherapies (probiotics and symbiotics) may potentially be efficacious in reducing complications associated with chemotherapy, radiotherapy and surgery in patients with cancer (124). However, further research is required to determine whether probiotics can treat cancer, improve survival rates and influence time to progression. Future basic or clinical studies should be performed to enhance therapy or synergize with other oncology treatments to analyze their effects. Assessing changes in immunity, the tumor microenvironment and the tumor cell survival cycle will be important to future work.

Carcinogenic substances, inflammation and the regulation of host cell metabolism are oncogenic factors; however, it is not known which factors dominate and whether there are interactions between them. Future studies should determine the additive or multiplicative effects of these factors in animal models or in epidemiological studies.

The current review provided a comprehensive reference for future research. For example, oral microbes may be used as new biomarkers for disease diagnosis and surveillance. The particular targets of oral microorganisms in the process of tumorigenesis may also be used for precise targeted therapy. Additionally, it may be possible to control oral microbes in a variety of ways to prevent cancer.

Acknowledgements

Not applicable.

Funding

The present study was supported by the National Key Research and Development program of China (grant nos. 2019YFC1315804 and 2016YFC0901403), the National Natural Science Foundation of China (grant nos. 91846302 and 82073637) and Shanghai Municipal Science and Technology Major Project (grant no. 2017SHZDZX01).

Availability of data and materials

Not applicable.

Authors' contributions

XL wrote and revised the article. SZ provided the article idea and revised the article. TZ and XC revised the article and edited part of the manuscript. Data authentication is not applicable. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI

2 

Obeid R and Pietrzik K: Smoking, B vitamins, and lung cancer: The chicken or the egg causality dilemma. J Clin Oncol. 36:626–627. 2018. View Article : Google Scholar : PubMed/NCBI

3 

Seitz H and Poschl G: Alcohol and gastrointestinal cancer: Pathogenic mechanisms. Addict Biol. 2:19–33. 1997. View Article : Google Scholar : PubMed/NCBI

4 

Aghilinejad M, Kabir-Mokamelkhah E, Imanizade Z and Danesh H: Occupational class groups as a risk factor for gastrointestinal cancer: A case-control study. Int J Occup Environ Med. 8:21–31. 2017. View Article : Google Scholar : PubMed/NCBI

5 

He J, Li Y, Cao Y, Xue J and Zhou X: The oral microbiome diversity and its relation to human diseases. Folia Microbiol (Praha). 60:69–80. 2015. View Article : Google Scholar : PubMed/NCBI

6 

Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI and Knight R: Bacterial community variation in human body habitats across space and time. Science. 326:1694–1697. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Ahn J, Chen CY and Hayes RB: Oral microbiome and oral and gastrointestinal cancer risk. Cancer Causes Control. 23:399–404. 2012. View Article : Google Scholar : PubMed/NCBI

8 

Zhang Y, Niu Q, Fan W, Huang F and He H: Oral microbiota and gastrointestinal cancer. Onco Targets Ther. 12:4721–4728. 2019. View Article : Google Scholar : PubMed/NCBI

9 

Karpinski TM: Role of oral microbiota in cancer development. Microorganisms. 7:202019. View Article : Google Scholar : PubMed/NCBI

10 

Yang L, Zheng R, Wang N, Yuan Y, Liu S, Li H, Zhang S, Zeng H and Chen W: Incidence and mortality of stomach cancer in China, 2014. Chin J Cancer Res. 30:291–298. 2018. View Article : Google Scholar : PubMed/NCBI

11 

Bhaskar KR, Garik P, Turner BS, Bradley JD, Bansil R, Stanley HE and LaMont JT: Viscous fingering of HCl through gastric mucin. Nature. 360:458–461. 1992. View Article : Google Scholar : PubMed/NCBI

12 

Bik EM, Eckburg PB, Gill SR, Nelson KE, Purdom EA, Francois F, Perez-Perez G, Blaser MJ and Relman DA: Molecular analysis of the bacterial microbiota in the human stomach. Proc Natl Acad Sci USA. 103:732–737. 2006. View Article : Google Scholar : PubMed/NCBI

13 

Theisen J, Nehra D, Citron D, Johansson J, Hagen JA, Crookes PF, DeMeester SR, Bremner CG, DeMeester TR and Peters JH: Suppression of gastric acid secretion in patients with gastroesophageal reflux disease results in gastric bacterial overgrowth and deconjugation of bile acids. J Gastrointest Surg. 4:50–54. 2000. View Article : Google Scholar : PubMed/NCBI

14 

Hunt RH, Camilleri M, Crowe SE, El-Omar EM, Fox JG, Kuipers EJ, Malfertheiner P, McColl KE, Pritchard DM, Rugge M, et al: The stomach in health and disease. Gut. 64:1650–1668. 2015. View Article : Google Scholar : PubMed/NCBI

