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Review Articles

Oral microbiota and cancer

Jukka H. MeurmanInstitute of Dentistry, University of Helsinki, Helsinki, Finland;Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, FinlandCorrespondencejukka.meurman@helsinki.fi
Article: 5195 | Received 04 Apr 2010, Accepted 29 Jun 2010, Published online: 10 Aug 2010

Abstract

Inflammation caused by infections may be the most important preventable cause of cancer in general. However, in the oral cavity the role of microbiota in carcinogenesis is not known. Microbial populations on mouth mucosa differ between healthy and malignant sites and certain oral bacterial species have been linked with malignancies but the evidence is still weak in this respect. Nevertheless, oral microorganisms inevitably up-regulate cytokines and other inflammatory mediators that affect the complex metabolic pathways and may thus be involved in carcinogenesis. Poor oral health associates statistically with prevalence of many types of cancer, such as pancreatic and gastrointestinal cancer. Furthermore, several oral micro-organisms are capable of converting alcohol to carcinogenic acetaldehyde which also may partly explain the known association between heavy drinking, smoking, poor oral health and the prevalence of oral and upper gastrointestinal cancer. A different problem is the cancer treatment-caused alterations in oral microbiota which may lead to the emergence of potential pathogens and subsequent other systemic health problems to the patients. Hence clinical guidelines and recommendations have been presented to control oral microbiota in patients with malignant disease, but also in this area the scientific evidence is weak. More controlled studies are needed for further conclusion.

Introduction

Human microbiota may play a role in carcinogenesis. Helicobacter pylori is the best known bacterium causally linked with cancer Citation1. However, the general concept of human microbiota is changing when molecular techniques have revealed its vast diversity, but, at the same time, individual stability of micro-organisms residing on skin and gastrointestinal tract mucosa Citation2. Micro-organisms seem to play an important role in metabolism but it is not known how the diversity relates to function and to the rest of the genes in the collective genomes of the microbiota. Extensive studies have shown in the gut that its totality of microbes, the microbiome, is shared among family members, but that each person's microbial community varies in the specific bacterial lineages present, with a comparable degree of co-variation. A wide array of shared microbial genes have been observed among sampled individuals, comprising an extensive, identifiable ‘core microbiome’ at the gene level rather than at the organismal lineage Citation3. Corresponding studies on oral microbiota are on their way Citation4.

Traditionally it has been thought that mouth mucosa Citation5, the tongue Citation6, and the pharynx Citation7 harbor characteristic bacterial pathogens causing chronic inflammation and focal infections Citation8. Many of these infections derive from oral biofilms commonly linked with the highly prevalent dental diseases Citation9 Citation10 Citation11 . For a long time, particularly periodontal disease has been emphasized in this respect Citation12. Oral microbiota may also associate with the development of cancer. It is a well-known clinical fact that the patients with oral cancer often present with poor oral hygiene. Studies have shown that the association between oral microorganisms and cancer may even be causal Citation13.

Inflammation is a key feature in many chronic diseases including cancer Citation14 Citation15. Investigations of gastrointestinal malignancies have shown that the large amount of cytokines and growth factors released during inflammation by immune and non-immune cells may influence carcinogenesis Citation16. In general, infection-driven inflammations have been estimated to be involved in the pathogenesis of approximately 15–20% of human tumors Citation17. Hence inflammation caused by infections might be one of the most important preventable causes of cancer Citation18.

The worldwide incidence of cancer also attributes to infections caused by virus such as hepatitis viruses, human papilloma virus (HPV), and Epstein-Barr virus (EBV) Citation19 Citation20. Characteristic to infections and inflammations linked with malignancies is indeed that they are persistent in the host for a long time and highly prevalent in populations Citation21. However, there may be a long latency between the initial infection and tumor appearance, and not at all does every infected person develop cancer. In general this area is difficult for research. The overall effect of the microbiome in these contexts is not known.

This review briefly outlines current knowledge about the role of oral microbiota in carcinogenesis with emphasis on oral cancer and microbial changes caused by cancer treatment. The focus is on bacterial and yeast infections and the reader interested in viral infections is advised to other texts. To put the viral infections in perspective, however, it has been estimated that at least six human viruses, EBV, hepatitis B virus (HBV), hepatitis C virus (HCV), HPV, human T-cell lymphotropic virus (HTLV-1) and Kaposi's associated sarcoma virus (KSHV) contribute to 10–15% of the cancers worldwide Citation22. No such figures exist for bacteria- or yeast-related malignancies. The role of viruses has recently been reviewed in this journal Citation23.

The current text is based on the PubMed literature searching 20 years back and up to the end of May 2010. The keywords used were ‘cancer” vs. ‘oral microbiota’ (20 hits), ‘dental hygiene’ (981 hits), ‘oral micro-organisms’ (136 hits); and ‘carcinogenesis’ vs. ‘oral infection’ (153 hits), and ‘oral infection control’ (37 hits). Based on relevance of the abstracts of the publications full texts were then searched and assessed for final inclusion. Because of scarcity of hard data and the descriptive nature of the majority of studies no systematic review could be conducted.

Oral health effects on cancer

The association between poor oral health and tooth loss with increased risk of gastric cancer has been reported in retrospective studies in many countries Citation24 Citation25 Citation26 . Furthermore, in a prospective study from China, Abnet and co-workers Citation27 reported that tooth loss increased the risk of developing gastrointestinal cancer. Positive associations between tooth loss and pancreatic cancer have also been reported Citation28 Citation29. A prospective cohort study in the US male health professionals showed that when compared with no periodontal disease, the history of periodontitis significantly associated with increased pancreatic cancer risk [risk ratio (RR) 1.64; 95% confidence interval (CI) 1.19–2.26] while the cumulative tooth loss during the 16-year follow-up was not associated with pancreatic cancer Citation30. There are also anecdotal data to show that oral streptococci may associate with colonic cancer Citation31. These data, however, rather present systemic complications of the patients than give any evidence for causal effect Citation32.

In the male health professionals study from the USA, periodontal disease has also been shown to increase the statistical risk for head and neck cancer with an odds ratio (OR) 4.36 (CI 6.01–93.16). The association persisted in subjects who never used alcohol or tobacco Citation33. Furthermore, a study from Buffalo, New York, on 51 cases with tongue cancer, showed that chronic periodontitis presented a 5.23-fold increase in the cancer risk when compared with 54 controls (OR 5.23; CI 2.64–10.35) Citation34. The same group reported that periodontitis patients were also more likely to have poorly differentiated oral squamous cell carcinomas than periodontally healthy patients Citation35. Interestingly, practicing no regular oral hygiene also conferred OR 2.37 (CI 1.42–3.97) for esophageal cancer when compared with those who undertook daily tooth brushing Citation36. Recently, in a study on 30,475 individuals also from the USA, the use of dental care was analyzed with respect to oral cancer. After controlling relevant covariates the results showed that when compared with no use of dental care those who had had dental appointments during the past 12 months were 62% less likely to have oral cancer (OR 0.38, CI 0.13–1.10) Citation37.

