Recent scientific advances have significantly contributed to our understanding of the complex connection between the microbiome and cancer. Our bodies are continuously exposed to microbial cells, both resident and transient, as well as their byproducts, including toxic metabolites. Circulation of toxic metabolites may contribute to cancer onset or progression at locations distant from where a particular microbe resides. Moreover, microbes may migrate to other locations in the human body and become associated with tumor development. Several case–control metagenomics studies suggest that dysbiosis in the commensal microbiota is also associated with inflammatory disorders and various cancer types throughout the body. Although the microbiome influences carcinogenesis through mechanisms independent of inflammation and immune system, the most recognizable link is between the microbiome and cancer via the immune system, as the resident microbiota plays an essential role in activating, training, and modulating the host immune response. Immunologic dysregulation is likely to provide mechanistic explanations as to how our microbiome influences cancer development and cancer therapies. In this review, we discuss recent developments in understanding the human gut microbiome's relationship with cancer and the feasibility of developing novel cancer diagnostics based on microbiome profiles. Cancer Prev Res; 10(4); 226–34. ©2017 AACR.

Obtaining a comprehensive view of the microbial ecosystems that are associated with the human body (the human microbiome) has become possible with advances in culture-independent “omics” analyses using next-generation sequencing (NGS) techniques (1, 2). Several studies have suggested a correlation between our microbiome and various diseases, including metabolic disorders, gastrointestinal complexities, and infectious diseases (3–6), and to date, thousands of articles focused on the human microbiome in health and disease conditions have been published. The estimated trillions of microbes that inhabit the human body establish a beneficial relationship with the host, but it is clear that dysbiotic relationships can develop, some of which are thought to result in the development of inflammatory diseases and cancers. Several animal models have provided insight on possible mechanisms for microbial cancer triggers, although the situation is complex as both tumor-promoting and antitumor effects have been observed in the presence or absence of particular microbial species (7–11). The microbiota may also induce carcinogenesis through the release of genotoxins that can damage host DNA. This can directly promote carcinogenesis. Bacterial toxins and tumor-promoting metabolites may also lead to chronic inflammation, which in turn may trigger damage to host cells and tissue linings (12, 13). In addition, immunologic dysregulation in response to the resident microbiome may lead to tumor growth (7). There is also an increasing understanding of the composition of the human virome (viruses and bacteriophages), particularly in the gut and oral cavity (14–17). The normal gut virome is proposed to have a role in protective immunity during gut inflammation (18).

The variability of microbial populations and physiologic environments at different sites of the human body suggests that microbial mechanisms and species that are involved in cancer onset will also vary depending on the location. Impaired microbiota can facilitate carcinogenesis through a variety of mechanisms that have been reported in the literature (12, 13). This minireview focuses on cancers promoted by pathogens and immune system–mediated mechanisms.

Cancers triggered or promoted by specific pathogens

Pathogens promote cancer development through well-described genetic mechanisms (13). There are 10 specific biological agents that have been designated by the International Agency for Cancer Research as carcinogenic to humans (19). One of them, Helicobacter pylori (H. pylori) colonizes the gastric mucosa of half of the world's population (20) and induces chronic gastric inflammation, which can progress toward gastric carcinoma. Although only about 1% to 3% of H. pylori–colonized individuals develop gastric cancer, it substantially contributes to global cancer mortality (21–23). The mechanism by which H. pylori induces onset of gastric cancer is largely attributed to the presence of cytotoxin-associated gene A (CagA) and secretion of virulence factors, such as VacA, urease, and NapA2, to promote chronic inflammation, oxidative stress, and host DNA damage, which can contribute to carcinogenesis (24–26). The pathogen uses the type IV secretion system to translocate CagA to gastric epithelial cells, which aberrantly modulates β-catenin to increase propensity for gastric cancer (27) (Fig. 1A). Chronic bacterial infections can also promote host genetic instability (28). For example, mice chronically infected with H. pylori show a 4-fold increase in mutation frequency compared with uninfected mice (29). However, studies in germ-free mice have shown that H. pylori alone is less likely to induce gastric cancer. The germ-free mice co-colonized with complex intestinal flora and H. pylori synergistically promote invasive gastrointestinal intraepithelial neoplasia (GIN) in 80% of mice, whereas only 10% of H. pylori only–colonized males developed GIN, with less severe gastric lesions and significantly delayed onset of GIN (30). The mice co-colonized with complex intestinal flora and H. pylori developed more severe gastric pathology, and the mice co-colonized with H. pylori and restricted altered Schaedler flora (Clostridium species, Lactobacillus murinus, and Bacteriodes species) were only slightly less severe (31). Interestingly H. pylori infection is also associated with decreased risk of esophageal adenocarcinoma, highlighting the complexity of microbial effects on tissue-specific carcinogenesis (32).

Figure 1.

Mechanisms by which microbes promote carcinogenesis. A, Microbes inject effectors into the host cells. These effectors modulate the Wnt/β-catenin signaling by activating β-catenin. For example, H. pylori effector protein CagA interacts with E-cadherin and disassociates the E-cadherin/β-catenin protein complex, which leads to increased accumulation of cytoplasmic and nuclear β-catenin. β-Catenin complexes with TCF/LEF transcription factors and activates target gene expression. F. nucleatum modulates β-catenin signaling via its FadA protein. Aberrant β-catenin signaling is associated with tumorigenesis and progression. Prolonged exposure to H. pylori protein VacA prevents autophagy. The interaction between F. nucleatum Fap2 protein and host polysaccharide (Gal-GalNAc) mediates F. nucleatum colonization in colorectal cancer. F. nucleatum mediates tumor-immune evasion via TIGIT. The Fap2 protein secreted by F. nucleatum interacts with TIGIT and inhibits natural killer (NK) cellmediated immunosurveillance of cancer. B, Several human viruses, including HPV, HBV, HCV, HTLV, EBV, and KSHV, are known to cause various cancers. They encode oncoproteins and pathways that have been shown to transform nonpermissive cell types and induce tumors in animal models. During active infection and latent phase, these cancer-causing viruses modify epigenetic programs and impair DNA repair mechanisms in various ways. These subversions lead to host genome instability, a hallmark of carcinogenesis. C, Proinflammatory signaling, as a result of barrier failure, induces genomic instability and chronic inflammation, hallmarks for carcinogenesis. D, Dysbiosis and altered microbiota–host interaction can induce carcinogenesis through various mechanisms; increased bacterial translocation and immune dysregulation are shown as examples. Microorganism-associated molecular patterns (MAMP) are recognized by TLRs in several cell types. Activation of TLRs by MAMPs and other microbial products contributes to carcinogenesis. For example, TLR4, the receptor for LPS component of the Gram-negative bacterial cell wall, promotes hepatocellular and pancreatic cancer colon cancer. TLR-induced NF-κB and STAT3 activation are key cancer-promoting signaling pathways. Microbiota-induced immune dysregulation can initiate inflammasomes-associated immune response and TLR-activated autophagy.