15 

Maffei HV and Nóbrega FJ: Gastric pH and microflora of normal and diarrhoeic infants. Gut. 16:719–726. 1975. View Article : Google Scholar : PubMed/NCBI

16 

Ijyuuin T and Umehara F: Case of Streptococcus salivarius bacteremia/meningoencephalitis leading to discovery of early gastric cancer. Rinsho Shinkeigaku. 52:360–363. 2012.(In Japanese). View Article : Google Scholar : PubMed/NCBI

17 

Yamamura K, Baba Y, Miyake K, Nakamura K, Shigaki H, Mima K, Kurashige J, Ishimoto T, Iwatsuki M, Sakamoto Y, et al: Fusobacterium nucleatum in gastroenterological cancer: Evaluation of measurement methods using quantitative polymerase chain reaction and a literature review. Oncol Lett. 14:6373–6378. 2017.PubMed/NCBI

18 

Shao DT and Wei WW: Progress in research of human microbiota for upper gastrointestinal tumors and precancerous lesions. Zhonghua Liu Xing Bing Xue Za Zhi. 39:382–386. 2018.(In Chinese). PubMed/NCBI

19 

Sun JH, Li XL, Yin J, Li YH, Hou BX and Zhang Z: A screening method for gastric cancer by oral microbiome detection. Oncol Rep. 39:2217–2224. 2018.PubMed/NCBI

20 

Wu J, Xu S, Xiang C, Cao Q, Li Q, Huang J, Shi L, Zhang J and Zhan Z: Tongue coating microbiota community and risk effect on gastric cancer. J Cancer. 9:4039–4048. 2018. View Article : Google Scholar : PubMed/NCBI

21 

Sun J, Zhou M, Salazar CR, Hays R, Bedi S, Chen Y and Li Y: Chronic periodontal disease, periodontal pathogen colonization, and increased risk of precancerous gastric lesions. J Periodontol. 88:1124–1134. 2017. View Article : Google Scholar : PubMed/NCBI

22 

Van Cutsem E, Sagaert X, Topal B, Haustermans K and Prenen H: Gastric cancer. Lancet. 388:2654–2664. 2016. View Article : Google Scholar : PubMed/NCBI

23 

Chen W, Zheng R, Zeng H, Zhang S and He J: Annual report on status of cancer in China, 2011. Chin J Cancer Res. 27:2–12. 2015. View Article : Google Scholar : PubMed/NCBI

24 

Klingelhofer D, Zhu Y, Braun M, Bruggmann D, Schoffel N and Groneberg DA: A world map of esophagus cancer research: A critical accounting. J Transl Med. 17:1502019. View Article : Google Scholar : PubMed/NCBI

25 

Wang LD, Shi ST, Zhou Q, Goldstein S, Hong JY, Shao P, Qiu SL and Yang CS: Changes in p53 and cyclin D1 protein levels and cell proliferation in different stages of human esophageal and gastric-cardia carcinogenesis. Int J Cancer. 59:514–519. 1994. View Article : Google Scholar : PubMed/NCBI

26 

Lin Y, Totsuka Y, Shan B, Wang C, Wei W, Qiao Y, Kikuchi S, Inoue M, Tanaka H and He Y: Esophageal cancer in high-risk areas of China: Research progress and challenges. Ann Epidemiol. 27:215–221. 2017. View Article : Google Scholar : PubMed/NCBI

27 

Zhou YC, Chen TT and Chen XD: Trend analysis in incidence rates of digestive system cancers in Taixing, 2006–2010. Chin J Prev Contr Chron Dis. 20:635–637. 2012.(In Chinese).

28 

Enzinger PC and Mayer RJ: Esophageal cancer. N Engl J Med. 349:2241–2252. 2003. View Article : Google Scholar : PubMed/NCBI

29 

Burki TK: Mutational subgroups for oesophageal adenocarcinoma. Lancet Oncol. 17:e4262016. View Article : Google Scholar : PubMed/NCBI

30 

Yang X, Ni Y, Yuan Z, Chen H, Plymoth A, Jin L, Chen X, Lu M and Ye W: Very hot tea drinking increases esophageal squamous cell carcinoma risk in a high-risk area of China: A population-based case-control study. Clin Epidemiol. 10:1307–1320. 2018. View Article : Google Scholar : PubMed/NCBI

31 

Yang X, Chen X, Zhuang M, Yuan Z, Nie S, Lu M, Jin L and Ye W: Smoking and alcohol drinking in relation to the risk of esophageal squamous cell carcinoma: A population-based case-control study in China. Sci Rep. 7:172492017. View Article : Google Scholar : PubMed/NCBI