Mucocutaneous candidiasis is also known to associate with the development of cancer in particular patients with a rare genetic disease called autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy Citation38. These patients call for frequent follow-up due to markedly increased oral cancer risk with subsequent malignancies presenting in young age of the patients. Recently, however, cases have been presented where chronic mucocutaneous Candida infection associated with esophageal cancer in patients with immunoglobulin-A deficiency Citation39. Thus, it can be speculated that impaired local immunity which renders the patient liable for oral candidiasis increases the risk for cancer. More studies are needed for further evidence, however.

Our unpublished results from a cohort study in Sweden with 16 years of follow-up showed that age, female gender, and periodontitis with loss of the first mandibular molars were the principal independent predictors of cancers in general, and breast cancer in particular, as registered in the Swedish Cancer Registry. From the same database, premature death of young individuals was observed to link statistically with periodontitis and missing molars whether the cause of death was because of cancer, cardiovascular, or gastrointestinal disease Citation40.

A confounding factor difficult to control in epidemiological studies, however, is the fact that oral health-related variables also link with the use of tobacco and alcohol Citation41. Furthermore, there are no studies conducted to show if aggressive forms of oral infections affect the incidence or prevalence of cancer compared with milder forms of infections Citation42. Hence there is a need for further studies in which also the severity of oral infection is taken into account together with encompassing all possible foci of infections and not only periodontitis. However, it is of interest to emphasize that in many studies the associations between periodontal disease and cancer, in particular, persisted after adjustment for major risk factors, including cigarette smoking and socioeconomic status Citation43. Thus, taken together the results from studies in this area seem to support the general hypothesis of chronic oral infection-based carcinogenesis Citation44.

Mechanisms involved in oral infection-linked carcinogenesis

In general, the association between periodontal disease and various systemic diseases has been intensively studied during the past two decades, but the exact mechanisms involved are still not known. Most studies have focused on the development of atherosclerosis; periodontal micro-organisms have been detected in atheroma plaques Citation45. The large potential wound area of inflamed periodontium in dentate subjects, the rich oral microbiota and the frequent transient bacteremia episodes in normal life, maintain a low-grade chronic inflammation which triggers a variety of systemic reactions. These in turn may lead to carcinogenic mechanisms which, however, are not clear. Irrespective of the focus of infection bacteria may induce cellular proliferation, inhibit apoptosis, interfere with cellular signaling mechanisms, and act as tumor promoters Citation46.

Up-regulation of cytokines and other inflammatory mediators affect complex metabolic pathways and there also seems to be a link between chronic infections and sugar metabolism. For example, the receptor for advanced glycation end products (RAGE), a multi-ligand receptor expressed on various cell membranes, has been suggested to play a role also in carcinogenesis. RAGE is activated by ligands in a variety of cell types and tissues, and may play a role in the oral infection-systemic health associations Citation47. This receptor is associated with pro-inflammatory responses and may underlie in diverse pathologies including periodontal disease Citation48. Oral infection may also directly reflect in endothelial dysfunction with systemic consequences Citation49. The cytokine reactions involved have been shown to play a role in the immune-related mechanisms of cancer development Citation50.

Another mechanism suggested to be involved in oral carcinogenesis is mediated via salivary factors. Poor oral health has been shown to associate with the genotoxic salivary activity. Bloching et al. Citation51 studied dental status and saliva of 100 subjects relating their oral health to in vitro salivary mutagenicity, using the Salmonella test. The authors reported a significant association (p<0.05) between high-plaque index and high number of carious teeth with the genotoxic activity in saliva. Studies on this field indicate, however, that salivary mutagenicity is the result of external chemicals and carcinogens introduced into the system. Thus, for example, the use of tobacco and areca nuts associates with the development of oral cancer Citation52. The polymicrobial burden caused by oral biofilms may also possess mutagenic interactions with saliva which may act as co-factors in carcinogenesis. These examples illustrate the complexity of tumor genesis.

Recently, a possible causal link between micro-organisms and oral cancer has been suggested. Several bacteria and Candida strains in the mouth convert ethanol to carcinogenic acetaldehyde thus explaining the epidemiological evidence between heavy drinking, smoking, and development of cancer Citation53 Citation54. Both the commonly encountered oral streptococci and yeasts possess metabolic pathways for this conversion Citation55 Citation56 Citation57 . Alcohol-related carcinogenesis is well-known and the enzymes involved have been characterized. Polymorphism in these genes may partly explain why subjects differ in their liability for the development of cancer; it may be a question of higher or lower metabolic activities involved in alcohol metabolism Citation58. Nevertheless, there is a significant dose–response relationship between alcohol intake frequency, duration of use, and oral cancer risk Citation59. Similarly, smoking associates with cancer and smoking also causes an increase in salivary acetaldehyde concentrations thus adding to the risk related to alcohol Citation60. The effect of smoking and alcohol is thus synergistic Citation61.

Differences in oral microbiota in patients with and without cancer

Microbial populations on mouth mucosa seem to differ between healthy and malignant sites. For example, Streptococcus anginosus and Treponema denticola associate with various upper gastrointestinal tract carcinomas Citation62. Shiga et al. Citation63 suggested that S. anginosus infection might be implicated in the carcinogenesis of head and neck squamous cell carcinoma in general. S. anginosus DNA has been detected in carcinoma tissue samples but not in lymphoma, rhabdomyosarcoma, or leukoplakia samples. Dental plaque could be a dominant reservoir of this bacterium Citation64. As a curiosity, syphilis has also been mentioned in textbooks to be associated with cancer, but there are no data found to support this statement.

Mager et al. Citation65 investigated the relationship of 40 common salivary bacteria counts between 45 patients with oral cancer compared with counts from 229 healthy controls. They observed that Capnocytophaga gingivalis, Prevotella melaninogenica, and Streptococcus mitis counts were significantly increased among the oral cancer patients. The authors further analyzed if these species could be used as diagnostic markers for oral cancer and found 80% sensitivity and 82% specificity, respectively. In oral cancer patients mutated salivary DNA at the 53p gene was observed in 62.5% of 10 patients when compared with 18.5% among 27 healthy controls in a study from Taiwan Citation66. In another study salivary mitochondrial DNA was found to be increased in patients with head and neck cancer directly in proportion to the degree of malignancy of the tissue, i.e. from mild to severe dysplasia Citation67. Again, however, further studies are needed to confirm these findings.