Figure 1.

Mechanisms by which microbes promote carcinogenesis. A, Microbes inject effectors into the host cells. These effectors modulate the Wnt/β-catenin signaling by activating β-catenin. For example, H. pylori effector protein CagA interacts with E-cadherin and disassociates the E-cadherin/β-catenin protein complex, which leads to increased accumulation of cytoplasmic and nuclear β-catenin. β-Catenin complexes with TCF/LEF transcription factors and activates target gene expression. F. nucleatum modulates β-catenin signaling via its FadA protein. Aberrant β-catenin signaling is associated with tumorigenesis and progression. Prolonged exposure to H. pylori protein VacA prevents autophagy. The interaction between F. nucleatum Fap2 protein and host polysaccharide (Gal-GalNAc) mediates F. nucleatum colonization in colorectal cancer. F. nucleatum mediates tumor-immune evasion via TIGIT. The Fap2 protein secreted by F. nucleatum interacts with TIGIT and inhibits natural killer (NK) cellmediated immunosurveillance of cancer. B, Several human viruses, including HPV, HBV, HCV, HTLV, EBV, and KSHV, are known to cause various cancers. They encode oncoproteins and pathways that have been shown to transform nonpermissive cell types and induce tumors in animal models. During active infection and latent phase, these cancer-causing viruses modify epigenetic programs and impair DNA repair mechanisms in various ways. These subversions lead to host genome instability, a hallmark of carcinogenesis. C, Proinflammatory signaling, as a result of barrier failure, induces genomic instability and chronic inflammation, hallmarks for carcinogenesis. D, Dysbiosis and altered microbiota–host interaction can induce carcinogenesis through various mechanisms; increased bacterial translocation and immune dysregulation are shown as examples. Microorganism-associated molecular patterns (MAMP) are recognized by TLRs in several cell types. Activation of TLRs by MAMPs and other microbial products contributes to carcinogenesis. For example, TLR4, the receptor for LPS component of the Gram-negative bacterial cell wall, promotes hepatocellular and pancreatic cancer colon cancer. TLR-induced NF-κB and STAT3 activation are key cancer-promoting signaling pathways. Microbiota-induced immune dysregulation can initiate inflammasomes-associated immune response and TLR-activated autophagy.

Close modal

Metagenomics and transcriptomics studies provide insights into the relationship between Fusobacterium nucleatum (F. nucleatum) and colorectal cancer. Several case–control human cohort studies found higher abundance of Fusobacterium spp. in colorectal adenomas compared with controls (33, 34). F. nucleatum introduction to a mouse model of intestinal tumorigenesis accelerated tumor development and modulated the tumor microenvironment through an NF-κB–driven proinflammatory response without inducing more widespread inflammation (35). Rubinstein and colleagues demonstrated that F. nucleatum promotes colorectal cancer by modulating E-cadherin/β-catenin signaling via its FadA protein (Fig. 1A; ref. 36), FadA binding to E-cadherin inhibits the latter's tumor-suppressive activity. Conversely, inhibition of FadA binding to E-cadherin using an inhibitory peptide abolishes the host inflammatory response and tumor growth (36). A recent study by Abed and colleagues investigated mechanisms underlying fusobacterial attachment to and invasion of colonic adenomas and colorectal cancer (37). The investigators observed that a host polysaccharide, Gal-GalNAc, is overexpressed in colorectal cancer and readily recognized by fusobacterial protein Fap2 to mediate F. nucleatum attachment to colorectal cancer (37) (Fig. 1A). F. nucleatum also mediates tumor-immune evasion via the T-cell immunoreceptor with Ig and ITIM domains (TIGIT). The Fap2 proteins, secreted by F. nucleatum, interact with TIGIT and inhibit the natural killer cell-mediated immunosurveillance of cancer (Fig. 1A; ref. 78).

Cancers promoted by viruses

The composition and role of the human virome in health is not well understood. However, there are viruses that are known to cause various cancers, some of which are sufficiently prevalent in the population to be considered part of the human virome. Recognized associations include human papillomaviruses (HPV) causing cervical carcinoma, hepatitis B (HBV) and C viruses (HCV) being the causative agents of hepatocellular carcinomas, human T-cell leukemia virus-1 (HTLV) being involved in T-cell leukemia, Epstein–Barr virus (EBV) being involved in B-cell lymphoproliferative diseases and nasopharyngeal carcinoma, and Kaposi sarcoma–associated herpesvirus (KSHV) being the etiologic factor for Kaposi sarcoma and primary effusion lymphomas (38–40). Human polyomaviruses such as Merkel cell polyomavirus (MCV) and Simian Virus 40 (SV40) are implicated in Merkel cell carcinoma (MCC) and mesothelioma, respectively (38, 39). In addition, MCV, which is highly prevalent virus in the general population, can lead to an aggressive form of skin cancer in the elderly and immunosuppressed individuals (41). These viruses contributed to about 1.3 million new cancer cases worldwide in 2008, demonstrating the importance of fully understanding their biology (19). The mechanisms by which these viruses cause cancer are quite complex. They encode oncoproteins and pathways that have been shown to transform nonpermissive cell types and induce tumors in animal models (38–40). During active infection, these cancer-causing viruses exploit host cell machinery to perform their own replication, including altering cellular structures, manipulating signaling pathways, modifying epigenetic programs, and impairing DNA repair mechanisms in various ways. Together, these subversions ultimately lead to genome instability, a hallmark of cancer (Fig. 1B; ref. 39). There is the added complication in that many of these viruses either integrate into the host genome (HPV, HTLV-1, and HBV among others) or are maintained as latent episomal genomes (EBV and KSHV), resulting in lifetime infections. For HPV, integration of its genome into the host is a central mechanism of oncogenesis because it results in the overexpression of the viral E6 and E7 genes, which synergistically act to immortalize host cells (38). The MCV genome is clonally integrated in the majority of MCC tumors and its regulatory small T antigen acts as a potent oncogene capable of inducing cell transformation (42, 43). For the latent viruses, even though almost all the viral gene expression is silenced, certain viral genes, including oncogenes, are expressed and manipulate pathways that can lead to genome instability (38, 39).

The epidemiologic association of these viruses with cancer is complicated by the fact that several viruses are highly prevalent in the human population. However, the malignancies that they are associated with are relatively rare and require genetic and/or environmental cofactors to develop. For example, seroprevalence of EBV is >80% in the United States (44). EBV is the causative agent of, and is associated with, all cases of nasopharyngeal cancer, which has particularly high incidence in specific geographic locations, suggesting that there are additional important cofactors for the development of disease (38). The virus may also act as a cofactor, as with Burkitt lymphoma where EBV is present in nearly 100% of Burkitt lymphoma cancers, but is not itself the causative agent (45). Burkitt lymphoma is caused by chromosomal translocations that deregulate the proto-oncogenic c-myc gene. There is evidence that Burkitt lymphoma cofactors EBV and malaria protect cells from c-myc–induced apoptosis and expand the number of EBV+ germinal center cells from which the lymphoma arises, respectively (46, 47). EBV is also associated with a subset of cases of Hodgkin disease and gastric cancers but is not causative (38). Interestingly, EBV viral gene expression is distinct in each of these malignancies because they arise at different stages of the viral life cycle (45). The varied interactions of EBV and other cofactors in a number of cancer types demonstrate the complicated interplay of contributing factors in cancer genesis and progression.