32 

Suo C, Yang Y, Yuan Z, Zhang T, Yang X, Qing T, Gao P, Shi L, Fan M, Cheng H, et al: Alcohol intake interacts with functional genetic polymorphisms of aldehyde dehydrogenase (ALDH2) and alcohol dehydrogenase (ADH) to increase esophageal squamous cell cancer risk. J Thorac Oncol. 14:712–725. 2019. View Article : Google Scholar : PubMed/NCBI

33 

Yu Z, Li XM, Huai M, Lu GJ, Wang C, Wang QY and Liu QY: Clinic features and prognostic analysis for T1 esophagus cancer. Zhonghua Zhong Liu Za Zhi. 40:268–273. 2018.(In Chinese). PubMed/NCBI

34 

Li H, Jiang C, Wu D, Shi S, Liao M, Wang J, Li Y and Xu Z: The prognostic and clinicopathologic characteristics of CD147 and esophagus cancer: A meta-analysis. PLoS One. 12:e01802712017. View Article : Google Scholar : PubMed/NCBI

35 

Peters BA, Wu J, Pei Z, Yang L, Purdue MP, Freedman ND, Jacobs EJ, Gapstur SM, Hayes RB and Ahn J: Oral microbiome composition reflects prospective risk for esophageal cancers. Cancer Res. 77:6777–6787. 2017. View Article : Google Scholar : PubMed/NCBI

36 

Halec G, Schmitt M, Egger S, Abnet CC, Babb C, Dawsey SM, Flechtenmacher C, Gheit T, Hale M, Holzinger D, et al: Mucosal alpha-papillomaviruses are not associated with esophageal squamous cell carcinomas: Lack of mechanistic evidence from South Africa, China and Iran and from a world-wide meta-analysis. Int J Cancer. 139:85–98. 2016. View Article : Google Scholar : PubMed/NCBI

37 

Narikiyo M, Tanabe C, Yamada Y, Igaki H, Tachimori Y, Kato H, Muto M, Montesano R, Sakamoto H, Nakajima Y and Sasaki H: Frequent and preferential infection of Treponema denticola, Streptococcus mitis, and Streptococcus anginosus in esophageal cancers. Cancer Sci. 95:569–574. 2004. View Article : Google Scholar : PubMed/NCBI

38 

Chen X, Winckler B, Lu M, Cheng H, Yuan Z, Yang Y, Jin L and Ye W: Oral microbiota and risk for esophageal squamous cell carcinoma in a high-risk area of China. PLoS One. 10:e01436032015. View Article : Google Scholar : PubMed/NCBI

39 

Domingues-Ferreira M, Grumach AS, Duarte AJ and De Moraes-Vasconcelos D: Esophageal cancer associated with chronic mucocutaneous candidiasis. Could chronic candidiasis lead to esophageal cancer? Med Mycol. 47:201–205. 2009.PubMed/NCBI

40 

Bonavina L, Incarbone R, Reitano M, Tortorano A, Viviani M and Peracchia A: Candida colonization in patients with esophageal disease: A prospective clinical study. Dis Esophagus. 16:70–72. 2003. View Article : Google Scholar : PubMed/NCBI

41 

Tanda N, Washio J, Kamei T, Akazawa K, Takahashi N and Koseki T: Professional oral care reduces carcinogenic acetaldehyde levels in mouth air of perioperative esophageal cancer patients: A prospective comparative study. Tohoku J Exp Med. 249:75–83. 2019. View Article : Google Scholar : PubMed/NCBI

42 

Nishino T, Takizawa H, Yoshida T, Inui T, Takasugi H, Matsumoto D, Kawakita N, Inoue S, Sakiyama S, Tangoku A, et al: Current status and effectiveness of perioperative oral health care management for lung cancer and esophageal cancer patients. Kyobu Geka. 69:30–34. 2016.(In Japanese). PubMed/NCBI

43 

Tirelli G, Gatto A, Boscolo Nata F, Bussani R, Piccinato A, Marcuzzo AV and Tofanelli M: Prognosis of oral cancer: A comparison of the staging systems given in the 7 and 8th editions of the American joint committee on cancer staging manual. Br J Oral Maxillofac Surg. 56:8–13. 2018. View Article : Google Scholar : PubMed/NCBI

44 

Kujan O, Glenny AM, Duxbury J, Thakker N and Sloan P: Evaluation of screening strategies for improving oral cancer mortality: A Cochrane systematic review. J Dent Educ. 69:255–265. 2005. View Article : Google Scholar : PubMed/NCBI

45 

Kunkler I: Treatment of oral cancer. Radiotherapy may be as effective as surgery. BMJ. 319:7061999. View Article : Google Scholar : PubMed/NCBI

46 

Patil VM, Noronha V, Joshi A, Dhumal S, Mahimkar M, Bhattacharjee A, Gota V, Pandey M, Menon N, Mahajan A, et al: Phase I/II study of palliative triple metronomic chemotherapy in platinum-refractory/early-failure oral cancer. J Clin Oncol. 37:3032–3041. 2019. View Article : Google Scholar : PubMed/NCBI