Several researchers have observed viral or pro-viral DNA in saliva or gingival crevicular fluid samples of patients with malignancies Citation68 Citation69. These and other biomarkers of oral cancer have been recently reviewed by Seoane Lestón and Diz Dios Citation70 and Wu et al. Citation71. In the future laboratory methods such as microarray analyses and gene expression profiling might be applicable for investigating changes in oral microbiota on malignant sites. For example, pyrosequencing of the oral cavity and salivary samples has greatly improved our understanding in the wider perspective of the complex microbiota of the mouth Citation72.

In general, novel approaches to map oral cancer lesions are based on molecular techniques Citation73 Citation74. It has been shown that genes express differently on malignant vs. healthy sites and that more accurately than conventional histology certain gene profiles can be used to assess the disease course. It remains to be shown how specifically these changes possibly affect oral microbiota, however. Further, studies are called for to investigate whether combined molecular techniques such as genomics, transcriptomics, and proteomics could be used to profile both the host tissue and the microbiota for accurate diagnostics Citation75.

Finally, it should also be kept in mind that the sampling site as such may influence the results. In oral cancer patients optimal sampling may be difficult Citation76. Consequently, proper sampling technique for both the conventional cultivation and the new molecular methods needs to be emphasized Citation77. There is a need for standardized guidelines in this area.

Effect of cancer treatment on oral microbiota

Microbiological studies have been conducted in particular in patients undergoing treatment for cancer. Radiotherapy-caused hyposalivation may affect the oral microbiota. Variations in quantity, complexity, and quality of the oral microbiota also occur during chemotherapy, leading to a major imbalance of the ecosystem Citation78. For example, in a study from Sweden, Candida albicans was found in one or more sites in 54% of the subjects who had received radiotherapy to the head and neck in comparison to 15% of the controls. These patients also harbored enterococci in 38% vs. none of the controls. Lactobacillus spp. were detected in 92% of the subjects and the proportion of the species was high compared with the controls. Mutants streptococci were also detected in high numbers; 31% in the patients vs. 23% in controls Citation79. On the other hand, in a study from China mutants streptococci were not isolated in radiotherapy patients while lactobacilli, S. mitis and S. salivarius were the predominant caries-related oral bacteria following radiotherapy Citation80.

Bacteria in gingival pockets in head- and neck-irradiated patients have also been investigated. A comprehensive study from Hong Kong showed that the major components of sub-gingival microbiota appear similar to that of gingivitis sites in the normal population although among the radiotherapy patients bacterial or fungal species uncommon in normal subjects were also detected Citation81. These species included micro-organisms such as Gemella, Peptostreptococcus, Staphylococcus, Stomatococcus, Streptococcus, Actinomyces, Eubacterium, Lactobacillus, Propionibacterium, Neisseria, Veillonella, Bacteroides, Campylobacter, Capnocytophaga, Fusobacterium, Kingella, Porphyromonas, and Prevotella. Also species of microbes that are characteristic to the normal microbiota of skin (Peptostreptococcus prevotii and Propionibacterium granulosum) and gut (Eubacterium aerofaciens, Fusobacterium mortiferum, and Fusobacterium varium) were detected in this material Citation81.

How permanent are the shifts in oral microbiota after the treatment of cancer is another question of interest. Radiotherapy or cytostatic treatment-caused changes in bacterial composition need not be permanent. For example, in child allogenic bone marrow transplantation patients in the UK no differences were seen in the total anaerobic counts or in the proportion of the S. oralis group bacteria between the baseline and end of a 119-day study or between the patients and controls Citation82. However, caries risk may still be increased in particular in pediatric patients surviving a malignant disease Citation83.

In immunosuppressed patients treated with cytostatic drugs pathogenic and opportunistic micro-organisms colonizing the mouth may indeed be dangerous. Enterobacteria and genera such as Pseudomonas, Neisseria, and Veillonella have been observed in oral samples from granulocytopenic patients with leukemia Citation84. Yeasts can also be predominant but not always Citation85. It appears that the pre-treatment oral health status is important in this respect. For example, in a study on non-lymphocytic leukemia patients in Baltimore periodontal disease status and attachment loss were positively correlated with increase in the proportional recovery of Staphylococcus spp. from supra-gingival sites and total yeasts from supra- and sub-gingival sites Citation86. The authors suggested that host factors such as periodontal disease may contribute to the patterns of oral microbial successions during cancer chemotherapy. Finally, pathogens such as Capnocytophaga may pose a systemic risk in patients with cancer. Hence continuous attention is called for in order to prevent bacteremia and also to overcome problems of developing antibiotic resistance as pointed out by Sixou et al. Citation87. Above all, however, studies are lacking to show how different cancer treatments affect oral microbiota as a whole. It can be anticipated that all the oral cancer treatment modes, include surgery, radiotherapy, and cytostatic drugs, affect oral micro-organisms differently with possible characteristic shifts in biofilm composition. Hence more studies are needed in this area which is important in order to get evidence-based guidelines to the maintaining satisfactory dental health of an individual with cancer Citation88. These are briefly discussed below.

Controlling oral microbiota in cancer patients

Potential oral infection foci need to be diagnosed and treated before starting immunosuppressive therapy Citation89. To avoid complications antiseptic oral rinses have been recommended. Chlorhexidine has been the golden standard in controlling oral microbiota in cancer patients. Oncologic units and wards have guidelines explaining how and at what phase of the treatment the mouthwashes should be administered to the patients. Chlorhexidine in general has shown effective in preventing dentogenic bacteremia. For example, in a study by Tomás et al. Citation90, the prevalence of bacteremia after dental extraction by using chlorhexidine and control groups were 79% vs. 96%, respectively, at 30 s (p<0.01), 30% vs. 64% at 15 min (p<0.001), and 2% vs. 20% at 1 h (p<0.01) after the treatment. In their study the most frequently identified bacteria were Streptococcus spp., particularly of the viridans group. These were detected from blood cultures of both the chlorhexidine and control groups (64% and 68% of the subjects, respectively).

Chlorhexidine mouthwash has also shown effective in preventing oral mucocitis during cancer chemotherapy. In a randomized double-blind study on 206 patients receiving fluorouracil-based chemotherapy in gastrointestinal cancer mucositis occurred more frequently (33%) if the patients did not receive chlorhexidine in comparison to the study phase when three daily chlorhexidine mouth rinses were administered (13%, p<0.01) Citation91. Similarly in a study on head and neck cancer patients undergoing radiotherapy using either 0.12% chlorhexidine or 1% povidone–iodine mouthwash was efficient in reducing oral mucositis episodes when compared with saline or soda rinses Citation92.

