The oncogenic roles of bacterial infections in development of cancer

Journal Pre-proof The oncogenic roles of bacterial infections in development of cancer Shirin Eyvazi, Mehdi Asghari Vostakolaei, Azita Dilmaghani, Omid Borumandi, Mohammad Saeid Hejazi, Houman Kahroba, Vahideh Tarhriz PII:

S0882-4010(19)31592-X

DOI:

https://doi.org/10.1016/j.micpath.2020.104019

Reference:

YMPAT 104019

To appear in:

Microbial Pathogenesis

Received Date: 7 September 2019 Revised Date:

3 January 2020

Accepted Date: 28 January 2020

Please cite this article as: Eyvazi S, Vostakolaei MA, Dilmaghani A, Borumandi O, Hejazi MS, Kahroba H, Tarhriz V, The oncogenic roles of bacterial infections in development of cancer, Microbial Pathogenesis (2020), doi: https://doi.org/10.1016/j.micpath.2020.104019. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd.

The Oncogenic Roles of Bacterial Infections in Development of Cancer

Shirin Eyvazi1,2†, Mehdi Asghari Vostakolaei3†, Azita Dilmaghani4,5, Omid Borumandi5, Mohammad Saeid Hejazi3,5,6, Houman Kahroba3,6*, Vahideh Tarhriz6* 1

Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2 Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran 3 Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran 4 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. 5 Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran 4 Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran

*Correspondences: 1

Vahideh Tarhriz, PhD Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran Phone: +98(914)2577057 Email: [email protected] 2

Homan Kahroba Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran Phone: +98(936)9411587 E-mail: [email protected] †: These authors contributed equally to this study and should be considered as co-first authors.

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Abstract

Initiation of cancer is interconnected with different factors like infections. It has been estimated that infections, particularly viruses, participate in about 20% of all cancers. Bacteria as the most common infectious agents are also reported to be emerging players in the establishment of malignant cells. Microbial infections are able to modulate host cell transformation for promoting malignant features through the production of carcinogenic metabolites participating in inflammation responses, disruption of cell metabolism, and integrity and also genomic or epigenetic manipulations. It seems that the best example of the role of bacteria in cancer promotion is Helicobacter pylori infection, which is related to gastric cancer. World Health Organization (WHO) describes bacterium as class I carcinogens. Several bacterial infections have been reported in association with prevalent cancers. In this review, we will summarize the role of known bacterial infections in the initiation of the main common cancers, which show high mortality in the world. Examining the microbiomes in cancer patients is important and necessary to better understand the pathogenesis of this disease and also to plan therapeutic interventions.

Keywords: Microbial Infections, Bacterial Carcinogenesis, Cancer, H. pylori.

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Introduction Genomic alterations are considered as the main cause of cancer establishment which are inducible through various pathogenic infections. About 20% of global cancer is attributed to infections. Pivotal role of viral infections is well understood in cancer initiation due to interfering activity of viruses in host genomic content (1). Certain bacteria are reported to cause chronic infections or participate in production of toxins which interrupt the cell cycle and lead to altered cell growth (2). Microbial infections are also reported to be associated with malignant behavior to promote cancers such as Schistosoma haematobium in bladder, Helicobacter pylori (H. pylori) in gastric, chronic infection of Salmonella Typhi in gallbladder, and Salmonella Enteritidis in colon cancers (3-5). Microbial infections are able to modulate host cell transformation for promoting malignant features through the production of carcinogenic metabolites participating in inflammation responses, disruption of cell metabolism, and integrity and also genomic or epigenetic manipulations (6). Microbiome and host mutual crosstalk represent complicated networks, and understanding of direct role for pathogenic bacterial infection is point of doubt due to vast effects of bacterial infection on manipulation and exploiting of human host cell niche in numerous approaches throughout different stages of infection cycles (7). Several bacterial infections have been reported in association with prevalent cancers. In this review, we will summarize the role of the known bacterial infections in the initiation of the main common cancers which show high mortality in the world.

The role of bacterial infection in esophageal cancer

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Esophageal cancer is a common malignancy known as the sixth most common cause of cancer related deaths (8). Adenocarcinoma and squamous cell carcinoma (SCC) are the most common types of esophageal cancer which are developed in different parts of the esophagus (9). Gut microbiota is not stable and varies from the oral cavity to the rectum, diversity and number of gut bacteria changes ranging from 101 per gram of contents in the esophagus and stomach to 1012 per gram of contents in the colon and distal gut (10). Streptococcus viridans is known as the most frequent microorganism in the normal esophagus using the bacterial culture-based methods (11); however, the presence of other phyla such as Firmicutes, Bacteroides, Actinobacteria, Proteobacteria, Fusobacteria, and TM7 has also been reported using PCR of 16S ribosomal RNA (12). Blackett et al. compared the microbiota in patients with GERD, Barrett’s esophagus, esophageal adenocarcinoma, and also in reflux asymptomatic controls (13). They observed that in the specimens from GERD and Barrett patients, Campylobacter is significantly more enriched than the specimens from controls and esophageal adenocarcinoma. Also, the expression of cytokines associated with carcinogenesis (IL-18) is increased in the presence of Campylobacter. Therefore, according to the pathogenicity of Campylobacter species, it seems that the role of Campylobacter in progression of esophageal adenocarcinoma might be resemble that of H. pylori in gastric cancer (13). In another study, the effects of microbiome altering with antibiotics in the development of esophageal adenocarcinoma were verified. The results showed that the microbiome altering did not affect the incidence of esophageal adenocarcinoma; however, the using of antibiotics resulted in increasing and decreasing of the proportions of Lactobacillales and Clostridium in the esophagus, respectively (14). A recent study, in a rat model, revealed the role of Escherichia coli (E. coli) in Barrett’s esophagus and esophageal adenocarcinoma. In the study, the expression of TLR 1-3, 6, 7, and 9