47 

Yang JS, Wu CC, Lee HZ, Hsieh WT, Tang FY, Bau DT, Lai KC, Lien JC and Chung JG: Suppression of the TNF-alpha level is mediated by Gan-Lu-Yin (traditional Chinese medicine) in human oral cancer cells through the NF-kappa B, AKT, and ERK-dependent pathways. Environ Toxicol. 31:1196–1205. 2016. View Article : Google Scholar : PubMed/NCBI

48 

Lee HC, Liang A, Lin YH, Guo YR and Huang SY: Low dietary n-6/n-3 polyunsaturated fatty acid ratio prevents induced oral carcinoma in a hamster pouch model. Prostaglandins Leukot Essent Fatty Acids. 136:67–75. 2018. View Article : Google Scholar : PubMed/NCBI

49 

Takahashi Y, Park J, Hosomi K, Yamada T, Kobayashi A, Yamaguchi Y, Iketani S, Kunisawa J, Mizuguchi K, Maeda N and Ohshima T: Analysis of oral microbiota in Japanese oral cancer patients using 16S rRNA sequencing. J Oral Biosci. 61:120–128. 2019. View Article : Google Scholar : PubMed/NCBI

50 

Schmidt BL, Kuczynski J, Bhattacharya A, Huey B, Corby PM, Queiroz EL, Nightingale K, Kerr AR, DeLacure MD, Veeramachaneni R, et al: Changes in abundance of oral microbiota associated with oral cancer. PLoS One. 9:e987412014. View Article : Google Scholar : PubMed/NCBI

51 

Zhao H, Chu M, Huang Z, Yang X, Ran S, Hu B, Zhang C and Liang J: Variations in oral microbiota associated with oral cancer. Sci Rep. 7:117732017. View Article : Google Scholar : PubMed/NCBI

52 

Guerrero-Preston R, Godoy-Vitorino F, Jedlicka A, Rodríguez-Hilario A, González H, Bondy J, Lawson F, Folawiyo O, Michailidi C, Dziedzic A, et al: 16S rRNA amplicon sequencing identifies microbiota associated with oral cancer, human papilloma virus infection and surgical treatment. Oncotarget. 7:51320–51334. 2016. View Article : Google Scholar : PubMed/NCBI

53 

Lee WH, Chen HM, Yang SF, Liang C, Peng CY, Lin FM, Tsai LL, Wu BC, Hsin CH, Chuang CY, et al: Bacterial alterations in salivary microbiota and their association in oral cancer. Sci Rep. 7:165402017. View Article : Google Scholar : PubMed/NCBI

54 

Perera M, Al-Hebshi NN, Perera I, Ipe D, Ulett GC, Speicher DJ, Chen T and Johnson NW: Inflammatory bacteriome and oral squamous cell carcinoma. J Dent Res. 97:725–732. 2018. View Article : Google Scholar : PubMed/NCBI

55 

Yost S, Stashenko P, Choi Y, Kukuruzinska M, Genco CA, Salama A, Weinberg EO, Kramer CD and Frias-Lopez J: Increased virulence of the oral microbiome in oral squamous cell carcinoma revealed by metatranscriptome analyses. Int J Oral Sci. 10:322018. View Article : Google Scholar : PubMed/NCBI

56 

Hsiao JR, Chang CC, Lee WT, Huang CC, Ou CY, Tsai ST, Chen KC, Huang JS, Wong TY, Lai YH, et al: The interplay between oral microbiome, lifestyle factors and genetic polymorphisms in the risk of oral squamous cell carcinoma. Carcinogenesis. 39:778–787. 2018. View Article : Google Scholar : PubMed/NCBI

57 

Wu JS, Zheng M, Zhang M, Pang X, Li L, Wang SS, Yang X, Wu JB, Tang YJ, Tang YL and Liang XH: Porphyromonas gingivalis promotes 4-nitroquinoline-1-oxide-induced oral carcinogenesis with an alteration of fatty acid metabolism. Front Microbiol. 9:20812018. View Article : Google Scholar : PubMed/NCBI

58 

Gonzalez-Ramirez I, Irigoyen-Camacho ME, Ramirez-Amador V, Lizano-Soberón M, Carrillo-García A, García-Carrancá A, Sánchez-Pérez Y, Méndez-Martínez R, Granados-García M, Ruíz-Godoy L and García-Cuellar C: Association between age and high-risk human papilloma virus in Mexican oral cancer patients. Oral Dis. 19:796–804. 2013. View Article : Google Scholar : PubMed/NCBI

59 

Nagy KN, Sonkodi I, Szöke I, Nagy E and Newman HN: The microflora associated with human oral carcinomas. Oral Oncol. 34:304–308. 1998. View Article : Google Scholar : PubMed/NCBI