However, scientific evidence for the practise of recommending chlorhexidine (or any other chemical) during cancer treatment is weak and the results are partly controversial. For example, in a study on leukemia patients one group rinsed with a 0.2% of chlorhexidine solution twice daily while the other group did not. The results showed that chlorhexidine had no significant effect on any clinical parameters such as the number of days with fever, number of oral lesions, plaque score, gingival bleeding score, or the occurrence of candidiasis Citation93. Recently, Antunes et al. Citation94 confirmed in their study on hematopoietic stem cell transplantation patients that using extra soft toothbrush and toothpaste was enough during immunsuppression to prevent systemic spread of alpha-hemolytic Streptococcus viridans and C. albicans. Using 0.12% chlorhexidine mouthrinse thrice daily in addition to the mechanical cleaning did not add anything in preventing streptococcal bacteremia Citation94. Nevertheless chlorhexidine has been routinely used since the early 1970s when, for example, oral application of 0.2% chlorhexidine was found to reduce the suffering of leukemic children and prevented spread of thrush from the oral cavity Citation95.

Other chemicals except chlorhexidine may, however, also have some value in controlling oral bacteria during cancer chemotherapy. A 1-year randomized trial from our clinic on 79 Hodgkin and non-Hodgkin lymphoma patients showed that using mouthwash containing 0.025% amine fluoride–stannous–fluoride caused a significant decrease in visible plaque, gingival bleeding, and salivary S. mutans counts while an increase was found in the group using 0.05% sodium fluoride rinses Citation96. However, also in this study a short-term use of 0.12% chlorhexidine at the induction phase of chemotherapy was most efficient in reducing dental plaque scores in both the fluoride-rinsing groups Citation97.

In a meta-analysis, Stokman et al. Citation98 concluded that of the several chemicals reported in controlled trials for preventing oral mucositis the combined use of polymyxin E, tobramycine, and amphotericin B showed an OR 0.61 (CI 0.39–0.96) and amifostine OR 0.37 (CI 0.15–0.89). The authors concluded that ‘to date, no single intervention completely prevents oral mucositis, so combined preventive therapy strategies seem to be required to ensure more successful outcomes’. The important issue of anticancer therapy-related oral mucositis has also been recently assessed in the Cochrane collaboration. The systematic review was based on trials meeting the following criteria: design was random allocation of participants; participants were anyone with cancer receiving chemotherapy or radiotherapy; interventions with agents prescribed to prevent oral mucositis; and the outcomes were prevention of mucositis, pain, amount of analgesia, dysphagia, systemic infection, length of hospitalization, costs incurred, and patient quality-of-life. The authors conclude their meta-analysis stating that ‘there is a need for well-designed and -conducted trials with sufficient numbers of participants to perform subgroup analyses by type of disease and chemotherapeutic agent’ Citation99. There is nothing to add to this conclusion.

In addition to preventing oral bacteremia complications due to the direct spread of micro-organisms is of further concern among immunosuppressed and cancer patients. For example, pneumonia may follow and the risk increases if the level of oral hygiene is poor Citation100. Akutsu et al. Citation101 observed that pathogens in preoperative dental plaque are risk factors for postoperative pneumonia in patients with esophageal cancer.

Taken into consideration the weak scientific evidence and partly controversial results from studies investigating the control of oral microbiota in cancer patients there nevertheless is agreement that oral health care is important during and after the treatment of cancer. The oral health care personnel are in a key position in advising the patients Citation102. We have recently reviewed this topic more thoroughly Citation88.

Prevention of oral microbiota-linked carcinogenesis

If there is indeed a causal link between oral microbiota and cancer then the ultimate goal would be to prevent the development of cancer by interfering with the putative carcinogenic potential of the microbiome. Intervention of acetaldehyde-related carcinogenesis has been investigated using cysteine Citation103 Citation104. This non-essential amino acid binds effectively acetaldehyde by forming a stable thiazolidine–carboxylic acid compound hence eliminating the local carcinogenic effect Citation105 Citation106 Citation107 . Cysteine has also been shown to exert inhibitory effect on the gelatinolytic activity of matrix metalloproteinases and to reduce metastases in animal models Citation108. Studies are now in progress for assessing the local effect of orally administered cysteine on oral microbiota in this perspective. In general, this compound is widely available in a number of dietary supplements.

Several other compounds have been introduced for the prevention of oral cancer. The main target, however, has been interfering with the cellular carcinogenic mechanisms rather than addressing oral microbiota. Nevertheless, many such compounds also exert antimicrobial activity. These include retinoids Citation109, anti-oxidant vitamins E and A, and carotenoids Citation110 Citation111. However, data are sparse on their effect in preventing oral carcinogenesis. Liede et al. Citation112 Citation113 could not show any effect of beta-carotene on the prevalence of oral mucosal lesions and buccal cell dysplasia in a controlled 5–7-year study in men in Finland.

Many naturally occurring spices and herbs have been used from the early history of mankind in foods and to treat ailments. These include spices such as garlic, cumin, cloves, cinnamon, thyme, mustard, and rosemary, which possess antimicrobial properties Citation114. Green tea has been particularly investigated in this perspective Citation115. The common nominators in many of these items are the potent phytochemicals the plants contain; several compounds have been tested in animal models Citation116. It is of interest in this context to cite results from a recent study from Japan where in women the hazard ratios of oral cancer for green tea consumption of 1–2, 3–4, and 5 or more cups per day were 0.51 (CI 0.10–2.68), 0.60 (CI 0.17–2.10), and 0.31 (CI 0.09–1.07), respectively, compared with those who daily drank less than one cup of green tea (p for trend was 0.08) Citation117. However, scientific evidence is weak of the topic and more controlled long-term studies are called for further conclusions. In the future the development of anti-carcinogenic products from naturally occurring compounds is fascinating but certainly a big challenge.

Finally, during the past two decades probiotic or health-beneficial bacteria have been re-introduced for strengthening immune function. The early discovery in the turn of the nineteenth century by Nobel laureate Ilya Metchnikoff was long forgotten until the globally increased antibiotic drug resistance problem and functional food concept brought these bacteria again into daylight Citation118 Citation119. It has been suggested that consuming of dairy products with probiotic lactic acid bacteria may have anti-tumor effects. The mechanisms involved are attributed to the inhibition of mutagenic activity, the decrease in several enzymes implicated in the generation of carcinogens, mutagens, or tumor-promoting agents, suppression of tumors, adjuvant effects including modulation of cell-mediated immune responses, activation of the reticuloendothelial system, augmentation of cytokine pathways, and regulation of interleukins and tumor necrosis factors Citation120. However, these findings are mainly based on laboratory or animal studies. Evidence regarding probiotic effect on human carcinogenesis is weak or non-existent. These bacteria seem to have some effect on preventing oral mucositis caused by treatment of cancer, however Citation121. But there are no studies on the effect of probiotics on oral cancer. It can be anticipated, however, that the same mechanisms are involved here as in the lower parts of the gastrointestinal tract. This certainly is an area of interest in future studies.