Barrier failure and microbial toxins

Anatomic separation of intestinal microbiota from the host epithelial cells is critical for regulating immune activation and upholding mutualistic host–microbial associations (12, 48). The goblet cells produce intestinal mucus and Paneth cells produce antimicrobial peptides, which contribute to the separation of host and microbial compartments across the mucosal interface, which limits interaction between the microbiome and immune system (49, 50). Disrupted barrier function may trigger inflammation and carcinogenesis. Ulcerative colitis and Crohn disease are well-known examples of intestinal barrier dysfunction and contribute to the risk of colon cancers (51–53) (Fig. 1C). A genome-wide association study suggests an association between colorectal tumor risk and polymorphisms in crucial barrier proteins, such as laminins (13, 54). Experiments in laboratory animals have shown that reduction of mucus or induced barrier failure increase the circulation of carcinogens through a disrupted gut, leading to the development of intestinal adenocarcinoma as well as tumors in distant organs (55, 56).

Impaired barrier function allows bacterial access to intestinal epithelium, which enables delivery of toxins. Bacterial toxins, such as colibactin-expressing Escherichia coli (encoded within the pks genomic island), potentiate colorectal cancer in azoxymethane-exposed mice (57). Toxins produced by enterotoxigenic Bacteroides fragilis (B. fragilis) have been associated with acute inflammatory bowel disease (58), and colorectal neoplasia, especially in late-stage colorectal cancer (59). Similarly, several Gram-negative bacteria produce cytolethal distending toxin (CDT) that together with colibactin can cause DNA damage in mammalian cells. Chronic exposure to CDT promotes genomic instability in fibroblasts and colon epithelial cells (60). As stated earlier, genome instability is a hallmark of cancer.

Intestinal microbiota and their metabolites impact the development of cancer in sites distant from the intestine. For example, the liver does not contain a known microbiome. Yet, intestinal bacteria promote hepatocellular carcinoma (also caused by HBV and HCV) via inflammatory microorganism-associated molecular patterns and bacterial metabolites, which can circulate to distant sites (8, 13, 61). Sustained accumulation of lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, also promotes inflammation-associated hepatocarcinogenesis in animal models (61). Although mouse models have shown that gut commensal microflora and dietary fiber may protect against colonic inflammation and colon cancer through the microbe-produced metabolite butyrate (62–64), data from another study show the opposite effect (65). These studies, which are outside of the scope of the current review, highlight the issues when comparing microbiome studies across different research groups, as well as challenges in translating research data to consensus guidelines for dietary interventions to prevent cancer risks. Further investigation is required to delineate the role of butyrate and other diet-induced metabolites in carcinogenesis.

Gut microbiome and cancer

Although findings that associate the human microbiome with cancers are preliminary in nature, some hint at possible new microbe–cancer relationships that were not observed before the advent of high-throughput sequencing. This is likely due to the difficulty associated with cultivating microbial species, with an estimated less than 30% of human microbial species being culturable in the laboratory, and recent studies have suggested in some cases polymicrobial disease causation. In addition to human studies, there have been many studies performed in animal models, and some of these observations are outlined below.

One of the most deadly cancers is esophageal cancer. This is a disease that evolves from inflammation due to reflux esophagitis to metaplasia (Barrett esophagus; refs. 66, 67). The disease is possibly the result of several complicating factors, including antibiotics usage, diet, and smoking. Recent studies have shown a potential role of the microbiome in the esophagus in healthy and disease conditions (68). Microbiome analyses of the normal and esophagitis or Barrett esophagus biopsy samples reveal a significant difference between the microbiome of normal esophagus, which is dominated by the genus Streptococcus and the microbiome of esophagitis and Barrett esophagus with an increase in the relative abundance of Gram-negative anaerobic species (69). Similarly, Gall and colleagues observed that Streptococcus was the most prevalent genus in normal esophagus or reflux esophagitis versus Veillonella in Barrett esophagus; Fusobacterium was found only in patients with reflux esophagitis or Barrett esophagus but not in a normal esophagus (70). Another study in Barrett esophagus cohort found an association between the ratio of Streptococcus to Prevotella species and abdominal obesity as well as hiatal hernia length, which are two known esophageal adenocarcinoma risk factors in Barrett esophagus (70). To address a role for infectious disease species and the human microbiome in this disease etiology, our team recently performed NGS on gastroesophageal reflux disease samples derived from 121 subjects in different phenotypic groups (unpublished data). Samples for NGS were collected from the mouth, esophagus, stomach, and colon, and the resulting sequences clustered into 1,607 operational taxonomic units. We observed that the overall community composition was affected by body site and disease phenotype. Several bacterial phyla had significant correlations with disease stage. In the esophagus, Firmicutes was the only phylum with a significant positive correlation to disease.

Expression of pattern recognition receptors, such as Toll-like receptors (TLR), is known to be progressively increased in different stages of gastric cancer (Fig. 1D; refs. 71, 72). Whereas TLRs are localized to the apical and basolateral compartments in normal gastric epithelial cells, they become homogeneously distributed in tumor cells (73, 74). Interestingly, a similar paradigm has recently been observed in esophageal cancer. When the expression of TLR1, TLR2, TLR4, and TLR6 was examined in esophageal specimens from patients using IHC, expression for all of these TLRs was found to increase in Barrett mucosa and dysplasia and remain high in adenocarcinoma (75). Moreover, high expression of TLR4 in the nucleus and the cytoplasm was associated with metastasis and poor prognosis (75). Various cancer cells, including cells of an esophageal cancer cell line, demonstrated cellular invasion in an in vitro Matrigel assay when stimulated with DNA, a TLR9 ligand (76). A future challenge will be to define microbial interactions involving TLRs in an effort to understand cancer progression in the esophagus.