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significantly increased in esophageal adenocarcinoma compared with normal epithelium. Therefore, the results suggested that E. coli can cause early molecular changes in esophageal adenocarcinoma carcinogenesis by altering the TLR signaling pathway (15). In the case of SCC, the microbiome is less well known. Gao et al. reported that Porphyromonas gingivalis infects the esophageal mucosa of esophageal SCC patients. It seems that Porphyromonas gingivalis plays a pathogenesis role in esophageal SCC because the presence of the bacterium is associated with cancer cell differentiation, metastasis, and poor clinical outcome in SCC patients. Fusobacterium nucleatum is another bacterium related to SCC (16). The presence of Fusobacterium nucleatum in SCC patients is associated with shorter survival time. It has been known that the bacterium contributes to increasing the number of specific chemokines genes such as CCL20 (16).

The role of bacterial infection in gasteric cancer Gastric cancer is an aggressive disease which is known as the second leading cause of cancerrelated death in the world. The majority (approximately 90%) of gastric cancers are adenocarcinomas, which arise from the glands of the mucous layer of the stomach (17). Historically, it has been thought that the stomach is a sterile organ due to acid production. The discovery of H. pylori by Barry J. Marshall and Robin Warren changed the idea (18, 19) and recently, DNA sequencing technology has confirmed the presence of other bacteria from different phyla including Proteobacteria, Firmicutes, Bacteroidetes, Actinobacteria, and Fusobacteria in the stomach (20). It is now well established that H. pylori infection is the strongest risk factor for developing of the gastric adenocarcinoma (21). World Health Organization (WHO) classified H. pylori as a class I carcinogen in 1994 (22, 23). H. pylori can exert its oncogenic effects through a variety of mechanisms, including indirect inflammatory 5

effects, direct epigenetic effects and may be also in contribution with other microorganisms (Fig.1). The H. pylori infection in the corpus results in atrophic gastritis. H. pylori-gastritis is characterized by a cellular inflammatory infiltrate which displays feature of both innate and adaptive immune response (24). CD4 Th1-cell response is the main cause of the inflammation (25). Accumulating of the reactive oxygen and nitrogen species (ROS/RNS) through activation of neutrophils and macrophages and also the secretion of the superoxide and the hydroxyl ion by H. pylori increase oxidative stress and disrupt DNA of mucosal cells (26, 27). Also, H. pylori induce the apoptosis of macrophages and increase the expression of proinflammatory factors (28). The persistent presence of the infection increases the pH and hypochlorhydria which facilitates the colonization and proliferation of the bacterium and also its migration proximally, leading to pangastritis and adenocarcinoma (29). H. pylori also can exert its carcinogenesis effect directly through its virulence factors such as cytotoxin-associated gene A (CagA) containing the Cag Pathogenicity Island (cagPAI) and vacuolating cytotoxin A (VacA) (30). The strains harboring cagA can cause more inflammatory responses and progression to gastric cancer (31). CagPAI encodes a bacterial type IV secretion system which secretes CagA and peptidoglycan into the epithelial cells. CagA and peptidoglycan induce multiple cellular signaling pathways such as MAPK cascade and phosphoinositide-3 kinase (PI3K-AKT) signaling pathways, respectively (32, 33). Also, cagPAI+ strains increase the ectopic expression of the enzyme Activation Induced Deaminase (AID) in mucosal cells which causes mutations in TP53 gene (34). VacA proteins assemble in defined oligomeric complexes and form anion channels in the cell membranes (35). The strains harboring VacA, particularly containing s1/m1 alleles, are cytotoxic and induce intracellular acid vacuoles in the gastric epithelial cells. Additionally, they interact with the immune system, modify the permeability of polarized

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epithelial cell monolayers, and also cause programmed cell death in the epithelial cells (36). Other virulence factors, such as adhesions and outer membrane proteins including outer inflammatory protein A (OipA), blood group antigen-binding adhesin A (BabA), and sialic acidbinding adhesin A (SabA) which play roles in the bacterial colonization of the gastric mucosa, have been identified more frequently in gastric cancer sera (37). Also, it has been kwon that BabA leads to double stranded DNA breaks and progression of gastric carcinogenesis (38). Besides the mentioned mechanisms, H. pylori can also change the DNA methylation in gastric epithelial cells and silence the tumor suppressor genes such as E- cadherin (39). Finally, the hypothetical cross-talk between H. pylori and other bacteria may cause gastric carcinogenesis (40). However, there are few studies in this field. It seems that by the colonization of H. pylori and increasing the pH, the constitution of gastric microbiota will change, and some bacteria progress gastric carcinogenesis. The link between H. pylori and other bacteria in the pathogenesis of gastric cancer can be related to Toll-like receptors. It has been demonstrated that Toll-like receptors’ expression increases during gastric carcinogenesis in H. pylori infection. The increase may be done by H. pylori initially, and then by other microorganisms, playing an important role in gastric carcinogenesis (40, 41).