60 

Byakodi R, Krishnappa R, Keluskar V, Bagewadi A and Shetti A: The microbial flora associated with oral carcinomas. Quintessence Int. 42:e118–e123. 2011.PubMed/NCBI

61 

Karpiński TM: The microbiota and pancreatic cancer. Gastroenterol Clin North Am. 48:447–464. 2019. View Article : Google Scholar

62 

Hettmann A, Demcsak A, Decsi G, Bach Á, Pálinkó D, Rovó L, Nagy K, Takács M and Minarovits J: Infectious agents associated with head and neck carcinomas. Adv Exp Med Biol. 897:63–80. 2016. View Article : Google Scholar : PubMed/NCBI

63 

Muto M, Hitomi Y, Ohtsu A, Shimada H, Kashiwase Y, Sasaki H, Yoshida S and Esumi H: Acetaldehyde production by non-pathogenic Neisseria in human oral microflora: Implications for carcinogenesis in upper aerodigestive tract. Int J Cancer. 88:342–350. 2000. View Article : Google Scholar : PubMed/NCBI

64 

Yokoi A, Ekuni D, Hata H, Yamane-Takeuchi M, Maruyama T, Yamanaka R and Morita M: Relationship between acetaldehyde concentration in mouth air and characteristics of microbiota of tongue dorsum in Japanese healthy adults: A cross-sectional study. J Appl Oral Sci. 27:e201806352019. View Article : Google Scholar : PubMed/NCBI

65 

Hooper SJ, Crean SJ, Fardy MJ, Lewis MAO, Spratt DA, Wade WG and Wilson MJ: A molecular analysis of the bacteria present within oral squamous cell carcinoma. J Med Microbiol. 56:1651–1659. 2007. View Article : Google Scholar : PubMed/NCBI

66 

Vakevainen S, Tillonen J, Blom M, Jousimies-Somer H and Salaspuro M: Acetaldehyde production and other ADH-related characteristics of aerobic bacteria isolated from hypochlorhydric human stomach. Alcohol Clin Exp Res. 25:421–426. 2001. View Article : Google Scholar : PubMed/NCBI

67 

Meurman JH and Uittamo J: Oral micro-organisms in the etiology of cancer. Acta Odontol Scand. 66:321–326. 2008. View Article : Google Scholar : PubMed/NCBI

68 

Abranches J, Zeng L, Kajfasz JK, Palmer SR, Chakraborty B, Wen ZT, Richards VP, Brady LJ and Lemos JA: Biology of oral Streptococci. Microbiol Spectr. 6:10.1128/microbiolspec.GPP3. 0042-2018. 2018. View Article : Google Scholar : PubMed/NCBI

69 

di Meo S, Reed TT, Venditti P and Victor VM: Role of ROS and RNS sources in physiological and pathological conditions. Oxid Med Cell Longev. 2016:12450492016. View Article : Google Scholar : PubMed/NCBI

70 

Ikeda T, Kurita-Ochiai T, Takizawa T and Hirasawa M: Isolation and characterization of the substance isolated from Streptosporangium species which inhibits lactic acid production by oral bacteria. Gen Pharmacol. 24:905–910. 1993. View Article : Google Scholar : PubMed/NCBI

71 

van Maanen JM, van Geel AA and Kleinjans JC: Modulation of nitrate-nitrite conversion in the oral cavity. Cancer Detect Prev. 20:590–596. 1996.PubMed/NCBI

72 

Suzuki H, Iijima K, Scobie G, Fyfe V and McColl KE: Nitrate and nitrosative chemistry within Barrett's oesophagus during acid reflux. Gut. 54:1527–1535. 2005. View Article : Google Scholar : PubMed/NCBI

73 

Schett G, Elewaut D, McInnes IB, Dayer JM and Neurath MF: How cytokine networks fuel inflammation: Toward a cytokine-based disease taxonomy. Nat Med. 19:822–824. 2013. View Article : Google Scholar : PubMed/NCBI

74 

Jones SA, Scheller J and Rose-John S: Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest. 121:3375–3383. 2011. View Article : Google Scholar : PubMed/NCBI

75 

Neogi T: Clinical practice. Gout. N Engl J Med. 364:443–452. 2011. View Article : Google Scholar : PubMed/NCBI

76 

Murata M: Inflammation and cancer. Environ Health Prev Med. 23:502018. View Article : Google Scholar : PubMed/NCBI

77 

Agassandian M and Shurin GV: Bacterial infections and cancer development. Infection and cancer: Bi-directorial interactions. 49–74. 2015.