Although imbalances in the gut microbiota have been linked to colorectal adenomas and cancer, only Fusobacterium has been identified as a risk factor. Fusobacterium has been found to be associated with colorectal tumor tissue in several different studies (33, 77), but the presence of Porphyromonas species as well suggests the possibility of a polymicrobial disease trigger. In addition, other studies have identified Peptostreptococcus, Prevotella, Parvimonas, Leptotrichia, Campylobacter, and Gemella as additional genera that are associated with the detection of colorectal cancer (79). In studies of colon cancer, Zackular and colleagues used 16S rRNA gene signatures from the stool samples of healthy, precancerous adenomas, and colon cancer in humans to demonstrate that the feces of people with cancer tended to have an altered composition of bacteria, with an excess of the common mouth microbes, Fusobacterium or Porphyromonas (80). Similarly, Zeller his colleagues showed that the metagenomic profiling of fecal samples from colorectal cancer patients in comparison with tumor‐free controls reveals associations between the gut microbiota and cancer, distinguishing sample types with similar accuracy as the fecal occult blood test, used for clinical screening. Two Fusobacterium species, Porphyromonas asaccharolytica and Peptostreptococcus stomatis, were enriched in colorectal cancer patients (81). In addition, metatranscriptome data revealed a significant overrepresentation and cooccurrence of Fusobacterium, Campylobacter, and Leptotrichia genera in colorectal cancer tumor samples. These are Gram-negative anaerobes that are generally considered to be oral bacteria, but the tumor isolates of Fusobacterium and Campylobacter are genetically diverged from their oral complements (79). The Campylobacter isolate Campylobacter showae from the colorectal tumor was substantially diverged from their oral isolate (79). Other cancer-associated microbiome studies exist, although the cohorts used have invariably been relatively small. For example, to evaluate microbial association in oral cancers, Schmidt and colleagues (82) sequenced microbial DNA derived from cancer and normal tissues (matched) in patients. Comparison of 16S rRNA gene V4 data from these samples revealed changes in the abundance of Actinobacteria and Firmicutes between oral cancer and normal tissues (82).

Experiments with germ-free animals have helped to clarify causality between dysbiosis and cancer. For example, T-cell receptor β-chain and p53 knockout mice have the propensity to develop malignant tumors. When germ-free mice with the knockouts were colonized with gut microbiota, 70% of the animals developed adenocarcinomas in the colon, as expected. However, control germ-free animals did not develop adenocarcinomas in the same timeframe (83). Similarly, mice with a mutation in the tumor suppressor gene APC (adenomatous polyposis coli) had reduced occurrence of intestinal tumors when they were rendered germ free, as opposed to specific pathogen free, suggesting that commensal bacteria play a pathogenic role in this system (84). Tumors in the specific pathogen-free mice showed profiles of inflammation, signs of barrier damage, and activation of c-Jun/JNK and STAT3 pathways (84). An inflammation-based murine model can be generated by treating a normal mouse with the chemical carcinogen azoxymethane, followed by dextran sodium sulfate (85). When an antibiotic cocktail was administered in this model, the rate of colon tumors was reduced, although the total number of bacteria appeared to be unchanged, suggesting that specific species contribute to tumorigenesis (86). When germ-free mice were colonized with microbiota from cancer-bearing mice, the rate of tumors was higher than with microbiota from healthy mice (86). The demonstration of reduced frequencies of tumors in germ-free mice provides support for studies in which specific microbes added to conventional mice resulted in increased frequencies of cancer. Examples of specific microbes are F. nucleatum and enterotoxigenic B. fragilis as discussed above. Reconstitution of specific microbiotas in germ-free mice is an exciting approach for dissecting the network of microbial and host interactions involved in dysbiosis, inflammation, and cancer.

Immunoregulation and microbiome

Microbiota plays a significant, albeit incompletely mapped, role in the shaping of innate and acquired immunity (87). This process starts during the constitution of the microbial flora at birth, influencing the maturation of the immune system and the development of tolerance and containment of the microbiome (87–89). It continues throughout life via signaling by innate immunity receptors, through sampling of the microbiota by the acquired immune response, and by the generation of metabolic products (90, 91). The central role of immunity in the biology of cancer calls for attention to the exact contribution of microbiota in oncogenesis. For example, data from germ-free and antibiotic-treated mice suggest a diminished response to CpG stimulation in the setting of cancer immunotherapy (92). Upregulation of TLRs by LPS and other microbial products can activate the NF-κB, c-Jun/JNK, and JAK/STAT3 pathways that have well-defined roles in cell proliferation and immunosuppression (Fig. 1D; refs. 12, 93). More generally, the use of antibiotics in the clinical care of individuals with cancer, particularly during periods of immunosuppression, may interfere with effective anticancer immune responses (94).

Microbiome, autophagy, and cancer

Autophagy is a membrane-trafficking mechanism that delivers cytoplasmic constituents into the lysosome for protein degradation. Autophagy plays a significant role in the maintenance of cellular homeostasis. The role of autophagy in cancer is complex and context dependent. In preclinical models of carcinogenesis, autophagy prevents malignant transformation by degrading potentially harmful entities inside the cell but, later, promotes the growth of established tumors (95). One function of autophagy is to prevent intracellular viral and bacterial infection and control inflammation through innate immune signaling pathways (Fig. 1D; ref. 96). Many bacteria have evolved mechanisms to prevent degradation by autophagy, including H. pylori (97). Prolonged exposure to H. pylori protein VacA prevents autophagosome maturation, and the bacteria are able to persist in these compartments (98). This promotes an environment that favors carcinogenesis by the accumulation of damaged organelles and protein aggregates, persistent H. pylori infection, and chronic inflammation. The effect of autophagy on carcinogenesis also appears to be tissue specific, and its effects can be mediated through the microbiome. In the pancreas and lung, inhibition of autophagy predisposes the tissue to lesions (95). However, in models of colorectal cancer, the inhibition of autophagy prevents the development of precancerous lesions (99). The antitumor effects of this inhibition are mediated through the gut microbiome, as autophagy deficiency led to changes in the intestinal microbial community, and treatment with broad-spectrum antibiotics impairs the protective CD8+ antitumoral responses, and induced intestinal lesions (99).

As the scientific community continues to generate more microbiome data, and integrate other “omics” types such as transcriptomics, proteomics, and metabolomics from well-phenotyped cohorts, we will identify novel microbial signatures that are associated with disease onset and progression in many diseases, including cancer. These microbiome signatures (including circulating metabolites) have the potential to be developed into diagnostics and therapeutics. Our team, for example, recently studied the microbiome in childhood leukemia patients (an estimated 15,000 children under the age of 19 are diagnosed with leukemia, lymphoma, and other tumors in the United States every year) with the goal of measuring microbiome changes associated with disease onset (100). Our other goal was to identify novel therapies that could be developed for compromises associated with chemotherapy treatment. Known side effects of chemotherapeutic treatments often include drug-induced gastrointestinal mucositis with diarrhea, constipation, and increased risk of gastrointestinal infections. In our study, the gastrointestinal microbiomes of pediatric and adolescent patients with acute lymphoblastic leukemia were profiled by 16S rDNA gene sequencing before and during a chemotherapy course and compared with equivalent 16S rDNA data from their healthy siblings. The microbiome profiles of patients before chemotherapy and the control group were dominated by members of the genera Bacteroides, Prevotella, and Faecalibacterium, with these having mean relative abundances of 62.2%, 7.3%, and 6.4% respectively, in the patient group, and 40.2%, 12.2%, and 8.3% respectively, in the control group. Microbiome diversity, measured as the Shannon diversity index, of the patient group was significantly lower than that of the sibling control group, and discriminatory taxa included Anaerostipes, Coprococcus, Roseburia, and Ruminococcus, all of which had lower relative abundance in the disease group. This study is another example illustrating the potential for use of microbiome signatures that are associated with disease onset and progression to develop noninvasive approaches in cancer diagnosis.