The role of bacterial infection in gallbladder cancer Gallbladder cancer (GBC) is a rare malignancy which is more prevalent among senile women and middle aged people and more common in developing countries such as Chile, Poland, India, etc. The confirmed risk factors for this malignancy are the presence of gallstones, chronic infection, and pancreaticobiliary maljunction (42-44). Mirizzi's syndrome, genetic factors, bile reflux, familial history of gallstones, chemical exposure, gallbladder polyps, and excessive

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consumption of fried foods are also known as factors which make individuals susceptible (45, 46). It has been discovered that bacteria can be associated with the development of this cancer; however, findings are still inconsistent. The proliferation of bacteria can give rise to inflammation, irritation of the gallbladder wall, and subsequently, these changes may affect proto-oncogenes or tumor suppressor genes (47, 48). It is not completely determined how many bacteria can contribute to GBC, but a range of bacteria has been introduced as E. coli, Klebsiella pneumoniae, Citrobacter freundii, Salmonella spp., Helicobacter spp., Enterobacter spp., Enterococcus spp., Pseudomonas aeruginosa, Bacteroides fragilis, Staphylococcus aureus, Proteus spp. and Acinetobacter spp. which are the major isolated microbes by culture methods or identified by PCR (uncultured methods) in gallstones and gall bladder patients (49-51). In this case, Salmonella typhi (S. typhi), Helicobacter bilis (H. bilis), and H. pylori have the main roles to cause a risk of gallbladder cancer. Evidences show that gallbladder cancer and another disease, typhoid fever, which is caused by the bacterium S. Typhi, are common in India and Pakistan. S. Typhi does not cause serious symptoms; however, the chronically infected people can be at high risk for developing gallbladder cancer. It is believed that there is a collaboration between S. Typhi and gallstones (52). S. Typhi can form biofilms on gallstones and establish abnormal gallbladder mucosa (52, 53). However, more studies are needed to confirm the findings. Gallbladders colonized with bacteria manifest histopathological alterations such as epithelial destruction and massive infiltration of neutrophils attendant with local increase of proinflammatory cytokines (54). Gram-negative bacteria also have been obtained from gallstones and bile, and also several bacterial genes such as Salmonella, Helicobacter, Escherichia, and Klebsiella have been identified in gallbladder of patients with cholelithiasis and cholecystitis (43, 55), which increase the probability of association of these bacteria with GBC because

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gallstones accompanied by chronic cholecystitis are reported as an important risk factor for GBC (45, 48). These gram-negative bacteria have an outer membrane that contains LPS which is responsible for immune reactions against bacteria. In that case, LPS pathway proteins, including CD14 and LPS-binding protein (LBP) which are produced in response to LPS, were investigated in adults with GBC and gallstones in Shanghai, and it led researchers to the point that LBP and CD14 may contribute to the development of GBC mediated by inflammation although it is known that inflammation is not obligatory for inducing transformation by S. enteric (4, 55). In a study by Scanu et al., it was revealed that S. Typhi has ability in secreting of cytolethal distending toxin (CDT), which reaches the host cell's nucleus and causes genome instability accompanied by chromosome and chromatin defects in the murine gallbladder models. It also leads to production of mutagenic metabolites which cause transformation; furthermore, it consistently activates MAPK, AKT, and p38 survival pathways in order to sustain the transformation (Fig. 2). The production of CDT has been confirmed in other Gram-negative bacteria including E. coli and several Helicobacter species (4, 56). Another study by Guidi et al. revealed that long-term exposure to CDTs increases the number of genomic defects and decreases DNA damage response (DDR) efficiency in contaminated cells. The presence of these two factors promote anchorage-independent growth, and it can lead to malignant transformation (57). Other carcinogens produced by S. Typhi are bacterial glucoronidase, secondary bile acids, and nitroso compounds (53, 54, 56, 58). Studies suggest that degradation of bile salts and bacterial byproducts may participate in developing GBC (47, 56). According to recent studies, it seems that the capsular polysaccharide of S. Typhi suppresses the mucosa inflammation, so the researchers suggest that this suppression of acute inflammation might eventually lead to changed immune response and facilitate converting into chronic carrier state (54). Shukla et al. revealed