Conclusion

Oral microbiota with its hundreds of microbial species mainly residing in biofilms pose a threat to immunosuppressed cancer patients if microbes gain access to blood circulation or spread locally to adjacent tissues. Therefore a number of clinical guidelines and protocols have been introduced to control oral infections. However, the protocols are not evidence based, but rather derive from long-time clinical practice. Since bacteremia complications are life-threatening to patients whose defense systems are weakened obviously every effort should be taken to prevent such complications. All cancer patients, including patients with oral cancer, must therefore maintain satisfactory oral health which often calls for regular professional treatment given by the oral health care team. Another question is the role of oral microbiota in carcinogenesis. Certain bacteria and yeasts may trigger carcinogenic mechanisms at the cellular level. They may also participate in metabolizing substances to carcinogens. An example to this is the microbial metabolism of alcohol to carcinogenic acetaldehyde. Poor oral hygiene has been associated with increased risk of oral cancer where the known risk factors are heavy use of alcohol and tobacco. Modern molecular methods are anticipated to cast new light on the role of oral microbiome in carcinogenesis in general. It is noteworthy that some epidemiological studies have linked poor oral health with overall prevalence of malignancies.

Conflict of interest and funding

The author has not received any funding or benefits from industry to conduct this study.

References

  • Herrera V, Parsonnet J. Helicobacter pylori and gastric adenocarcinoma. Clin Microbiol Infect. 2009; 15: 971–6.
  • Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature. 2007; 449: 804–10.
  • Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, et al.. A core gut microbiome in obese and lean twins. Nature. 2009; 457: 480–4.
  • Preza D, Olsen I, Willumsen T, Grinde B, Paster BJ. Diversity and site-specificity of the oral microflora in the elderly. Eur J Clin Microbiol Infect Dis. 2009; 28: 1033–40.
  • Fischetti VA. Novel method to control pathogenic bacteria on human mucous membranes. Ann NY Acad Sci. 2003; 987: 207–14.
  • Tachibana M, Yoshida A, Ansai T, Takata Y, Akifusa S, Fukuhara M, et al.. Prevalence of periodontopathic bacteria on the tongue dorsum of elderly people. Gerodontology. 2006; 23: 123–6.
  • Brook I. The role of bacterial interference in otitis, sinusitis and tonsillitis. Otolaryngol Head Neck Surg. 2005; 33: 139–46.
  • Gendron R, Grenier D, Maheu-Robert L. The oral cavity as a reservoir of bacterial pathogens for focal infections. Microbes Infect. 2000; 2: 897–906.
  • Desai HG, Gill HH, Shankaran K, Mehta PR, Prabhu SR. Dental plaque: a permanent reservoir of Helicobacter pylori?. Scand J Gastroenterol. 1991; 26: 1205–8.
  • Komiyama K, Tynan JJ, Habbick BF, Duncan DE, Liepert DJ. Pseudomonas aeruginosa in the oral cavity and sputum of patients with cystic fibrosis. Oral Surg Oral Med Oral Pathol. 1985; 59: 590–4.
  • Scannapieco FA. Position paper of The American Academy of Periodontology: periodontal disease as a potential risk factor for systemic diseases. J Periodontol. 1998; 69: 841–50.
  • Slots J, Rams TE. New views on periodontal microbiota in special patient categories. J Clin Periodontol. 1991; 18: 411–20.
  • Meurman JH, Uittamo J. Oral micro-organisms in the etiology of cancer. Acta Odontol Scand. 2008; 66: 321–6.
  • Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002; 420: 860–7.
  • Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008; 454: 436–4.
  • Fantini MC, Pallone F. Cytokines: from gut inflammation to colorectal cancer. Curr Drug Targets. 2008; 9: 375–80.
  • Allavena P, Garlanda C, Borrello MG, Sica A, Mantovani A. Pathways connecting inflammation and cancer. Curr Opin Genet Dev. 2008; 18: 3–10.
  • Parsonnet J. Microbes and malignancy. Oxford University Press. New York, 1999; 3–15.
  • Butel JS. Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease. Carcinogenesis. 2000; 21: 405–26.
  • Kuper H, Adami HO, Trichopoulos D. Infections as a major preventable cause of human cancer. J Intern Med. 2000; 248: 171–83.
  • Megraud F, Brassens-Rabbe MP, Denis F, Belbouri A, Hoa DQ. Seroepidemiology of Campylobacter pylori infection in various populations. J Clin Microbiol. 1989; 27: 1870–3.
  • Martin D, Gutkind JS. Human tumor-associated viruses and new insights into the molecular mechanisms of cancer. Oncogene. 2008; 27: 31–42.
  • Grinde B, Olsen I. The role of viruses in oral disease. J Oral Microbiol. 2010; 2: 2127. DOI: 10.3402/jom.v2i0.5195.
  • Watabe K, Nishi M, Miyake H, Hirata K. Lifestyle and gastric cancer: a case-control study. Oncol Rep. 1998; 5: 1191–4.
  • Demirer T, Icli F, Uzunalimoglu O, Kucuk O. Diet and stomach cancer incidence. A case-control study in Turkey. Cancer. 1990; 65: 2344–8.
  • Wolff G, Lauter J. On epidemiology of gastric cancer (author's transl). Arch Geschwulstforsch. 1976; 46: 1–14.
  • Abnet CC, Qiao YL, Mark SD, Dong ZW, Taylor PR, Dawsey SM. Prospective study of tooth loss and incident esophageal and gastric cancers in China. Cancer Causes Control. 2001; 12: 847–54.
  • Hujoel PP, Drangsholt M, Spiekerman C, Weiss NS. An exploration of the periodontitis–cancer association. Ann Epidemiol. 2003; 13: 312–6.
  • Stolzenberg-Solomon RZ, Dodd KW, Blaser MJ, Virtamo J, Taylor PR, Albanes D. Tooth loss, pancreatic cancer, and Helicobacter pylori. Am J Clin Nutr. 2003; 78: 176–81.
  • Michaud DS, Joshipura K, Giovannucci E, Fuchs CS. A prospective study of periodontal disease and pancreatic cancer in US male health professionals. J Natl Cancer Inst. 2007; 99: 171–5.