Continued evaluation of the mechanisms used by microbes to trigger diseases will also enable the identification of therapeutic approaches, including the use of pre- and probiotics to restore a healthy microbiome and possibly to offset some of the impacts of toxic therapies. It has also been shown in murine models that commensal microbiota modulate the efficacy of anticancer therapy through the immune response. Loss of the microbiome decreased TNF expression, decreased proinflammatory cytokines, and reduced the production of reactive oxygen species, leading to impaired tumor regression and survival (92). Loss of the microbiome was also shown to reduce the stimulation of pathogenic Th 17 cells and eliminate chemotherapy effectiveness. Therefore, the efficacy of treatment may be improved through combined anticancer therapy with probiotics. When combined with novel approaches to vaccine design through synthetic biology, there are several opportunities for decreasing cancer incidence as a result of understanding our microbiome.

In this minireview, we presented a brief overview of recent history and advances that have been made with respect to understanding our microbiome and the development or correlation with cancer and future avenues of research that will be beneficial to this space, including the development of novel diagnostics, vaccines, and other therapeutic approaches to treatment.

J.C. Venter is the co-founder, executive chairman, at Human Longevity, Inc., the founder, chairman, and chief executive officer at J. Craig Venter Institute, has received speakers bureau honoraria from The Harry Walker Agency, and has ownership interest (including patents) in Human Longevity, Inc., Synthetic Genomics, Inc., and J. Craig Venter Institute. A. Telenti is the chief data scientist at Human Longevity, Inc. No potential conflicts of interest were disclosed by the other authors.

S.V. Rajagopala was funded by Hyundai Motor America and Hyundai Hope on Wheels and K.E. Nelson by the J. Craig Venter Institute.