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that chronic typhoid carrier is nine times more susceptible for developing GBC. In addition, these asymptomatic carriers act as mobile reservoirs for spreading bacteria (4, 56). There is little information about the carcinogenic effect of Salmonella in the absence of gallstones, but it is clear that Salmonella is efficient in the formation of gallstones, and both factors are able to induce inflammatory responses. Hence, it is possible that the concurrent presence of gallstones and Salmonella may elevate the risk of developing GBC (54). Non–typhoidal serovars such as Typhimurium and Enteritidis are also reported to contribute to GBC because their DNA traces have been detected in patients' tissues with GBC, and they seem to cause a strong inflammatory response in contrast to S. Typhi (54, 59). On the other hand, there are many controversial discussions about whether Helicobacter spp. has a significant role in the development of GBC or not. As mentioned above, H. pylori is a well-known factor for gastric cancer but there are still doubts about the role of this bacterium in GBC. In a study by Murphy et al., using multiplex serology assay, all cases that eventually developed GBC were seropositive for H. pylori (60). Hassan et al. also reported that the presence of H. pylori increases the mucosal lesions of gallbladder such as hyperplasia, metaplasia, and lymphoid infiltration which are considered to be potentially precancerous (61). There are also other Helicobacter species identified in bile and gallbladder tissue using molecular methods, i.e. H. bilis, H. hepaticus, H. cholecystis, and H. pullorum. Infection with H. bilis has been reported to lead to angiogenesis enhancement, which is essential for tumor progression. The gram negative H. bilis is another bacterium which plays a role in biliary tract disease, particularly in biliary tract cancer and gallbladder cancer (62).

The role of bacterial infection in colorectal cancer

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Colorectal cancer (CCR) is the third most common cancer that is responsible for 10 percent of cancer-related mortality in the world. Mistrial factors increase the risk of developing colorectal cancer. Inflammatory bowel diseases (IBD) after the hereditary cancer syndromes, familial adenomatous polyposis, hereditary nonpolyposis, and also infection with E. coli resisting a large number of antibiotics (63) are the risk factors for initiation of colorectal cancer. Bacteroides fragilis and a strain of E. coli are two types of bacteria which have a main role in the production of thin film covering the intestinal lining. The bacteria can perforate a mucus shield that lines the colon. The roles of the bacteria have been confirmed using different animal models in colon cancer. It has been identified that Bacteroides fragilis strains, including nontoxigenic B. fragilis (NTBF) and enterotoxigenic. B. fragilis (ETBF) are responsible for promoting the colorectal cancer development by increasing the levels of T-helper cell 17 (Th17) and T regulatory (Treg) cells. The metalloprotease toxin of Bacteroides fragilis as an Enterotoxigenic (ETBF) plays a key role in colon cancer development. Wu et al. (2009) showed that colitis and colonic tumors developed in mice which were infected with ETBF in chronically condition after 4 weeks. In fact, ETBF mediates STAT3 signaling which enhances the level of IL17-secreting CD4T cells by increasing inflammation. In another study, it was shown that ETBF in stool samples of colon cancer patients is more than control samples (64). Crohn's disease (CD) and Ulcerative colitis (UC) are two important disorders that increase the risk of colorectal cancer. IBD has a key role to enhance both of these disorders (2). Martin et al. (2004) found that some strains of E. coli are present in IBD at higher levels. They hypothesized that inflammatory bowel disease changes mucosal glycosylation which may modulate the mucosally adherent bacteria and may play a role in the pathogenesis of Crohn's disease which increases the risk of sporadic colon cancer development (65). In another study, Masseret et al. (2001) indicated that isolated E. coli strains

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from patients with chronic and recurrent Crohn's disease were remarkably more frequent than control patients (66). They also found that although a specific strain of E. coli could not be isolated in Crohn's ileal mucosa, some genotypes of E. coli associated with chronic or early recurrent ileal lesion were more likely than others. Ultimately, this research study revealed that pathologic strains of E. coli induce inflammation and enhance carcinogenesis in colorectal cancer development by releasing certain chemicals including cytolethal distending toxin (CDT) and cytotoxic necrotizing factor (CNF). Streptococcus gallolyticus subsp. gallolyticus Sgg (formerly known as Streptococcus bovis type I) was found as an inducer in colon cancer by McCoy and Mason as early as 1951 (67). In 1974, it was reported that the association of Streptococcus bovis and colonic neoplasia was observed in 25–80% of CCR patients (68). The colonic neoplasia may arise years after the bacteremia or infectious endocarditis. S. bovis after than streptococci is the main bacterial infection in pathogenesis of endocarditis and urinary infection (69). S. bovis is associated with gastrointestinal lesions, especially carcinoma of the colon (70). Gold et al. (2004) showed that pathological activity of S. bovis only occurred in the colonic mucosa in which preneoplastic lesions are established. It seems that the bacterium’s wall extracted antigens (WEA) act as an enhancer of carcinogenesis in a chemically-induced animal model (71). Biarc et al. (2004) indicated that the Caco-2 cells were stimulated with either S. bovis WEA or cell-associated proteins and released chemokines (human IL-8 or rat CINC/GRO) and prostaglandin E2 (PgE2) (72). The S300 proteins were able to increase PGE2 secretion from Caco-2 cells. PGE2 release in the human cells is correlated with an over-expression of cyclooxygease-2 (COX-2) which plays a critical role in mucosal inflammation, inhibition of apoptosis, and promotion of angiogenesis. In addition, S. bovis proteins can agitate MAPKs kinases for enhancement of proliferation (73, 74). Even though many clinical studies have