  • Lin CY, Chao PC, Hong GJ, Tsai YT, Lee CY, Tsai CS. Infective endocarditis from Streptococcus viridans associated with colonic carcinoma: a case report. J Card Surg. 2008; 23: 263–5.
  • Siegert CE, Overbosch D. Carcinoma of the colon presenting as Streptococcus sanguis bacteremia. Am J Gastroenterol. 1995; 90: 1528–9.
  • Michaud DS, Liu Y, Meyer M, Giovannucci E, Joshipura K. Periodontal disease, tooth loss, and cancer risk in male health professionals: a prospective cohort study. Lancet Oncol. 2008; 9: 550–8.
  • Tezal M, Sullivan MA, Reid ME, Marshall JR, Hyland A, Loree T, et al.. Chronic periodontitis and the risk of tongue cancer. Arch Otolaryngol Head Neck Surg. 2007; 133: 450–4.
  • Tezal M, Sullivan MA, Hyland A, Marshall JR, Stoler D, Reid ME, et al.. Chronic periodontitis and the incidence of head and neck squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev. 2009; 18: 2406–12.
  • Abnet CC, Kamangar F, Islami F, Nasrollahzadeh D, Brennan P, Aghcheli K, et al.. Tooth loss and lack of regular oral hygiene are associated with higher risk of esophageal squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev. 2008; 17: 3062–8.
  • Holmes L, desVignes-Kendrik M, Slomka J, Mahabir S, Beeravolu S, Emani SR. Is dental care utilization associated with oral cavity cancer in a large sample of community-based United States residents?. Community Dent Oral Epidemiol. 2009; 37: 134–42.
  • Rautemaa R, Hietanen J, Niissalo S, Pirinen S, Perheentupa J. Oral and oesophageal squamous cell carcinoma – a complication or component of autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED, APS-I). Oral Oncol. 2007; 43: 607–13.
  • Rosa DD, Pasqualotto AC, Denning DW. Chronic mucocutaneous candidiasis and oesophageal cancer. Med Mycol. 2008; 46: 85–91.
  • Söder B, Klinge B, Söder P-Ö. Periodontitis and premature death: a 16-year longitudinal study in a Swedish urban population. J Periodontal Res. 2007; 42: 361–6.
  • Hooper SJ, Wilson MJ, Crean SJ. Exploring the link between microorganisms and oral cancer: a systematic review of the literature. Head Neck. 2009; 31: 1228–39.
  • Migliorati CA. Periodontal disease and cancer. Periodontal diseases and cancer. Lancet Oncol. 2008; 9: 510–2.
  • Meyer MS, Joshipura K, Giovannucci E, Michaud DS. A review of the relationship between tooth loss, periodontal disease, and cancer. Cancer Causes Control. 2008; 19: 895–907.
  • Meurman JH. Infectious and dietary risk factors of oral cancer. Oral Oncol. 2010; 46: 411–3.
  • Meurman JH, Sanz M, Janket SJ. Oral health, atherosclerosis, and cardiovascular disease. Crit Rev Oral Biol Med. 2004; 15: 403–13.
  • Lax AJ, Thomas W. How bacteria could cause cancer: one step at a time. Trends Microbiol. 2002; 10: 293–9.
  • Katz J, Wallet S, Cha S. Periodontal disease and the oral-systemic connection: “Is it all the RAGE?”. Quintessence Int. 2010; 41: 229–37.
  • Lalla E, Lamster IB, Stern DM, Schmidt AM. Receptor for advanced glycation end products, inflammation, and accelerated periodontal disease in diabetes: mechanisms and insights into therapeutic modalities. Ann Periodontol. 2001; 6: 113–8.
  • Janket SJ, Jones JA, Meurman JH, Baird AE, Van Dyke TE. Oral infection, hyperglycemia, and endothelial dysfunction. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008; 105: 173–9.
  • Sheu BC, Chang WC, Cheng CY, Lin HH, Chang DY, Huang SC. Cytokine regulation networks in the cancer microenvironment. Front Biosci. 2008; 13: 6255–68.
  • Bloching M, Reich W, Schubert J, Grummt T, Sandner A. The influence of oral hygiene on salivary quality in the Ames Test, as a marker for genotoxic effects. Oral Oncol. 2007; 43: 933–9.
  • Jeng JH, Chang MC, Hahn LJ. Role of areca nut in betel quid-associated chemical carcinogenesis: current awareness and future perspectives. Oral Oncol. 2001; 37: 477–92.
  • Homann N, Tillonen J, Salaspuro M. Microbially produced acetaldehyde from ethanol may increase the risk of colon cancer via folate deficiency. Int J Cancer. 2000; 86: 169–73.
  • Homann N, Tillonen J, Meurman JH, Rintamäki H, Lindqvist C, Rautio M, et al.. Increased salivary acetaldehyde levels in heavy drinkers and smokers: a microbiological approach to oral cavity cancer. Carcinogenesis. 2000; 21: 663–8.
  • Kurkivuori J, Salaspuro V, Kaihovaara P, Kari K, Rautemaa R, Grönroos L, et al.. Acetaldehyde production from ethanol by oral streptococci. Oral Oncol. 2007; 43: 181–6.
  • Uittamo J, Siikala E, Kaihovaara P, Salaspuro M, Rautemaa R. Chronic candidosis and oral cancer in APECED-patients: production of carcinogenic acetaldehyde from glucose and ethanol by Candida albicans. Int J Cancer. 2009; 124: 754–6.
  • Nieminen MT, Uittamo J, Salaspuro M, Rautemaa R. Acetaldehyde production from ethanol and glucose by non-Candida albicans yeasts in vitro. Oral Oncol. 2009; 45: e245–8.
  • Marichalar-Mendia X, Rodriguez-Tojo MJ, Acha-Sagredo A, Rey-Barja N, Aguirre-Urizar JM. Oral cancer and polymorphism of ethanol metabolising genes. Oral Oncol. 2010; 46: 9–13.
  • Cancela Mde C, Ramadas K, Fayette JM, Thomas G, Muwonge R, Chapuis F, et al.. Alcohol intake and oral cavity cancer risk among men in a prospective study in Kerala, India. Community Dent Oral Epidemiol. 2009; 37: 342–9.
  • Morse DE, Psoter WJ, Cleveland D, Cohen D, Mohit-Tabatabai M, Kosis DL, et al.. Smoking and drinking in relation to oral cancer and oral epithelial dysplasia. Cancer Causes Control. 2007; 18: 919–29.
  • Salaspuro V, Salaspuro M. Synergistic effect of alcohol drinking and smoking on in vivo acetaldehyde concentration in saliva. Int J Cancer. 2004; 111: 480–3.