1.
Arumugam
M
,
Raes
J
,
Pelletier
E
,
Le Paslier
D
,
Yamada
T
,
Mende
DR
, et al
Enterotypes of the human gut microbiome
.
Nature
2011
;
473
:
174
80
.
2.
Human Microbiome Project C
. 
A framework for human microbiome research
.
Nature
2012
;
486
:
215
21
.
3.
Karlsson
F
,
Tremaroli
V
,
Nielsen
J
,
Backhed
F
. 
Assessing the human gut microbiota in metabolic diseases
.
Diabetes
2013
;
62
:
3341
9
.
4.
Le Chatelier
E
,
Nielsen
T
,
Qin
J
,
Prifti
E
,
Hildebrand
F
,
Falony
G
, et al
Richness of human gut microbiome correlates with metabolic markers
.
Nature
2013
;
500
:
541
6
.
5.
Pedersen
HK
,
Gudmundsdottir
V
,
Nielsen
HB
,
Hyotylainen
T
,
Nielsen
T
,
Jensen
BA
, et al
Human gut microbes impact host serum metabolome and insulin sensitivity
.
Nature
2016
;
535
:
376
81
.
6.
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
.
7.
Chen
GY
,
Shaw
MH
,
Redondo
G
,
Nunez
G
. 
The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis
.
Cancer Res
2008
;
68
:
10060
7
.
8.
Dapito
DH
,
Mencin
A
,
Gwak
GY
,
Pradere
JP
,
Jang
MK
,
Mederacke
I
, et al
Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4
.
Cancer Cell
2012
;
21
:
504
16
.
9.
Dove
WF
,
Clipson
L
,
Gould
KA
,
Luongo
C
,
Marshall
DJ
,
Moser
AR
, et al
Intestinal neoplasia in the ApcMin mouse: independence from the microbial and natural killer (beige locus) status
.
Cancer Res
1997
;
57
:
812
4
.
10.
Grivennikov
SI
,
Wang
K
,
Mucida
D
,
Stewart
CA
,
Schnabl
B
,
Jauch
D
, et al
Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth
.
Nature
2012
;
491
:
254
8
.
11.
Reddy
BS
,
Narisawa
T
,
Wright
P
,
Vukusich
D
,
Weisburger
JH
,
Wynder
EL
. 
Colon carcinogenesis with azoxymethane and dimethylhydrazine in germ-free rats
.
Cancer Res
1975
;
35
:
287
90
.
12.
Garrett
WS
. 
Cancer and the microbiota
.
Science
2015
;
348
:
80
6
.
13.
Schwabe
RF
,
Jobin
C
. 
The microbiome and cancer
.
Nat Rev Cancer
2013
;
13
:
800
12
.
14.
Columpsi
P
,
Sacchi
P
,
Zuccaro
V
,
Cima
S
,
Sarda
C
,
Mariani
M
, et al
Beyond the gut bacterial microbiota: The gut virome
.
J Med Virol
2016
;
88
:
1467
72
.
15.
Hannigan
GD
,
Meisel
JS
,
Tyldsley
AS
,
Zheng
Q
,
Hodkinson
BP
,
SanMiguel
AJ
, et al
The human skin double-stranded DNA virome: topographical and temporal diversity, genetic enrichment, and dynamic associations with the host microbiome
.
mBio
2015
;
6
:
e01578
15
.
16.
Lopetuso
LR
,
Ianiro
G
,
Scaldaferri
F
,
Cammarota
G
,
Gasbarrini
A
. 
Gut virome and inflammatory bowel disease
.
Inflamm Bowel Dis
2016
;
22
:
1708
12
.
17.
Pride
DT
,
Salzman
J
,
Haynes
M
,
Rohwer
F
,
Davis-Long
C
,
White
RA
 III
, et al
Evidence of a robust resident bacteriophage population revealed through analysis of the human salivary virome
.
ISME J
2012
;
6
:
915
26
.
18.
Yang
JY
,
Kim
MS
,
Kim
E
,
Cheon
JH
,
Lee
YS
,
Kim
Y
, et al
Enteric viruses ameliorate gut inflammation via toll-like receptor 3 and toll-like receptor 7-mediated interferon-beta production
.
Immunity
2016
;
44
:
889
900
.
19.
de Martel
C
,
Ferlay
J
,
Franceschi
S
,
Vignat
J
,
Bray
F
,
Forman
D
, et al
Global burden of cancers attributable to infections in 2008: a review and synthetic analysis
.
Lancet Oncol
2012
;
13
:
607
15
.
20.
Suerbaum
S
,
Michetti
P
. 
Helicobacter pylori infection
.
N Engl J Med
2002
;
347
:
1175
86
.
21.
Parkin
DM
. 
The global health burden of infection-associated cancers in the year 2002
.
Int J Cancer
2006
;
118
:
3030
44
.
22.
Polk
DB
,
Peek
RM
 Jr
. 
Helicobacter pylori: gastric cancer and beyond
.
Nat Rev Cancer
2010
;
10
:
403
14
.
23.
Uemura
N
,
Okamoto
S
,
Yamamoto
S
,
Matsumura
N
,
Yamaguchi
S
,
Yamakido
M
, et al
Helicobacter pylori infection and the development of gastric cancer
.
N Engl J Med
2001
;
345
:
784
9
.
24.
Hardbower
DM
,
de Sablet
T
,
Chaturvedi
R
,
Wilson
KT
. 
Chronic inflammation and oxidative stress: the smoking gun for Helicobacter pylori-induced gastric cancer?
Gut Microbes
2013
;
4
:
475
81
.
25.
Koeppel
M
,
Garcia-Alcalde
F
,
Glowinski
F
,
Schlaermann
P
,
Meyer
TF
. 
Helicobacter pylori infection causes characteristic DNA damage patterns in human cells
.
Cell Rep
2015
;
11
:
1703
13
.
26.
Wroblewski
LE
,
Peek
RM
 Jr
. 
Helicobacter pylori in gastric carcinogenesis: mechanisms
.
Gastroenterol Clin North Am
2013
;
42
:
285
98
.
27.
Muller
A
. 
Multistep activation of the Helicobacter pylori effector CagA
.
J Clin Invest
2012
;
122
:
1192
5
.
28.
Machado
AM
,
Figueiredo
C
,
Touati
E
,
Maximo
V
,
Sousa
S
,
Michel
V
, et al
Helicobacter pylori infection induces genetic instability of nuclear and mitochondrial DNA in gastric cells
.
Clin Cancer Res
2009
;
15
:
2995
3002
.
29.
Touati
E
,
Michel
V
,
Thiberge
JM
,
Wuscher
N
,
Huerre
M
,
Labigne
A
. 
Chronic Helicobacter pylori infections induce gastric mutations in mice
.
Gastroenterology
2003
;
124
:
1408
19
.
30.
Lofgren
JL
,
Whary
MT
,
Ge
Z
,
Muthupalani
S
,
Taylor
NS
,
Mobley
M
, et al
Lack of commensal flora in Helicobacter pylori-infected INS-GAS mice reduces gastritis and delays intraepithelial neoplasia
.
Gastroenterology
2011
;
140
:
210
20
.
31.
Lertpiriyapong
K
,
Whary
MT
,
Muthupalani
S
,
Lofgren
JL
,
Gamazon
ER
,
Feng
Y
, et al
Gastric colonisation with a restricted commensal microbiota replicates the promotion of neoplastic lesions by diverse intestinal microbiota in the Helicobacter pylori INS-GAS mouse model of gastric carcinogenesis
.
Gut
2014
;
63
:
54
63
.
32.
Xie
FJ
,
Zhang
YP
,
Zheng
QQ
,
Jin
HC
,
Wang
FL
,
Chen
M
, et al
Helicobacter pylori infection and esophageal cancer risk: an updated meta-analysis
.
World J Gastroenterol
2013
;
19
:
6098
107
.
33.
Kostic
AD
,
Gevers
D
,
Pedamallu
CS
,
Michaud
M
,
Duke
F
,
Earl
AM
, et al
Genomic analysis identifies association of Fusobacterium with colorectal carcinoma
.
Genome Res
2012
;
22
:
292
8
.
34.
McCoy
AN
,
Araujo-Perez
F
,
Azcarate-Peril
A
,
Yeh
JJ
,
Sandler
RS
,
Keku
TO
. 
Fusobacterium is associated with colorectal adenomas
.
PLoS One
2013
;
8
:
e53653
.
35.
Kostic
AD
,
Chun
E
,
Robertson
L
,
Glickman
JN
,
Gallini
CA
,
Michaud
M
, et al
Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment
.
Cell Host Microbe
2013
;
14
