Oral hygiene might prevent cancer

Review Article Oral hygiene might prevent cancer Oscar J. Cordero ∗ , Rub en Varela-Calvi~ no University of Santiago de Compostela, Department of Biochemistry and Molecular Biology, Campus Vida, 15782 Santiago de Compostela, Spain ∗ Corresponding author. E-mail address: [email protected] (O.J. Cordero). Abstract Many evidences support that species from the Human Oral Microbiome Database such as Fusobacterium nucleatum or Bacteroides, linked previously to periodontitis and appendicitis, play a role in colorectal cancer (CRC), including metastasis. These typically oral species are invasive anaerobes that form biofilms in their virulent state. Aspirin (a NSAID) has been recently included into routine CRC prevention rationale. NSAIDs can prevent the growth of neoplastic lesions by inhibiting COX enzymes and another set of recently identified COX-independent targets, which include the WNT, AMPK and MTOR signaling pathways, the crosstalk between nucleoli and NF-kB transcriptional activity in apoptosis, and the biochemistry of platelets. These are signaling pathways related to tumorpromoting inflammation. In this process, pathogens or simple deregulation of the microbiota play an important role in CRC. Aspirin and other NSAIDs are efficient inhibitors of biofilm formation and able to control periodontitis development preventing inflammation related to the microbiota of the gingival tissue, so its seems plausible to include this pathway in the mechanisms that aspirin uses to prevent CRC. We propose arguments suggesting that current oral hygiene methods and other future developments against periodontitis might prevent CRC and probably other cancers, alone or in combination with other options; and that the Received: 16 May 2018 Revised: 26 September 2018 Accepted: 19 October 2018 Cite as: Oscar J. Cordero, Rub en Varela-Calvi~ no.Oral hygiene might prevent cancer. Heliyon 4 (2018) e00879. doi: 10.1016/j.heliyon.2018. e00879 https://doi.org/10.1016/j.heliyon.2018.e00879 2405-8440/Ó2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). multidisciplinary studies needed to prove this hypothesis might be relevant for cancer prevention. Keywords: Microbiology, Cancer research, Evidence-based medicine, Dentistry 1. Introduction 1.1. Inflammation and immunity in cancer Accumulation of mutations in genes encoding either homeostatic regulators or DNA mismatch-repair factors, predominantly in stem cells becoming CSCs (cancer stem cells) is the leading event in carcinogenesis [1,2]. The crucial role of the immune system in this process, however, didn’t came into worldwide attention until Hanahan & Weinberg’s update of their “Hallmarks of Cancer”in 2011 [3]. These Hallmarks focused on immunosuppression, a better-known mechanism, on one hand but also in inflammation as an enabling characteristic of tumor growth [4]. Inflammation and immune system are activated to eliminate pathogens and non-self molecules, or to control at least their dissemination or systemic colonization of the organism, but the same physiological responses induce repair mechanisms that recover the function and integrity of tissues in an organ with tumor [5]. Moreover, the inflammation and immunitary cellular infiltrates responsible for tumor initiation and early progression are the same that can destroy the tumors before immunosuppression [6,7]. Therefore, both hallmarks are two sides of the same coin. In cancer, there are many possible origins for the inflammatory response. The inflammation is called intrinsic when the mechanisms driving the cell transformation and cancer initiation, overexpression of oncogenes (such as Ras, Myc, Src, or RET) and microRNAs (such as mi-R155), damage and mutation of DNA, and reactive oxygen species (ROS) production in mitochondria, also activate a pro-inflammatory program (the production of chemokines, interferons (IFNs) and tissue rearranging enzymes) in the proper altered cell [4,5,6]. Extrinsic inflammation is mediated, by contrast, by infiltrating immune cells [4,5,6]. Again DNA or mitochondrial damage, oncogene activation, or endoplasmic reticulum (ER) stress and oxidative damage of the altered cell, in addition to the many signals of cellular stress generated by the damage of the malignant cell-surrounding tissue (because of mechanical, chemical or irradiation causes, or genetic syndromes, hypoxia, the excessive temperature, or nutrients, or by senescence), serve to activate that infiltration. Chronic inflammation affects all phases of carcinogenesis. In a feedback loop, by the generation of mutations, modifications of functional proteins or epigenetic mechanisms, it drives cell transformation, particularly when a stem cell is affected and become CSCs [3,4,8,9]. At the same time, more hematopoietic inflammatory cells are recruited on the developing cancer. The leukocyte infiltrate includes neutrophils, dendritic cells, macrophages and lymphocytes, all of them capable of secreting those cytokines, ROS, 2https://doi.org/10.1016/j.heliyon.2018.e00879 2405-8440/Ó2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Article Nowe00879 membrane perforating agents, growth factors and cellular products that contribute to the inflammatory milieu present in the environment of a developing tumor, favoring the tumor growth and, later, dissemination of the transformed cells [5,10,11]. 