78 

Hoesel B and Schmid JA: The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer. 12:862013. View Article : Google Scholar : PubMed/NCBI

79 

Bradley JR: TNF-mediated inflammatory disease. J Pathol. 214:149–160. 2008. View Article : Google Scholar : PubMed/NCBI

80 

Francescone R, Hou V and Grivennikov SI: Microbiome, inflammation, and cancer. Cancer J. 20:181–189. 2014. View Article : Google Scholar : PubMed/NCBI

81 

Yan B, Wang H, Rabbani ZN, Zhao Y, Li W, Yuan Y, Li F, Dewhirst MW and Li CY: Tumor necrosis factor-alpha is a potent endogenous mutagen that promotes cellular transformation. Cancer Res. 66:11565–11570. 2006. View Article : Google Scholar : PubMed/NCBI

82 

Sisk EA, Bradford CR, Jacob A, Yian CH, Staton KM, Tang G, Harris MO, Carey TE, Lancaster WD and Gregoire L: Human papillomavirus infection in ‘young’ versus ‘old’ patients with squamous cell carcinoma of the head and neck. Head Neck. 22:649–657. 2000. View Article : Google Scholar : PubMed/NCBI

83 

Snider EJ, Freedberg DE and Abrams JA: Potential role of the microbiome in Barrett's esophagus and esophageal adenocarcinoma. Dig Dis Sci. 61:2217–2225. 2016. View Article : Google Scholar : PubMed/NCBI

84 

Moss SF and Blaser MJ: Mechanisms of disease: Inflammation and the origins of cancer. Nat Clin Pract Oncol. 2:90–97, 1, 113. 2005. View Article : Google Scholar : PubMed/NCBI

85 

Vogelmann R and Amieva MR: The role of bacterial pathogens in cancer. Curr Opin Microbiol. 10:76–81. 2007. View Article : Google Scholar : PubMed/NCBI

86 

Cho TJ, Wee SW, Woo VH, Choi JI, Kim SJ, Shin HI, Lee JH and Park HR: Porphyromonas gingivalis-induced autophagy suppresses cell proliferation through G1 arrest in oral cancer cells. Arch Oral Biol. 59:370–378. 2014. View Article : Google Scholar : PubMed/NCBI

87 

Li WQ, Ma JL, Zhang L, Brown LM, Li JY, Shen L, Pan KF, Liu WD, Hu Y, Han ZX, et al: Effects of Helicobacter pylori treatment on gastric cancer incidence and mortality in subgroups. J Natl Cancer Inst. 106:dju1162014. View Article : Google Scholar : PubMed/NCBI

88 

Geng W and Zhang HY: Research on the mechanism of HP mediated PI3K/AKT/GSK3β pathways in gastric cancer. Eur Rev Med Pharmacol Sci. 21 (Suppl 3):S33–S37. 2017.

89 

Xie Y and Liu L: Analysis of correlation between HP infection and activation of PI3K/Akt pathway in mucosal tissues of gastric cancer and precancerous lesions. Oncol Lett. 16:5615–5620. 2018.PubMed/NCBI

90 

Zhang Y, Wang X, Li H, Ni C, Du Z and Yan F: Human oral microbiota and its modulation for oral health. Biomed Pharmacother. 99:883–893. 2018. View Article : Google Scholar : PubMed/NCBI

91 

Font-Burgada J, Sun B and Karin M: Obesity and cancer: The oil that feeds the flame. Cell Metab. 23:48–62. 2016. View Article : Google Scholar : PubMed/NCBI

92 

Bao X, Chen F, Lin J, Chen Q, Chen L, Wang R, Liu F, Wang J, Yan L, Lin L, et al: Association between dietary inflammatory index and the risk of oral cancer in the southeast of China. Eur J Clin Nutr. 74:938–944. 2020. View Article : Google Scholar : PubMed/NCBI

93 

Adler CJ, Malik R, Browne GV and Norris JM: Diet may influence the oral microbiome composition in cats. Microbiome. 4:232016. View Article : Google Scholar : PubMed/NCBI

94 

Paul B, Barnes S, Demark-Wahnefried W, Morrow C, Salvador C, Skibola C and Tollefsbol TO: Influences of diet and the gut microbiome on epigenetic modulation in cancer and other diseases. Clin Epigenetics. 7:1122015. View Article : Google Scholar : PubMed/NCBI

95 

De Almeida CV, de Camargo MR, Russo E and Amedei A: Role of diet and gut microbiota on colorectal cancer immunomodulation. World J Gastroenterol. 25:151–162. 2019. View Article : Google Scholar : PubMed/NCBI

96 

Seidel DV, Azcarate-Peril MA, Chapkin RS and Turner ND: Shaping functional gut microbiota using dietary bioactives to reduce colon cancer risk. Semin Cancer Biol. 46:191–204. 2017. View Article : Google Scholar : PubMed/NCBI