  • Narikiyo M, Tanabe C, Yamada Y, Igaki H, Tachimori Y, Kato H, et al.. Frequent and preferential infection of Treponema denticola, Streptococcus mitis, and Streptococcus anginosus in esophageal cancers. Cancer Sci. 2004; 95: 569–74.
  • Shiga K, Tateda M, Saijo S, Hori T, Sato I, Tateno H, et al.. Presence of streptococcus infection in extra-oropharyngeal head and neck squamous cell carcinoma and its implication in carcinogenesis. Oncol Rep. 2001; 8: 245–8.
  • Sasaki M, Yamaura C, Ohara-Nemoto Y, Tajika S, Kodama Y, Ohya T, et al.. Streptococcus anginosus infection in oral cancer and its infection route. Oral Dis. 2005; 11: 151–6.
  • Mager DL, Haffajee AD, Devlin PM, Norris CM, Posner MR, Goodson JM. The salivary microbiota as a diagnostic indicator of oral cancer: a descriptive, non-randomized study of cancer-free and oral squamous cell carcinoma subjects. J Translational Med. 2009; 3: 27. DOI: 10.3402/jom.v2i0.5195.
  • Liao PH, Chang YC, Huang MF, Tai KW, Chou MY. Mutation of p53 gene codon 63 in saliva as a molecular marker for oral squamous cell carcinomas. Oral Oncol. 2000; 36: 272–6.
  • Kim MM, Clinger JD, Masayesva BG, Ha PK, Zahurak ML, Westra WH, et al.. Mitochondrial DNA quantity increases with histopathologic grade in premalignant and malignant head and neck lesions. Clin Cancer Res. 2004; 10: 8512–5.
  • Vieira J, O'Hearn P, Kimball L, Chandran B, Corey L. Activation of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) lytic replication by human cytomegalovirus. J Virol. 2001; 75: 1378–86.
  • Maticic M, Poljak M, Kramar B, Tomazic J, Vidmar L, Zakotnik B, et al.. Proviral HIV-1 DNA in gingival crevicular fluid of HIV-1-infected patients in various stages of HIV disease. J Dent Res. 2000; 79: 1496–501.
  • Seoane Lestón J, Diz Dios P. Diagnostic clinical aids in oral cancer. Oral Oncol. 2010; 46: 418–22.
  • Wu JY, Yi C, Chung HR, Wang DJ, Chang WC, Lee SY, et al.. Potential biomarkers in saliva for oral squamous cell carcinoma. Oral Oncol. 2010; 46: 226–31.
  • Keijser BJ, Zaura E, Huse SM, van der Vossen JM, Schuren FH, Montijn RC, et al.. Pyrosequencing analysis of the oral microflora of healthy adults. J Dent Res. 2008; 87: 1016–20.
  • Kuo WP. Overview of bioinformatics and its application to oral genomics. Adv Dent Res. 2003; 17: 89–94.
  • Kuo WP, Mendez E, Chen C, Whipple ME, Farell G, Agoff N, et al.. Functional relationships between gene pairs in oral squamous cell carcinoma. AMIA Annu Symp Proc. 2003: 371–5.
  • Fábián TK, Fejérdy P, Csermely P. Salivary genomics, transcriptomics and proteomics: the emerging concept of the oral ecosystem and their use in the early diagnosis of cancer and other diseases. Curr Genomics. 2008; 9: 11–21.
  • Rautemaa R, Rusanen P, Richardson M, Meurman JH. Optimal sampling site for mucosal candidosis in oral cancer patients is the labial sulcus. J Med Microbiol. 2006; 55: 1447–51.
  • Rusanen P, Siikala E, Uittamo J, Richardson M, Rautemaa R. A novel method for sampling the microbiota from the oral mucosa. Clin Oral Investig. 2009; 13: 243–6.
  • Sixou JL, De Medeiros-Batista O, Gandemer V, Bonnaure-Mallet M. The effect of chemotherapy on the supragingival plaque of pediatric cancer patients. Oral Oncol. 1998; 34: 476–83.
  • Almståhl A, Wikström M, Fagerberg-Mohlin B. Microflora in oral ecosystems in subjects with radiation-induced hyposalivation. Oral Dis. 2008; 14: 541–9.
  • Tong HC, Gao XJ, Dong XZ. Non-mutants streptococci in patients receiving radiotherapy in the head and neck area. Caries Res. 2003; 37: 261–6.
  • Leung WK, Jin LJ, Samaranayake LP, Chiu GK. Subgingival microbiota of shallow periodontal pockets in individuals after head and neck irradiation. Oral Microbiol Immunol. 1998; 13: 1–10.
  • Lucas VS, Beighton D, Roberts GJ, Challacombe SJ. Changes in the oral streptococcal flora of children undergoing allogeneic bone marrow transplantation. J Infect. 1997; 35: 135–41.
  • Dens FL, Boute P, Vinckier F, Declerck D. Salivary caries risk factors in long-term event-free survivors of pediatric malignant diseases. J Clin Pediatr Dent. 1996; 20: 241–5.
  • Peterson DE, Minah GE, Reynolds MA, Weikel DS, Overholser CD, DePaola LG, et al.. Effect of granulocytopenia on oral microbial relationships in patients with acute leukemia. Oral Surg Oral Med Oral Pathol. 1990; 70: 720–3.
  • Pompei R, Ingianni A, Cagetti MG, Rizzo A, Cotti S. Evaluation of the opportunistic microbial flora and of some antimicrobial factors in the oral cavity of leukaemic patients. Microbios. 1993; 75: 149–57.
  • Reynolds MA, Minah GE, Peterson DE, Weikel DS, Williams LT, Overholser CD, et al.. Periodontal disease and oral microbial successions during myelosuppressive cancer chemotherapy. J Clin Periodontol. 1989; 16: 185–9.
  • Sixou JL, Aubry-Leuliette A, De Medeiros-Battista O, Lejeune S, Jolivet-Gougeon A, Solhi-Pinsard H, et al.. Capnocytophaga in the dental plaque of immunocompromised children with cancer. Int J Paediatr Dent. 2006; 16: 75–80.
  • Meurman JH, Grönroos L. Oral and dental health care of oral cancer patients: hyposalivation, caries and infections. Oral Oncol. 2010; 46: 464–7.
  • Meurman JH, Pyrhönen S, Teerenhovi L, Lindqvist C. Oral sources of septicaemia in patients with malignancies. Oral Oncol. 1997; 33: 389–97.
  • Tomás I, Alvarez M, Limeres J, Tomás M, Medina J, Otero JL, et al.. Effect of a chlorhexidine mouthwash on the risk of postextraction bacteremia. Infect Control Hosp Epidemiol. 2007; 28: 577–82.
  • Sorensen JB, Skovsgaard T, Bork E, Damstrup L, Ingeberg S. Double-blind, placebo-controlled, randomized study of chlorhexidine prophylaxis for 5-fluorouracil-based chemotherapy-induced oral mucositis with nonblinded randomized comparison to oral cooling (cryotherapy) in gastrointestinal malignancies. Cancer. 2008; 112: 1600–6.