1.2. Molecular mechanism of inflammation The immune cells recruited to the tumor express multiple specialized families of pattern recognition receptors (PRRs) located at the plasma membrane, within intracellular vesicles, and in the cytosol. The most known are the Toll-like receptors (TLRs), NLRs (from Nod, nucleotide binding oligomerization domain, -like receptors), PYHIN (pyrin and HIN domain) receptors, C-type lectin receptors, RLRs (RIG-I, retinoic acid inducible gene-I, -like receptors), the oligoadenylate synthase (OAS) -like receptors, the related protein cyclic GMP-AMP synthase (cGAS), and DNA sensors such as STING (stimulator of interferon gene). Many of them assemble to form signaling complexes, including inflammasomes initiated by NLR and PYHIN receptors and related to cellular oxidative stress, the myddosomes initiated by TLRs and the Interleukin-1 receptor (IL-1R) involving among others the MyD88 protein, and the mitochondrial antiviral signaling protein (MAVS) CARD filament initiated by RIG-1 [10,12]. To note, these “innate receptors”, at least TLR 2 and 4 and NLRP3, have been recently identified also in the proper tumorigenic altered cells or in metabolic tissues, adipocytes, myocytes, liver or pancreas (see below how systemic metabolic alterations such as obesity or diabetes also cause inflammation) [13,14] in what may represent feedback loops. These receptors are very promiscuous by definition, i.e. one particular or a very similar ligand may bind to different receptors in the same or in a different cell. Therefore, they identify DAMPS (damage-associated molecular patterns) as those endogenous components released from cells damaged by molecular stress [10,11,12], but they were first identified as receptors of PAMPs (pathogen-associated molecular patterns) or receptors that identify components from microbial pathogens, this fact of particular interest for later content of the review. Recent evidence indicate that the major DAMP driving host antitumor immune responses is tumor-derived DNA, sensed by the STING pathway in a certain population of intratumoral DCs, driving the production of type I IFNs and the resulting downstream T cell response (reviewed in [15]). The same signal transduction pathway, adaptor protein MyD88, is shared by many of these receptors. Although in rodent models, MyD88 has shown a protective role in the development of colonic tumors, MyD88 innate immune signaling and specific micro- RNAs mechanistically control CRC chemoresistance (see next subheading). Likewise, the same inflammatory mediators induce the transcription factors nuclear factor-kB (NF-kB) and signal transducer and activator of transcription-3 (STAT-3) [1,8-16]. 3https://doi.org/10.1016/j.heliyon.2018.e00879 2405-8440/Ó2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Article Nowe00879 The first one seems particularly relevant to gastrointestinal cancer development [5] and, in fact, NF-kB signaling pathway has been identified as a COX-independent target of NSAIDs (as reviewed later). STAT-3 of tumor, stromal and immune cells is activated by many of factors released by the tumor and tumor stroma, for example VEGF, interleukin-6 (IL-6), IL-10, IL-11, or IL-23, are transcriptionally regulated by STAT-3 regulates transcriptionally several of these cytokines generating a positive feedback loop [17]. In addition to the carcinogenesis mentioned above, they also allow the tumor to progress and metastasize by establishing a tumoral microenvironment (for example, angiogenesis), including the immunosuppressive mechanisms that prevent the effective immune surveillance. Finally, it must be emphasized that all these inflammatory mechanisms also affect the response to therapy [1,15,18]. 1.3. Gut microbiota and CRC As IBD patients dwith Crohn’s disease or ulcerative colitisdhave a several-fold increased susceptibility to CRC principally, they were considered typical examples of colitis-associated cancer (CAC), the first inflammation-related cancer [19,20]. In this cancer, the intestinal epithelial barrier already includes in the healthy individual complex molecular and cellular interactions of commensal microbiota with the epithelial, mesenchymal and immune cells to achieve intestinal homeostasis, regeneration, and healing (reviewed in [21]). The gut microbiota composition can be altered by the presence of a specific bacterial species or modulated by an environmental change. The presence of different natural mutagens and carcinogens, of a metabolism provided by the commensal flora that requires or can be regulated by a specific enzymatic activity, or the straightforward interaction of the bacteria or their products with those innate receptors or sensors described above, all can generate either pro- or anti-inflammatory effects (reviewed in [11,18]). At the beginning of the millennium the first experimental CAC models mimicking human CRC in rodents clearly established that immune cells, cytokines and the STAT-3 and NF- kB transduction pathways all participate in the induction of inflammatory colitis (revs [8,10,11,12]). The IBD patients also show increased susceptibility to lymphomas/leukemias and hepatocarcinomas among other tumors, which suggests that the pathological intestinal inflammation triggered by the commensal microbiota is responsible for the local tumor-promoting effects but also, through the immune system, to have additional deep systemic effects [11,18,21]. In addition, later on the text, reviewed data suggest new roles for the microbiota, for example in CRC metastasis. Likewise, most of the known main risk factors for CRC, obesity, lack of exercise, fat-rich diets, use of alcohol and tobacco [8,22], are related with nutrition, being 4https://doi.org/10.1016/j.heliyon.2018.e00879 2405-8440/Ó2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Article Nowe00879 environmental agents that can alter the commensal microbiota [7,11,13,14,15,16]. As the wide geographical variation in the incidence of CRC are lost in migrating populations within one generation, it is likely that these risk factors are responsible of CRC in the host populations [22,23]. Two enterobacterial species, Klebsiella pneumoniae and Proteus mirabilis, participated in the development of colitis and cancer in TRUC (immunodeficient Tbet / and Rag2 / ulcerative colitis) mice [24,25], however, they didn’t induce colitis alone but modify either the healthy gut microbiota composition or its physiology, acting in synergy to activate colon inflammation. Actually, another fact suggesting the role of the commensal flora in CRC is that germfree animals [26], or treated with mildly colitogenic bacterium Bacteroides vulgatus (the azoxymethane (AOM)-treated Il10 L/L model) [27], do not develop tumors. Helicobacter hepaticus infection of the gut enhanced small intestine and colon cancer in APC min/þ mice, but also mammary adenocarcinoma [28] or hepatocarcinomas [29], thus showing systemic tumor-promoting effects. Likewise, infection with Helicobater pylori in humans is an example that a single bacterial species can trigger carcinogenesis, in this case gastric cancer [30]. Other pathogenic species identified while elucidating molecular mechanisms affected by the microbiota were the enteropathogenic Bacteroides fragilis (activated WNT and NF-kB signalling pathways on the carcinogenic cells) and Escherichia coli, also associated with increased risk of CRC (through actions that down-regulate mismatch-repair genes, at least in vitro [11,12,13,14,15, 16,17,31,32]). This enteric microbiota also influences the T helper 17 (Th17) response [33,34] and APC, in particular dendritic cells (DCs), activation [24]. More recently in Nlrp6 L/L mice the expansion of other anaerobic genus of bacterial phyla Bacteroidetes (like Bacteroides), Prevotellaceae (traditionally related to periodontal disease), and TM7 (Saccharibacteria, interestingly, recently cultured from the human oral cavity)in the fecal microbiota correlated with susceptibility to colitis [35,36]. Therefore, at least the NLRP6 receptor of the inflammasome in the innate system [10,12] also regulates colonic microbial ecology. However, although IBDs are the main risk factor for CRC, the relative increased risk for colorectal cancer in these patients is only threefold with respect to the control population, the tumors are generated after many years of intestinal pathology, and the cumulative lifetime risk is 18% [19,20], i.e. most CRCs are not related to any pre-existing obvious intestinal inflammatory disease. 5https://doi.org/10.1016/j.heliyon.2018.e00879 2405-8440/Ó2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Article Nowe00879 2. Main text 2.1. Gut microbiota of oral origin and biofilms in CRC In parallel, high-throughput DNA sequencing developments ignited the identification of microbiota that affected the progression of CRC, not only in the experimental animal models mentioned above [37] but also in humans (in biopsies or stool). The marked over-representation of Fusobacterium nucleatum sequences in CRC tumors relative to control specimens was a striking discovery: Fusobacteria are rare constituents of the fecal microbiota, but had been cultured previously from biopsies of inflamed gut mucosa [21,38], and F. nucleatum in particular is an invasive anaerobe that had been linked previously to periodontitis and appendicitis, but not to cancer. This and the other anaerobic species of the same or similar genera including Bacteroides, or typically oral species such as some Selenomonas,Prevotella, and Parvimonas micra and Peptostreptococcus stomatis, some mentioned in the previous subheadings, are species included in the Human Oral Microbiome Database and also found in the gut microbiota in a significant percentage of CRC, supporting a role for the aggregate of them in CRC [39,40,41], although no microbial feature was