97 

Bravi F, Bosetti C, Filomeno M, Levi F, Garavello W, Galimberti S, Negri E and La Vecchia C: Foods, nutrients and the risk of oral and pharyngeal cancer. Br J Cancer. 109:2904–2910. 2013. View Article : Google Scholar : PubMed/NCBI

98 

Klaenhammer TR, Kleerebezem M, Kopp MV and Rescigno M: The impact of probiotics and prebiotics on the immune system. Nat Rev Immunol. 12:728–734. 2012. View Article : Google Scholar : PubMed/NCBI

99 

Guarner F, Perdigon G, Corthier G, Salminen S, Koletzko B and Morelli L: Should yoghurt cultures be considered probiotic? Br J Nutr. 93:783–786. 2005. View Article : Google Scholar : PubMed/NCBI

100 

He L, Yang H, Tang J, Liu Z, Chen Y, Lu B, He H, Tang S, Sun Y, Liu F, et al: Intestinal probiotics E. coli Nissle 1917 as a targeted vehicle for delivery of p53 and Tum-5 to solid tumors for cancer therapy. J Biol Eng. 13:582019. View Article : Google Scholar : PubMed/NCBI

101 

Jan G, Belzacq AS, Haouzi D, Rouault A, Métivier D, Kroemer G and Brenner C: Propionibacteria induce apoptosis of colorectal carcinoma cells via short-chain fatty acids acting on mitochondria. Cell Death Diff. 9:179–188. 2002. View Article : Google Scholar : PubMed/NCBI

102 

Baldwin C, Millette M, Oth D, Ruiz MT, Luquet FM and Lacroix M: Probiotic Lactobacillus acidophilus and L. casei mix sensitize colorectal tumoral cells to 5-fluorouracil-induced apoptosis. Nutr Cancer. 62:371–378. 2010. View Article : Google Scholar : PubMed/NCBI

103 

Fotiadis CI, Stoidis CN, Spyropoulos BG and Zografos ED: Role of probiotics, prebiotics and synbiotics in chemoprevention for colorectal cancer. World J Gastroenterol. 14:6453–6457. 2008. View Article : Google Scholar : PubMed/NCBI

104 

Mima K, Nakagawa S, Sawayama H, Ishimoto T, Imai K, Iwatsuki M, Hashimoto D, Baba Y, Yamashita YI, Yoshida N, et al: The microbiome and hepatobiliary-pancreatic cancers. Cancer Lett. 402:9–15. 2017. View Article : Google Scholar : PubMed/NCBI

105 

Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, et al: Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 359:97–103. 2018. View Article : Google Scholar : PubMed/NCBI

106 

Zhou H, Suo J and Zhu J: Therapeutic relevance of human microbiota and lung cancer. Zhongguo Fei Ai Za Zhi. 22:464–469. 2019.(In Chinese). PubMed/NCBI

107 

Catry E, Bindels LB, Tailleux A, Lestavel S, Neyrinck AM, Goossens JF, Lobysheva I, Plovier H, Essaghir A, Demoulin JB, et al: Targeting the gut microbiota with inulin-type fructans: Preclinical demonstration of a novel approach in the management of endothelial dysfunction. Gut. 67:271–283. 2018. View Article : Google Scholar : PubMed/NCBI

108 

Ambalam P, Raman M, Purama RK and Doble M: Probiotics, prebiotics and colorectal cancer prevention. Best Pract Res Clin Gastroenterol. 30:119–131. 2016. View Article : Google Scholar : PubMed/NCBI

109 

Raman M, Ambalam P, Kondepudi KK, Pithva S, Kothari C, Patel AT, Purama RK, Dave JM and Vyas BR: Potential of probiotics, prebiotics and synbiotics for management of colorectal cancer. Gut Microbes. 4:181–192. 2013. View Article : Google Scholar : PubMed/NCBI

110 

Zheng C, Chen T, Wang Y, Gao Y, Kong Y, Liu Z and Deng X: A randomised trial of probiotics to reduce severity of physiological and microbial disorders induced by partial gastrectomy for patients with gastric cancer. J Cancer. 10:568–576. 2019. View Article : Google Scholar : PubMed/NCBI

111 

Guglielmetti S, Taverniti V, Minuzzo M, Arioli S, Stuknyte M, Karp M and Mora D: Oral bacteria as potential probiotics for the pharyngeal mucosa. Appl Environ Microbiol. 76:3948–3958. 2010. View Article : Google Scholar : PubMed/NCBI

112 

Cortes-Dorantes N, Ruiz-Rodriguez MS, Karakowsky-Kleiman L, Garrocho-Rangel JA, Sanchez-Vargas LO and Pozos-Guillen AJ: Probiotics and their effect on oral bacteria count in children: A pilot study. Eur J Paediatr Dent. 16:56–60. 2015.PubMed/NCBI