:
207
15
.
36.
Rubinstein
MR
,
Wang
X
,
Liu
W
,
Hao
Y
,
Cai
G
,
Han
YW
. 
Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/beta-catenin signaling via its FadA adhesin
.
Cell Host Microbe
2013
;
14
:
195
206
.
37.
Abed
J
,
Emgard
JE
,
Zamir
G
,
Faroja
M
,
Almogy
G
,
Grenov
A
, et al
Fap2 mediates fusobacterium nucleatum colorectal adenocarcinoma enrichment by binding to tumor-expressed Gal-GalNAc
.
Cell Host Microbe
2016
;
20
:
215
25
.
38.
Pagano
JS
,
Blaser
M
,
Buendia
MA
,
Damania
B
,
Khalili
K
,
Raab-Traub
N
, et al
Infectious agents and cancer: criteria for a causal relation
.
Semin Cancer Biol
2004
;
14
:
453
71
.
39.
Weitzman
MD
,
Weitzman
JB
. 
What's the damage? The impact of pathogens on pathways that maintain host genome integrity
.
Cell Host Microbe
2014
;
15
:
283
94
.
40.
Xu
W
,
Liu
Z
,
Bao
Q
,
Qian
Z
. 
Viruses, other pathogenic microorganisms and esophageal cancer
.
Gastrointest Tumors
2015
;
2
:
2
13
.
41.
Liu
W
,
MacDonald
M
,
You
J
. 
Merkel cell polyomavirus infection and Merkel cell carcinoma
.
Curr Opin Virol
2016
;
20
:
20
7
.
42.
Shuda
M
,
Kwun
HJ
,
Feng
H
,
Chang
Y
,
Moore
PS
. 
Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator
.
J Clin Invest
2011
;
121
:
3623
34
.
43.
Wu
JH
,
Simonette
RA
,
Nguyen
HP
,
Rady
PL
,
Tyring
SK
. 
Merkel cell polyomavirus in Merkel cell carcinogenesis: small T antigen-mediates c-Jun phosphorylation
.
Virus Genes
2016
;
52
:
397
9
.
44.
Dowd
JB
,
Palermo
T
,
Brite
J
,
McDade
TW
,
Aiello
A
. 
Seroprevalence of Epstein-Barr virus infection in U.S. children ages 6–19, 2003–2010
.
PLoS One
2013
;
8
:
e64921
.
45.
Thorley-Lawson
DA
,
Allday
MJ
. 
The curious case of the tumour virus: 50 years of Burkitt's lymphoma
.
Nat Rev Microbiol
2008
;
6
:
913
24
.
46.
Anderton
E
,
Yee
J
,
Smith
P
,
Crook
T
,
White
RE
,
Allday
MJ
. 
Two Epstein-Barr virus (EBV) oncoproteins cooperate to repress expression of the proapoptotic tumour-suppressor Bim: clues to the pathogenesis of Burkitt's lymphoma
.
Oncogene
2008
;
27
:
421
33
.
47.
Torgbor
C
,
Awuah
P
,
Deitsch
K
,
Kalantari
P
,
Duca
KA
,
Thorley-Lawson
DA
. 
A multifactorial role for P. falciparum malaria in endemic Burkitt's lymphoma pathogenesis
.
PLoS Pathog
2014
;
10
:
e1004170
.
48.
Johansson
ME
,
Phillipson
M
,
Petersson
J
,
Velcich
A
,
Holm
L
,
Hansson
GC
. 
The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria
.
Proc Natl Acad Sci U S A
2008
;
105
:
15064
9
.
49.
Kim
YS
,
Ho
SB
. 
Intestinal goblet cells and mucins in health and disease: recent insights and progress
.
Curr Gastroenterol Rep
2010
;
12
:
319
30
.
50.
Salzman
NH
,
Underwood
MA
,
Bevins
CL
. 
Paneth cells, defensins, and the commensal microbiota: a hypothesis on intimate interplay at the intestinal mucosa
.
Semin Immunol
2007
;
19
:
70
83
.
51.
Bergstrom
K
,
Liu
X
,
Zhao
Y
,
Gao
N
,
Wu
Q
,
Song
K
, et al
Defective intestinal mucin-type O-glycosylation causes spontaneous colitis-associated cancer in mice
.
Gastroenterology
2016
;
151
:
152
64
.
52.
Hollander
D
,
Vadheim
CM
,
Brettholz
E
,
Petersen
GM
,
Delahunty
T
,
Rotter
JI
. 
Increased intestinal permeability in patients with Crohn's disease and their relatives. A possible etiologic factor
.
Ann Intern Med
1986
;
105
:
883
5
.
53.
Jess
T
,
Rungoe
C
,
Peyrin-Biroulet
L
. 
Risk of colorectal cancer in patients with ulcerative colitis: a meta-analysis of population-based cohort studies
.
Clin Gastroenterol Hepatol
2012
;
10
:
639
45
.
54.
Peters
U
,
Jiao
S
,
Schumacher
FR
,
Hutter
CM
,
Aragaki
AK
,
Baron
JA
, et al
Identification of genetic susceptibility Loci for colorectal tumors in a genome-wide meta-analysis
.
Gastroenterology
2013
;
144
:
799
807
.
55.
Velcich
A
,
Yang
W
,
Heyer
J
,
Fragale
A
,
Nicholas
C
,
Viani
S
, et al
Colorectal cancer in mice genetically deficient in the mucin Muc2
.
Science
2002
;
295
:
1726
9
.
56.
Lin
JE
,
Snook
AE
,
Li
P
,
Stoecker
BA
,
Kim
GW
,
Magee
MS
, et al
GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity
.
PLoS One
2012
;
7
:
e31686
.
57.
Arthur
JC
,
Perez-Chanona
E
,
Muhlbauer
M
,
Tomkovich
S
,
Uronis
JM
,
Fan
TJ
, et al
Intestinal inflammation targets cancer-inducing activity of the microbiota
.
Science
2012
;
338
:
120
3
.
58.
Prindiville
TP
,
Sheikh
RA
,
Cohen
SH
,
Tang
YJ
,
Cantrell
MC
,
Silva
J
 Jr
. 
Bacteroidesfragilis enterotoxin gene sequences in patients with inflammatory bowel disease
.
Emerg Infect Dis
2000
;
6
:
171
4
.
59.
Boleij
A
,
Hechenbleikner
EM
,
Goodwin
AC
,
Badani
R
,
Stein
EM
,
Lazarev
MG
, et al
The Bacteroidesfragilis toxin gene is prevalent in the colon mucosa of colorectal cancer patients
.
Clin Infect Dis
2015
;
60
:
208
15
.
60.
Guidi
R
,
Guerra
L
,
Levi
L
,
Stenerlow
B
,
Fox
JG
,
Josenhans
C
, et al
Chronic exposure to the cytolethal distending toxins of Gram-negative bacteria promotes genomic instability and altered DNA damage response
.
Cell Microbiol
2013
;
15
:
98
113
.
61.
Yu
LX
,
Yan
HX
,
Liu
Q
,
Yang
W
,
Wu
HP
,
Dong
W
, et al
Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents
.
Hepatology
2010
;
52
:
1322
33
.
62.
Donohoe
DR
,
Holley
D
,
Collins
LB
,
Montgomery
SA
,
Whitmore
AC
,
Hillhouse
A
, et al
A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner
.
Cancer Discov
2014
;
4
:
1387
97
.
63.
Lupton
JR
. 
Microbial degradation products influence colon cancer risk: the butyrate controversy
.
J Nutr
2004
;
134
:
479
82
.
64.
Singh
N
,
Gurav
A
,
Sivaprakasam
S
,
Brady
E
,
Padia
R
,
Shi
H
, et al
Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis
.
Immunity
2014
;
40
:
128
39
.
65.
Belcheva
A
,
Irrazabal
T
,
Robertson
SJ
,
Streutker
C
,
Maughan
H
,
Rubino
S
, et al
Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells
.
Cell
2014
;
158
:
288
99
.
66.
Moons
LM
,
Kusters
JG
,
van Delft
JH
,
Kuipers
EJ
,
Gottschalk
R
,
Geldof
H
, et al
A pro-inflammatory genotype predisposes to Barrett's esophagus
.
Carcinogenesis
2008
;
29
:
926
31
.
67.
Souza
RF
,
Huo
X
,
Mittal
V
,
Schuler
CM
,
Carmack
SW
,
Zhang
HY
, et al
Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury
.
Gastroenterology
2009
;
137
:
1776
84
.
68.
Snider
EJ
,
Freedberg
DE
,
Abrams
JA