universally present in the tumors. This story is very similar to the role that bacteria are playing in the pathogenesis of autoimmune rheumatoid arthritis, opening the door to the study of auto-antibodies against these bacteria both for diagnostic uses and mechanistical studies [42]. Interestingly, these are bacteria capable of forming biofilms. Biofilm structures are a consistent feature of right-sided (proximal) (although not left-sided, distal) CRC. They are constituted by symbionts of Bacteroides fragilis and other mentioned oral pathogens, having tumorigenesis capacity in the mucus layer of the gut [41] by disrupting the normal mucosal barrier, changing the tissue homeostasis, and inducing inflammation [43,44]. In addition, these structures contribute to the polyamine metabolite pool altering the cancer metabolome and inducing colon cancer growth and progression [43,45]. However, bacteria originally studied in oral biofilms were also detected in healthy individuals. It was found that a high abundance of Lachnospiraceae avoided the colonization of colonic tissue by oral-like bacterial networks, suggesting that certain microbiota types can protect against CRC, possibly by conferring colonization resistance. Interestingly, these protective types might be dependent of a healthy diet [39]. Some people expected a future similar to that of Helicobacter pylori and stomach cancer, and recently a mouse model of CRC showed that the antibiotic metronidazole partially impaired colorectal tumor growth [30]. Metronidazole is used for some genitourinary infections, but the target in that study was Fusobacterium 6https://doi.org/10.1016/j.heliyon.2018.e00879 2405-8440/Ó2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Article Nowe00879 nucleatum [30]. One concern of this study, apart of the lack of a F. nucleatum specific antibiotic is that other players are also involved. A novel study in humans has shown that the abundance of F. nucleatum in feces is strongly associated with the presence of CRC but not with the presence of advanced adenomas or non-advanced adenomas, and no association with dietary or lifestyle habits was found [46]. In other study [47], bacterial biofilms found in patients with familial adenomatous polyposis showed increased interleukin-17 and DNA damage in colonic epithelium and faster tumor onset and greater mortality when transplanted to mice. However, their predominant species are Escherichia coli and Bacteroides fragilis [47]. These observations support the hypothesis that Fusobacterium is a passenger that multiplies when the tumor environment is favorable rather than a causal factor in tumorigenesis. Recent reviews [48,49] discuss this issue, concluding that both initiation and progression of CRC require the organization of these higher-order structures of bacterial communities termed biofilms [50]. Flynn et al have proposed a model in which initial changes in the normal gut microbiota allow oral bacteria such as F. nucleatum to colonize the gut mucosa disrupting the epithelial barrier, and to form biofilms with early and late-colonizing microbes; and the persistent state of inflammation in the colon sustaining both the biofilm and the tumorigenesis [50]. Interestingly, although biofilm formation has been explained as a cooperative enterprise of strains and species for a common goal, biofilm formation should be understood as a response to ecological competition [51]. Strikingly, the presence of F. nucleatum in CRC has been related to the process of metastasis, at least to the liver [30] and lymph node [38]. Although the mechanism is unknown, these bacteria might interact with the metastatic cells [30] and not only be present in the mucosal microbiota where they can adhere to epithelial tumor cells or be found inside the cells [30,52]. Very recently it has been suggested that F. nucleatum orchestrates on tumor cells a molecular network of the TLR4 and MyD88 innate immune signaling as well as specific microRNAs that activate the autophagy pathway and mechanistically control CRC chemoresistance [52]. Likewise, there are another examples of biofilms associated with cancer, such as Salmonella typhi and development of gallbladder cancer [53], and others should be expected in the multiple organ systems spanning these microbial networks [54]. In this sense, the use of probiotics should also be tested for a hypothetical long-term effect on metastasis or recurrence in patients with these CRC-related microbiota [51, 55]. Emerging human microbiome intervention strategies have been recently reviewed [18,56,57]. In addition, conventional chemotherapeutic regimens might be affected by this CRC microbiota and/or will modify it. 7https://doi.org/10.1016/j.heliyon.2018.e00879 2405-8440/Ó2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Article Nowe00879 2.2. Obesity, metabolic syndrome, cancer cachexia, stress and microbiota Recent studies have confirmed the association between obesity and cancer susceptibility and survival after detection, including CRC [58,59] despite the so-called “obesity-paradox”[60]. There