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strongly revealed the presence of S. bovis biotype I, renamed Streptococcus gallolyticus subsp. gallolyticus (Sgg), in colorectal cancer, the first strain TX20005of Streptococcus bovis biotype I was isolated very recently, demonstrated as an enhancer in colorectal cancer development (75). S. bovis can secrete a specific “bacteriocin” which kills closely related gut commensals and lead to better colonization of murine colon in colorectal cancer-context (76). It seems that S. bovis is not the main cause of colorectal cancer because for the first times, S. bovis must be colonized in the colon before pre-malignant conditions exist. In fact, it is an auxiliary factor for accelerating of colorectal cancer development. However, more information is necessary to investigate the relationship between S. bovi and host immunity as a critical role in colorectal cancer development. Finally, it seems that for sensitive detection and identification of bacteria associated with colorectal cancer, development of novel molecular tools is required (77-79). Another bacterium as the candidate in colon cancer is Clostridium species. However, the results from this field are very variable between patients with colon cancer and controls (80).

The role of bacterial infection in lung cancer Lung cancer (LC) is the most common cancer in the world with high fatality than other cancers (81). After recognition of LC cases, only 18% of patients survived around five years. LC cases are more common in men than women and overly influence African American males (82). Many studies suggest that LC is related to chronic infection (83). Environmental pollution, gene mutation, and diverse bacteria seem to play important roles in the initiation and progress of lung cancer (81). Mycoplasma is one of the most apperceived pathogen in lung carcinomas (84). Also Acidovorax Sp. has an important role in gene-microbiome relation in human LC (81).

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Furthermore, Staphyloccus and Chlamydia pneumonia infection have been obtained in many cases of LC patients (85). The rest of the microorganisms are represented in Table 1. Different findings display a possible role of bacteria in the development of LC, such as the increased bacterial colonization in chronic obstructive pulmonary disease (COPD), which is a known risk factor for lung cancer development (86). Therefore, patients who have a history of COPD and LC should be further examined. The cell cycle regulatory molecule cyclin D1 in a mitogen-activated protein kinase (MAPK) has been related to LC. Microbes have tremendous influence on how our organs respond to immunologic challenges as they affect innate immune responses and immune homeostasis (87). Examining the microbiomes in patients with LC is important and necessary to better understand the pathogenesis of this disease and to plan therapeutic interventions. Recent studies have shown that Megasphaera as well as Veillonella could serve as a biomarker in the diagnosis of LC. However, a lot of question have not been replied yet, especially regarding LC (88). Ultimately, manipulation of the lung microbiota together with use of immune modulators such as inhaled TLR4 antagonists may prevent and treat LC.

The role of bacterial infection in prostate cancer Prostate cancer (PC) is recognized as the most prevalent men solid tumor and second cause of malignancy derived death worldwide. Diverse genetic and environmental factors are documented for PC initiation and progression. The association of infections and infectioninduced chronic inflammation for prostate atrophy and inflammatory cell infiltration is wellestablished, also documentation of infectious agents in prostate tumors confirm this role (89, 90). 14

Constant infection causes chronic inflammation of the prostate which promotes DNA damage due to production of leukocyte-derived active oxygen and nitrogen species (91). Acute- and chronic-bacterial prostatitis and prostate inflammation only account for 5–10% of prostatitis cases; E. coli and Enterococcus species (with ability of biofilm establishment) are reported as dominant infectious agents (92). An improved risk of PC in patients with a history of inflammatory sexually transmitted diseases offers an indirect link for chronic inflammation and prostate carcinogenesis (93). Infection is a stimulatory factor for carcinogenesis; however, most of the underlying molecular mechanisms for infection-derived-PCs are not well-known except in E. coli. During inflammation, the extracellular matrix (ECM) residential inflammatory cells release numerous stimulatory cytokines like tumor necrosis factor, interleukin-7, interleukin-2, RANTES, and macrophage inflammatory protein-1 to promote growth factors’ secretion such as basic fibroblast growth factor and transform growth factor-β into the ECM for activation of surrounding stromal cells’ growth that provoke PC hyperplasia and metastasis (91). Inflammatory cells upregulate vasculation, DNA damage, cytoskeleton remodeling, and ECM degradation to prepare an appropriate microenvironment for cancer growth (91). E. coli’s presence in genitourinary tract modulates epithelial barriers in favor of malignancy development and also elevates acute inflammatory response, proliferation of epithelial cells, reactive hyperplasia besides prostate specific antigens (PSA) (94). E. coli is able to adhere Carcinoembryonic antigen-related cell adhesion molecules of epithelial cells through Afa/Dr adhesion molecules; furthermore, E. coli causes hyper methylation of cyclin-dependent kinase inhibitor 2A gene in urothelium cells which leads to PC (95-97). Animal model evaluation of human prostatitis derived CP1 E. coli strain indicates stromal and epithelial hyperplasia which is the result of elevated pro-inflammatory cytokine profiles to induce inflammation-depended

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prostate carcinogenesis through functional cells including macrophages, lymphocytes, and particularly Th17 (98). Chronic inflammation is highly effected PC progression by induction of angiogenesis and epithelial mesenchymal transition (99). Recently, Pentraxin 3 is detected as an inflammatory biomarker for diagnosis of tumor progression in inflammation-derived-PCs (100). Despite high impact of inflammation on PC, most molecular pathways are not well-understood.