. 
Potential role of the microbiome in Barrett's Esophagus and esophageal adenocarcinoma
.
Dig Dis Sci
2016
;
61
:
2217
25
.
69.
Yang
L
,
Lu
X
,
Nossa
CW
,
Francois
F
,
Peek
RM
,
Pei
Z
. 
Inflammation and intestinal metaplasia of the distal esophagus are associated with alterations in the microbiome
.
Gastroenterology
2009
;
137
:
588
97
.
70.
Gall
A
,
Fero
J
,
McCoy
C
,
Claywell
BC
,
Sanchez
CA
,
Blount
PL
, et al
Bacterial composition of the human upper gastrointestinal tract microbiome is dynamic and associated with genomic instability in a Barrett's Esophagus Cohort
.
PLoS One
2015
;
10
:
e0129055
.
71.
Fernandez-Garcia
B
,
Eiro
N
,
Gonzalez-Reyes
S
,
Gonzalez
L
,
Aguirre
A
,
Gonzalez
LO
, et al
Clinical significance of toll-like receptor 3, 4, and 9 in gastric cancer
.
J Immunother
2014
;
37
:
77
83
.
72.
Pimentel-Nunes
P
,
Afonso
L
,
Lopes
P
,
Roncon-Albuquerque
R
 Jr
,
Goncalves
N
,
Henrique
R
, et al
Increased expression of toll-like receptors (TLR) 2, 4 and 5 in gastric dysplasia
.
Pathol Oncol Res
2011
;
17
:
677
83
.
73.
Pimentel-Nunes
P
,
Goncalves
N
,
Boal-Carvalho
I
,
Afonso
L
,
Lopes
P
,
Roncon-Albuquerque
R
 Jr
, et al
Helicobacter pylori induces increased expression of Toll-like receptors and decreased Toll-interacting protein in gastric mucosa that persists throughout gastric carcinogenesis
.
Helicobacter
2013
;
18
:
22
32
.
74.
Schmausser
B
,
Andrulis
M
,
Endrich
S
,
Muller-Hermelink
HK
,
Eck
M
. 
Toll-like receptors TLR4, TLR5 and TLR9 on gastric carcinoma cells: an implication for interaction with Helicobacter pylori
.
Int J Med Microbiol
2005
;
295
:
179
85
.
75.
Huhta
H
,
Helminen
O
,
Lehenkari
PP
,
Saarnio
J
,
Karttunen
TJ
,
Kauppila
JH
. 
Toll-like receptors 1, 2, 4 and 6 in esophageal epithelium, Barrett's esophagus, dysplasia and adenocarcinoma
.
Oncotarget
2016
;
7
:
23658
67
.
76.
Kauppila
JH
,
Karttunen
TJ
,
Saarnio
J
,
Nyberg
P
,
Salo
T
,
Graves
DE
, et al
Short DNA sequences and bacterial DNA induce esophageal, gastric, and colorectal cancer cell invasion
.
APMIS
2013
;
121
:
511
22
.
77.
Castellarin
M
,
Warren
RL
,
Freeman
JD
,
Dreolini
L
,
Krzywinski
M
,
Strauss
J
, et al
Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma
.
Genome Res
2012
;
22
:
299
306
.
78.
Gur
C
,
Ibrahim
Y
,
Isaacson
B
,
Yamin
R
,
Abed
J
,
Gamliel
M
, et al
Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack
.
Immunity
2015
;
42
:
344
55
.
79.
Warren
RL
,
Freeman
DJ
,
Pleasance
S
,
Watson
P
,
Moore
RA
,
Cochrane
K
, et al
Co-occurrence of anaerobic bacteria in colorectal carcinomas
.
Microbiome
2013
;
1
:
16
.
80.
Zackular
JP
,
Rogers
MA
,
Ruffin
MTt
,
Schloss
PD
. 
The human gut microbiome as a Screening tool for colorectal cancer
.
Cancer Prev Res (Phila)
2014
;
7
:
1112
21
.
81.
Zeller
G
,
Tap
J
,
Voigt
AY
,
Sunagawa
S
,
Kultima
JR
,
Costea
PI
, et al
Potential of fecal microbiota for early-stage detection of colorectal cancer
.
Mol Syst Biol
2014
;
10
:
766
.
82.
Schmidt
BL
,
Kuczynski
J
,
Bhattacharya
A
,
Huey
B
,
Corby
PM
,
Queiroz
EL
, et al
Changes in abundance of oral microbiota associated with oral cancer
.
PLoS One
2014
;
9
:
e98741
.
83.
Kado
S
,
Uchida
K
,
Funabashi
H
,
Iwata
S
,
Nagata
Y
,
Ando
M
, et al
Intestinal microflora are necessary for development of spontaneous adenocarcinoma of the large intestine in T-cell receptor beta chain and p53 double-knockout mice
.
Cancer Res
2001
;
61
:
2395
8
.
84.
Li
Y
,
Kundu
P
,
Seow
SW
,
de Matos
CT
,
Aronsson
L
,
Chin
KC
, et al
Gut microbiota accelerate tumor growth via c-jun and STAT3 phosphorylation in APCMin/+ mice
.
Carcinogenesis
2012
;
33
:
1231
8
.
85.
Tanaka
T
,
Kohno
H
,
Suzuki
R
,
Yamada
Y
,
Sugie
S
,
Mori
H
. 
A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate
.
Cancer Sci
2003
;
94
:
965
73
.
86.
Zackular
JP
,
Baxter
NT
,
Iverson
KD
,
Sadler
WD
,
Petrosino
JF
,
Chen
GY
, et al
The gut microbiome modulates colon tumorigenesis
.
mBio
2013
;
4
:
e00692
13
.
87.
Thaiss
CA
,
Zmora
N
,
Levy
M
,
Elinav
E
. 
The microbiome and innate immunity
.
Nature
2016
;
535
:
65
74
.
88.
Honda
K
,
Littman
DR
. 
The microbiota in adaptive immune homeostasis and disease
.
Nature
2016
;
535
:
75
84
.
89.
Tamburini
S
,
Shen
N
,
Wu
HC
,
Clemente
JC
. 
The microbiome in early life: implications for health outcomes
.
Nat Med
2016
;
22
:
713
22
.
90.
Kayama
H
,
Takeda
K
. 
Functions of innate immune cells and commensal bacteria in gut homeostasis
.
J Biochem
2016
;
159
:
141
9
.
91.
Levy
M
,
Thaiss
CA
,
Elinav
E
. 
Metabolites: messengers between the microbiota and the immune system
.
Genes Dev
2016
;
30
:
1589
97
.
92.
Iida
N
,
Dzutsev
A
,
Stewart
CA
,
Smith
L
,
Bouladoux
N
,
Weingarten
RA
, et al
Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment
.
Science
2013
;
342
:
967
70
.
93.
Hamm
AK
,
Weir
TL
. 
Editorial on “Cancer and the microbiota” published in Science
.
Ann Transl Med
2015
;
3
:
175
.
94.
Karin
M
,
Jobin
C
,
Balkwill
F
. 
Chemotherapy, immunity and microbiota–a new triumvirate?
Nat Med
2014
;
20
:
126
7
.
95.
Galluzzi
L
,
Pietrocola
F
,
Bravo-San Pedro
JM
,
Amaravadi
RK
,
Baehrecke
EH
,
Cecconi
F
, et al
Autophagy in malignant transformation and cancer progression
.
EMBO J
2015
;
34
:
856
80
.
96.
Deretic
V
,
Saitoh
T
,
Akira
S
. 
Autophagy in infection, inflammation and immunity
.
Nat Rev Immunol
2013
;
13
:
722
37
.
97.
Huang
J
,
Brumell
JH
. 
Bacteria-autophagy interplay: a battle for survival
.
Nat Rev Microbiol
2014
;
12
:
101
14
.
98.
Greenfield
LK
,
Jones
NL
. 
Modulation of autophagy by Helicobacter pylori and its role in gastric carcinogenesis
.
Trends Microbiol
2013
;
21
:
602
12
.
99.
Levy
J
,
Cacheux
W
,
Bara
MA
,
L'Hermitte
A
,
Lepage
P
,
Fraudeau
M
, et al
Intestinal inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune response and suppresses tumour growth
.
Nat Cell Biol
2015
;
17
:
1062
73
.
100.
Rajagopala
SV
,
Yooseph
S
,
Harkins
DM
,
Moncera
KJ
,
Zabokrtsky
KB
,
Torralba
MG
, et al
Gastrointestinal microbial populations can distinguish pediatric and adolescent Acute Lymphoblastic Leukemia (ALL) at the time of disease diagnosis
.
BMC Genomics
2016
;
17
:
635
.