are still many challenges exploring the association of cancer with overweight and obesity, but consensus exists about that long-term efforts in prevention should remain focused not only on further reduction of smoking but also engaging in healthy lifestyles, balanced diets and regular physical exercise [58,61,62]. Metabolic syndrome is a controversial concept associated with abdominal obesity, blood lipid disorders, inflammation, insulin resistance or full-blown diabetes, and increased risk of developing cardiovascular disease. Abdominal obesity is the most prevalent manifestation of metabolic syndrome and a marker of ‘dysfunctional adipose tissue’[63] or metaflammation [64]. This metabolic inflammatory state is chronic and low-grade, and has been found not only in adipocytes but also in stromal and immune cells of metabolic tissues that include liver, muscle, pancreas or brain, in response to an excess of nutrients and energy [64]. Decades of research have identified the complex signaling networks between immune response and metabolism, and the cellular and molecular events that take place in situations of altered nutrient or energy flows [7,13,14,15,16,65,66]. Maintaining this delicate balance is crucial for health. How risk factors in general interact with commensal flora in colorectal carcinogenesis has been reviewed [7,10,21]. A recent review exposes how obesity alters the microenvironment of adipose tissue affecting the adipokine secretome, with actions on remote tissues [67]. Moreover, adipocytes, like tumor cells and macrophages, also express TLR 2 and 4. These receptors in adipose tissues can be reached not only by nonbacterial agonists such as diet saturated fatty acids, but also by the commensal flora or their bacterial products such as LPS and lipopeptides, and activate them (rev in [11,13,21,68,69]). Obesity is also associated with changes in the composition of the gut microbiota. Overall, bacterial diversity of obese individuals is reduced, in the rate between phylum (an increase in Firmicutes and a corresponding decrease in Bacteroidetes), and in the representation of genes and metabolic pathways that favor energy harvest in bacteria [70]. Intestinal microbiota imbalance (dysbiosis or dismicrobism) has been suggested as the link between IBD, CRC and Type 2 diabetes (T2D) [22,40,41,42,71]. However, the arrival of the concept of enterotype suggests that this knowledge will be enhanced soon [72,73]. Although we did not find any report linking gut 8https://doi.org/10.1016/j.heliyon.2018.e00879 2405-8440/Ó2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Article Nowe00879 Fusobacterium nucleatum with obesity, it has been recently reported a relationship of obesity with the subgingival microbiota in periodontal disease [74]. Inflammation and energy metabolism are linked in the wasting syndrome, also called cancer cachexia, present in many patients of certain types of cancer at advanced stages [75,76,77]. For example, liver metabolism in cachexia leads to suppression of antitumor immunity mainly through IL-6 [78]. Importantly, this axe of interactive metabolic pathways and immune system can be targeted by psychological stress, particularly those pathways mediated by the sympathetic nervous system [79]. For a general review of the tight coordination between the immune and nervous systems see the review by Talbot S et al [80]. The central nervous system also influences the commensal microbiota through several pathways of the gastrointestinal physiology, for example neurotransmitters affecting epithelial functions such as cell permeability and their production of mucus and antibacterial peptides. Conversely, gut microbiota is interacting with local and systemic inflammatory and immune cells and activating the production of inflammatory metabolites such as cytokines that may reach the brain and affect behavior [81, 82,83]. This bidirectional axe nervous system-intestinal microbiota can also be, therefore, targeted by stress. Stress is likely to alter the innate immune responses to pathogens generating dysbiosis. Alteration of the gut enterotypes can modify the inflammatory environment and, with the consequent feedback loop, affect the energy metabolism, not only in the tumor but also systemically. 2.3. CRC prevention by nonsteroidal anti-inflammatory drugs After many studies had shown that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) used in a daily basis for extended periods (at least 5 years of aspirin use) reduced the risk of CRC or polyp recurrence, and a recommendation against its use for the prevention of CRC by the U.S. Preventive Services Task Force (USPSTF) in 2007 [84] because of the considerable damage induced to stomach and intestinal lining, or even brain bleeding [85], the USPSTF reversed that position in 2015 [86,87]. Low-dose aspirin use among certain subgroups of adults distinguished aspirin as the first pharmacologic agent for chemoprevention of cancer in a population not characterized as high risk [88,89]. 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