The role of bacterial infection in cervical cancer Cervical cancer is one of the most common malignancies among women. Also, it is the fourth leading cause of cancer-related deaths among women in the world (101). The main types of cervical cancers are squamous cell carcinoma and adenocarcinoma. Persistent infection with human papillomavirus (HR-HPV) is a major causal factor in the development of cervical cancer (102). The vagina has a dynamic and relative microbial balance. Lactobacillus are the predominant bacteria inhabitant in the healthy vagina (102). The bacteria play an important role in the protection of the women reproduction system. The imbalance of vaginal flora under physiological conditions leads to several gynecological diseases, such as coleitis, high-grade cervical intraepithelial neoplasia (CIN), and cervical cancer (103). A decline in the Lactobacillus population under physiological conditions leads to an overgrowth of anaerobic bacteria (104). The association between vaginal bacteria and cervical cancer has not been elucidated yet; however, in some studies, the prevalence of several bacteria has been observed, including Gardnerella vaginalis, Prevotella bivia, Mycoplasma genitalium, Staphylococcus epidermidis, Enterococci spp., Escherichia coli, Fusobacterium ssp. and Bacteriodes species in the cancer patients, which are different from that in normal people (105-107). These bacteria can play role in carcinogenesis through mechanisms which are related to the pathogenesis of the 16

microorganism and host immunity. When anaerobes bacteria overgrow in the vagina, they produce elevated amount of polyamine which are cytotoxic to the vaginal cells along with vaginal organic acids such as acetic and succinic acids. The increasing amount of nitrosamines leads to higher DNA damage and change in cytokine profiles which affect the host immune responses to the HPV infection. Therefore, the anaerobic bacteria can increase the risk of HPV infection and cervical cancer (108, 109). Furthermore, the vaginal bacteria can produce several immunomodulatory substances such as proteases, sialydases, and succinate and also possess inflammatory-inducing

components

such

as

lipoteichoic

acid,

peptidoglycans,

and

lipopolysaccharides (LPS) which lead to secretion of proinflammatory cytokines including IL-6 and IL-8 (109). It has been elucidated that the cytokines have proangiogenic properties and promote the tumorigenesis of solid tumors (84). The vaginal bacteria can also activate transforming growth factor beta (TGFbeta) through activation of TLR. TGFbeta stimulates the expression of integrins (109). Integrins regulate various cellular functions which are crucial to the initiation, progression, and metastasis of solid tumors (110).

The role of bacterial infection in ovarian cancer Ovarian cancer (OC) is one of the most prevalent and mortal gynecologic cancers. The lethality of ovarian cancer is due to lack of early symptoms, late diagnosis, and limited treatment option (111). Up to date, the origin and pathogenesis of OC is not completely understood. Reproductive factors, oral contraceptives, hormone replacement therapy, diet, use of non-steroidal antiinflammatory drugs, and genetics are predisposing or protective risk factors for the ovarian cancer (112). As other cancers, the association of ovarian cancer and bacterial infection has been

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investigated. The two important bacteria which can affect the carcinogenesis of ovarian cancer are Chlamydia trachomatis and Mycoplasma genitalium (113). C. trachomatis is an obligate intracellular bacterium which causes sexually transmitted infections (STIs) 9 (114). It has been reported that 80 % of ovarian cancer samples are infected by Chlamydia (115). Also, there is a positive relationship between IgG of Chlamydia trachomatis and ovarian cancer (116). Chlamydia activates both of the innate and adaptive immune systems in its host which leads to inflammation. As mentioned in previous sections, persistent inflammation and also disruption in apoptosis of host cells may lead to carcinogenesis. In chlamydia infection (IFN)-γ, IL-6, IL-8, IL-10, and IL-12 increase (117). Mycoplasma genitalium is a sexually transmitted, small, and pathogenic bacterium which can be related to ovarian cancer (118). However, the role of the bacterium in ovarian cancer is doubtful. Although a study showed that M. genitalium IgG antibodies significantly increased in ovarian tumors (116), in another study, the bacterium was not present in ovarian tumor samples (119). Several researchers have shown that persistent M. genitalium infection increases the secretion of IL-6, IL-8, granulocyte colony-stimulating factor, granulocyte/macrophage colony-stimulating factor (GM-CSF), and monocyte chemotactic protein (MCP)-1 and enhances the sensitivity to TLR agonists (120, 121). Therefore, M. genitalium is able to promote the carcinogenesis of ovarian cells.

The role of bacterial infection in Breast Cancer Breast cancer is an invasive tumor that develops from breast tissue. Numerous risk factors, such as bacterial infection, have been identified which may be involved in breast cancer progression. A number of recent studies propose that some of bacteria can interfere with breast cancer (122).