  • Madan PD, Sequeira PS, Shenoy K, Shetty J. The effect of three mouthwashes on radiation-induced oral mucositis in patients with head and neck malignancies: a randomized control trial. J Cancer Res Ther. 2008; 4: 3–8.
  • Wahlin YB. Effects of chlorhexidine mouthrinse on oral health in patients with acute leukemia. Oral Surg Oral Med Oral Pathol. 1989; 68: 279–87.
  • Antunes HS, Ferreira EM, de Faria LM, Schirmer M, Rodrigues PC, Small IA, et al.. Streptococcal bacteraemia in patients submitted to hematopoietic stem cell transplantation: the role of tooth brushing and use of chlorhexidine. Med Oral Patol Oral Cir Bucal. 2010; 15: e303–9.
  • Langslet A, Olsen I, Lie SO, Lokken P. Chlorhexidine treatment of oral candidiasis in seriously diseased children. Acta Paediatr Scand. 1974; 63: 809–11.
  • Laine P, Meurman JH, Murtomaa H, Lindqvist C, Torkko H, Pyrhönen S, et al.. One-year trial of the effect of rinsing with an amine fluoride–stannous–fluoride-containing mouthwash on gingival index scores and salivary microbial counts in lymphoma patients receiving cytostatic drugs. J Clin Periodontol. 1993; 20: 628–34.
  • Meurman JH, Laine P, Murtomaa H, Lindqvist C, Torkko H, Teerenhovi L, et al.. Effect of antiseptic mouthwashes on some clinical and microbiological findings in the mouths of lymphoma patients receiving cytostatic drugs. J Clin Periodontol. 1991; 18: 587–91.
  • Stokman MA, Spijkervet FK, Boezen HM, Schouten JP, Roodenburg JL, de Vries EG. Preventive intervention possibilities in radiotherapy- and chemotherapy-induced oral mucositis: results of meta-analyses. J Dent Res. 2006; 85: 690–700.
  • Worthington HV, Clarkson JE, Eden OB. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev. 2007; 4: CD000978.
  • Sjögren P, Nilsson E, Forsell M, Johansson O, Hoogstraate J. A systematic review of the preventive effect of oral hygiene on pneumonia and respiratory tract infection in elderly people in hospitals and nursing homes: effect estimates and methodological quality of randomized controlled trials. J Am Geriatr Soc. 2008; 56: 2124–30.
  • Akutsu Y, Matsubara H, Okazumi S, Shimada H, Shuto K, Shiratori T, et al.. Impact of preoperative dental plaque culture for predicting postoperative pneumonia in esophageal cancer patients. Dig Surg. 2008; 25: 93–7.
  • Chandu A, Stulner C, Bridgeman AM, Smith AC. Maintenance of mouth hygiene in patients with oral cancer in the immediate post-operative period. Aust Dent J. 2002; 47: 170–3.
  • Salaspuro V, Hietala J, Kaihovaara P, Pihlajarinne L, Marvola M, Salaspuro M. Removal of acetaldehyde from saliva by a slow-release buccal tablet of L-cysteine. Int J Cancer. 2002; 97: 361–4.
  • Salaspuro V.. Pharmacological treatments and strategies for reducing oral and intestinal acetaldehyde. Novartis Found Symp. 2007; 285: 145–53. (Discussion 153–7, 198–9).
  • De Vries N, De Flora S. N-acetyl-L-cysteine. J Cell Biochem. 1993; 17: 270–7.
  • Van Schooten FJ, Besaratinia A, De Flora S, D'Agostini F, Izzotti A, Camoirano A, et al.. Effects of oral administration of N-acetyl-L-cysteine: a multi-biomarker study in smokers. Cancer Epidemiol Biomarkers Prev. 2002; 11: 167–75.
  • Salaspuro VJ, Hietala JM, Marvola ML, Salaspuro MP. Eliminating carcinogenic acetaldehyde by cysteine from saliva during smoking. Cancer Epidemiol Biomarkers Prev. 2006; 15: 146–9.
  • Morini M, Cai T, Aluigi MG, Noonan DM, Masiello L, De Flora S, et al.. The role of the thiol N-acetylcysteine in the prevention of tumor invasion and angiogenesis. Int J Biol Markers. 1999; 14: 268–71.
  • King K, Jones DH, Daltrey DC, Cunliffe WJ. A double-blind study of the effects of 13-cis-retinoic acid on acne, sebum excretion rate and microbial population. Br J Dermatol. 1982; 107: 583–90.
  • Krinsky NI. Antioxidant functions of carotenoids. Free Radic Biol Med. 1989; 7: 617–35.
  • Tengerdy RP. The role of vitamin E in immune response and disease resistance. Ann NY Acad Sci. 1990; 587: 24–33.
  • Liede K, Hietanen J, Saxen L, Haukka J, Timonen T, Häyrinen-Immonen R, et al.. Long-term supplementation with alpha-tocopherol and beta-carotene and prevalence of oral mucosal lesions in smokers. Oral Dis. 1998; 4: 78–83.
  • Liede KE, Alfthan G, Hietanen JH, Haukka JK, Saxen LM, Heinonen OP. Beta-carotene concentration in buccal mucosal cells with and without dysplastic oral leukoplakia after long-term beta-carotene supplementation in male smokers. Eur J Clin Nutr. 1998; 52: 872–6.
  • Lai PK, Roy J. Antimicrobial and chemopreventive properties of herbs and spices. Curr Med Chem. 2004; 11: 1451–60.
  • Taylor PW, Hamilton-Miller JM, Stapleton PD. Antimicrobial properties of green tea catechins. Food Sci Technol Bull. 2005; 2: 71–81.
  • Miller EG, Peacock JJ, Bourland TC, Taylor SE, Wright JM, Patil BS, et al.. Inhibition of oral carcinogenesis by citrus flavonoids. Nutr Cancer. 2008; 60: 69–74.
  • Ide R, Fujino Y, Hoshiyama Y, Mizoue T, Kubo T, Pham TM, et al.. A prospective study of green tea consumption and oral cancer incidence in Japan. Ann Epidemiol. 2007; 17: 821–6.
  • Meurman JH, Stamatova I. Probiotics: contributions to oral health. Oral Dis. 2007; 13: 443–51.
  • Stamatova I, Meurman JH. Probiotics: health benefits in the mouth. Am J Dent. 2009; 22: 329–38.
  • Kumar M, Kumar A, Nagpal R, Mohania D, Behare P, Verma V, et al.. Cancer-preventing attributes of probiotics: an update. Int J Food Sci Nutr. 2010; 61: 473–96.
  • Maria-Aggeliki KS, Nikolaos KL, George KM, Vassilis KE. The potential clinical impact of probiotic treatment for the prevention and/or anti-inflammatory therapeutic effect against radiation induced intestinal mucositis. A review. Recent Pat Inflamm Allergy Drug Discov. 2009; 3: 195–200.
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