113 

Nase L, Hatakka K, Savilahti E, Saxelin M, Pönkä A, Poussa T, Korpela R and Meurman JH: Effect of long-term consumption of a probiotic bacterium, Lactobacillus rhamnosus GG, in milk on dental caries and caries risk in children. Caries Res. 35:412–420. 2001. View Article : Google Scholar : PubMed/NCBI

114 

Krasse P, Carlsson B, Dahl C, Paulsson A, Nilsson A and Sinkiewicz G: Decreased gum bleeding and reduced gingivitis by the probiotic Lactobacillus reuteri. Swed Dent J. 30:55–60. 2006.PubMed/NCBI

115 

Xie H, Lu Q, Wang H, Zhu X and Guan Z: Effects of probiotics combined with enteral nutrition on immune function and inflammatory response in postoperative patients with gastric cancer. J BUON. 23:678–683. 2018.PubMed/NCBI

116 

Verhoog S, Taneri PE, Roa Díaz ZM, Marques-Vidal P, Troup JP, Bally L, Franco OH, Glisic M and Muka T: Dietary factors and modulation of bacteria strains of Akkermansia muciniphila and Faecalibacterium prausnitzii: A systematic review. Nutrients. 11:15652019. View Article : Google Scholar : PubMed/NCBI

117 

Chen XH, Wang A, Chu AN, Gong YH and Yuan Y: Mucosa-associated microbiota in gastric cancer tissues compared with non-cancer tissues. Front Microbiol. 10:12612019. View Article : Google Scholar : PubMed/NCBI

118 

Clarridge JE III: Impact of 16S rRNA gene sequence analysis for identification of bacteria on clinical microbiology and infectious diseases. Clin Microbiol Rev. 17:840–862. 2004. View Article : Google Scholar : PubMed/NCBI

119 

Sanschagrin S and Yergeau E: Next-generation sequencing of 16S ribosomal RNA gene amplicons. J Vis Exp. 90:e517092014.PubMed/NCBI

120 

Deo PN and Deshmukh R: Oral microbiome: Unveiling the fundamentals. J Oral Maxillofac Pathol. 23:122–128. 2019.PubMed/NCBI

121 

Pleguezuelos-Manzano C, Puschhof J, Rosendahl Huber A, van Hoeck A, Wood HM, Nomburg J, Gurjao C, Manders F, Dalmasso G, Stege PB, et al: Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli. Nature. 580:269–273. 2020. View Article : Google Scholar : PubMed/NCBI

122 

Lavelle A and Sokol H: Gut microbiota: Beyond metagenomics, metatranscriptomics illuminates microbiome functionality in IBD. Nat Rev Gastroenterol Hepatol. 15:193–194. 2018. View Article : Google Scholar : PubMed/NCBI

123 

Kleiner M, Thorson E, Sharp CE, Dong X, Liu D, Li C and Strous M: Assessing species biomass contributions in microbial communities via metaproteomics. Nat Commun. 8:15582017. View Article : Google Scholar : PubMed/NCBI

124 

Miarons M, Roca M and Salvà F: The role of pro-, pre- and symbiotics in cancer: A systematic review. J Clin Pharm Ther. 46:50–65. 2021. View Article : Google Scholar : PubMed/NCBI

125 

Hu J, Han S, Chen Y and Ji Z: Variations of tongue coating microbiota in patients with gastric cancer. Biomed Res Int. 2015:1737292015. View Article : Google Scholar : PubMed/NCBI

126 

Dong Z, Chen B, Pan H, Wang D, Liu M, Yang Y, Zou M, Yang J, Xiao K, Zhao R, et al: Detection of microbial 16S rRNA gene in the serum of patients with gastric cancer. Front Oncol. 9:6082019. View Article : Google Scholar : PubMed/NCBI

127 

Liu AQ and Chen W: Advances in esophageal microbiota and esophageal related diseases. Zhonghua Zhong Liu Za Zhi. 41:561–564. 2019.(In Chinese). PubMed/NCBI

Related Articles

Journal Cover

August-2021
Volume 46 Issue 2

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Li X, Zhu S, Zhang T and Chen X: Association between oral microflora and gastrointestinal tumors (Review). Oncol Rep 46: 160, 2021
APA
Li, X., Zhu, S., Zhang, T., & Chen, X. (2021). Association between oral microflora and gastrointestinal tumors (Review). Oncology Reports, 46, 160. https://doi.org/10.3892/or.2021.8111
MLA
Li, X., Zhu, S., Zhang, T., Chen, X."Association between oral microflora and gastrointestinal tumors (Review)". Oncology Reports 46.2 (2021): 160.
Chicago
Li, X., Zhu, S., Zhang, T., Chen, X."Association between oral microflora and gastrointestinal tumors (Review)". Oncology Reports 46, no. 2 (2021): 160. https://doi.org/10.3892/or.2021.8111