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Different bacterial genes can produce estrogen-metabolizing enzymes which modulate estrogen serum levels. For example, several bacteria including Clostridia and Ruminococcaceae families produce β-glucuronidase which de-conjugate with estrogen-like metabolites. As a result, they can be re-absorbed as free estrogens through enterohepatic circulation and uptaken by various organs, particularly breast (123). Estrogen-like compounds have bilateral effects; on the one hand, they can enhance proliferation of specific bacteria, and on the other, they can induce synthesis of estrogen-inducible growth factors, which might have a carcinogenic potential (124). Bacteria may enhance breast cancer with the presence of chronic, persistent, and dysregulated inflammation (125). Thompson et al. showed that the major population of bacteria in the tumor sites were Proteobacteria (48.0%), Actinobacteria (26.3%), and Firmicutes (16.2%). Also, in another study, Mycobacterium fortuitum and Mycobacterium phlei were two of the prevalent species differentially abundant in tumor samples (126). The correlation between bacteria and breast cancer has been unclear to date and needs further studies. The critical point in this case is still unclear whether the bacteria are causative or contributory to breast cancer. Wang et al. showed the frequency of gram-positive bacteria including Corynebacterium, Staphylococcus, Actinomyces, and Propionibacteriaceae along with Lactobacillus remarkably decreased in women with breast cancer compared to healthy subjects (127). For diagnostic improvement and treatment interventions, study of whole bacteria and their function in breast cancer patients is recommended.

The role of bacterial infection in brain tumors

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Brain tumors are an uncontrolled growth of cells in the brain or spinal cord. Gliomas are the most common type of malignant brain tumors which account for 27% of all brain tumors and 80% of malignant tumors (128). The most aggressive glioma is Glioblastoma, which is also known as glioblastoma multiforme (GBM). Glioblastomas are malignant Grade IV tumors. The tumors form

astrocytes cells which support nerve cells (129). The prevalence of

glioblastoma varies among different races or ethnicities and also geographic region. It has been known that several risk factors are associated with brain tumors including age and race, gender, hormonal status, exposure to ionizing radiation as well as electromagnetic fields, and use of mobile phones (130). Also, the association of infection and brain tumors has been reported in several documents. It has been reported that the IE1, pp65, and late antigens of human cytomegalovirus (HCMV) are present in 100% of 27 GBM specimens. However, glioblastoma incidence and cytomegalovirus seropositivity differ among ethnic groups (131). Also the association of brain cancer with polyomaviruses such as SV40, BKV, and JCV has been proven (132). Infection with intracellular parasites such as Toxoplasma gondii is also related to brain cancer (133). The association between bacteria and brain cancer is dim. Although Mycoplasma infections have been reported in glioma, the infection is associated with various CNS diseases (134). A study showed that Brucella DNA is present in 5 of 20 medulloblastoma tumor samples (135). Therefore, more investigations are needed for elucidation of the role of bacterial infection in brain tumors.

Conclusion Although numerous epidemiological studies confirm a link among bacterial infections and cancer incidence and as there are quantities of bacterial mechanisms that participate in cellular 20

transformation, regarding the great frequency of bacterial infection in the world, only several cancers are well confirmed to be due to oncogenic activity of the bacteria. Bacterial host cell modulation is involved in provoking of cancer development which typically accounts for only single step in the multi-step procedure mandatory for cellular transformation and cancer establishment. It can explain the reason why chronic bacterial infections indicate higher statistical chance of promoting tumorigenesis, and the probability of encountering a pretransformed cell would then be evidently improved. Despite, viral infections, bacterial infections are usually treatable, and the outlook of antibiotic treatments to avoid, alleviate, or cure cancers is clearly appealing. A certain mechanism for bacterial infection is not well understood for all species, but certain signaling pathways are reported as oncogenic inducing paths. The challenge for discovery of real relations among bacterial infections and cancers is indeed great, but it also decelerates great rewards. The role of bacteria in tumor mass for cancer growth inhibition is still point of doubt regarding certain bacteria role in treatment of cancer.

Acknowledgments This work was supported by Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz (Grand number: 64015), Iran. There are neither ethical nor financial conflicts of interest involved in the manuscript. The manuscript contains only unpublished review and is not being submitted for publication elsewhere. Compliance with Ethical Standards Conflict of interest All other authors declare no conflict of interest. Ethical Approval

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There is no involvement of human or animal in this study.

Reference 1. de Oliveira DE, Müller-Coan BG, Pagano JS. Viral carcinogenesis beyond malignant transformation: EBV in the progression of human cancers. Trends in microbiology. 2016;24(8):649-64. 2. Mager D. Bacteria and cancer: cause, coincidence or cure? A review. Journal of translational medicine. 2006;4(1):14. 3. Botelho MC, Alves H, Richter J. Halting Schistosoma haematobium-associated bladder cancer. International journal of cancer management. 2017;10(9). 4. Scanu T, Spaapen RM, Bakker JM, Pratap CB, Wu LE, Hofland I, et al. Salmonella Manipulation of Host Signaling Pathways Provokes Cellular Transformation Associated with Gallbladder Carcinoma. Cell Host Microbe. 2015;17(6):763-74. 5. Plummer M, Franceschi S, Vignat J, Forman D, de Martel C. Global burden of gastric cancer attributable to Helicobacter pylori. International journal of cancer. 2015;136(2):487-90. 6. Blaser MJ, Webb GF. Host demise as a beneficial function of indigenous microbiota in human hosts. MBio. 2014;5(6):e02262-14. 7. van Elsland D, Neefjes J. Bacterial infections and cancer. EMBO reports. 2018;19(11). 8. Ferlay J. GLOBOCAN 2008, cancer incidence and mortality worldwide: IARC CancerBase No. 10. http://globocan iarc fr. 2010. 9. Holmes RS, Vaughan TL, editors. Epidemiology and pathogenesis of esophageal cancer. Seminars in radiation oncology; 2007: Elsevier. 10. O'Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO reports. 2006;7(7):688-93. 11. Gagliardi D, Makihara S, Corsi P, De Toledo Viana A, Wiczer M, Nakakubo S, et al. Microbial flora of the normal esophagus. Diseases of the Esophagus. 1998;11(4):248-50. 12. Pei Z, Yang L. Bacterial biota in reflux esophagitis and Barrett’s esophagus. World journal of gastroenterology. 2005;11(46):7277. 13. Blackett K, Siddhi S, Cleary S, Steed H, Miller M, Macfarlane S, et al. Oesophageal bacterial biofilm changes in gastro‐oesophageal reflux disease, Barrett's and oesophageal carcinoma: association or causality? Alimentary pharmacology & therapeutics. 2013;37(11):1084-92. 14. Sawada A, Fujiwara Y, Nagami Y, Tanaka F, Yamagami H, Tanigawa T, et al. Alteration of esophageal microbiome by antibiotic treatment does not affect incidence of rat esophageal adenocarcinoma. Digestive diseases and sciences. 2016;61(11):3161-8. 15. Zaidi AH, Kelly LA, Kreft RE, Barlek M, Omstead AN, Matsui D, et al. Associations of microbiota and toll-like receptor signaling pathway in esophageal adenocarcinoma. BMC Cancer. 2016;16:52. 16. Yamamura K, Baba Y, Nakagawa S, Mima K, Miyake K, Nakamura K, et al. Human Microbiome Fusobacterium Nucleatum in Esophageal Cancer Tissue Is Associated with Prognosis. Clin Cancer Res. 2016;22(22):5574-81. 17. Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F. Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol Biomarkers Prev. 2014;23(5):700-13. 18. Marshall BJ. The discovery that Helicobacter pylori, a spiral bacterium, caused peptic ulcer disease. Helicobacter Pioneers Singapore: Blackwell Science Asia. 2002:165-202. 19. Hakemi Vala M, Eyvazi S, Goudarzi H, Sarie HR, Gholami M. Evaluation of Clarithromycin Resistance Among Iranian Helicobacter pylori Isolates by E-Test and Real-Time Polymerase Chain Reaction Methods. Jundishapur J Microbiol. 2016;9(5):e29839.

22

20. Bik EM, Eckburg PB, Gill SR, Nelson KE, Purdom EA, Francois F, et al. Molecular analysis of the bacterial microbiota in the human stomach. Proceedings of the National Academy of Sciences. 2006;103(3):732-7. 21. Eyvazi S, Hakemi-Vala M. A Review Article on Helicobacter pylori Antibiotic Resistance Profile in Iran. Int J Trop Dis Health. 2015;10(1):1-12. 22. Cancer IAfRo. Schistosomes, liver flukes and Helicobacter pylori: IARC Lyon; 1994. 23. Vala MH, Eyvazi S, Goudarzi H, Sarie HR, Gholami M. Evaluation of clarithromycin resistance among Iranian Helicobacter pylori isolates by E-Test and real-time polymerase chain reaction methods. Jundishapur journal of microbiology. 2016;9(5). 24. Larussa T, Leone I, Suraci E, Imeneo M, Luzza F. Helicobacter pylori and T Helper Cells: Mechanisms of Immune Escape and Tolerance. J Immunol Res. 2015;2015:981328. 25. Bagheri N, Salimzadeh L, Shirzad H. The role of T helper 1-cell response in Helicobacter pyloriinfection. Microb Pathog. 2018;123:1-8. 26. Adamsson J, Ottsjo LS, Lundin SB, Svennerholm AM, Raghavan S. Gastric expression of IL17A and IFNgamma in Helicobacter pylori infected individuals is related to symptoms. Cytokine. 2017;99:30-4. 27. Figueiredo CA, Marques CR, Costa Rdos S, da Silva HB, Alcantara-Neves NM. Cytokines, cytokine gene polymorphisms and Helicobacter pylori infection: friend or foe? World J Gastroenterol. 2014;20(18):5235-43. 28. Tavares R, Pathak SK. Helicobacter pylori Secreted Protein HP1286 Triggers Apoptosis in Macrophages via TNF-Independent and ERK MAPK-Dependent Pathways. Front Cell Infect Microbiol. 2017;7:58. 29. Graham DY. Helicobacter pylori update: gastric cancer, reliable therapy, and possible benefits. Gastroenterology. 2015;148(4):719-31.e3. 30. Kao CY, Sheu BS, Wu JJ. Helicobacter pylori infection: An overview of bacterial virulence factors and pathogenesis. Biomed J. 2016;39(1):14-23. 31. Hatakeyama M. Helicobacter pylori CagA and gastric cancer: a paradigm for hit-and-run carcinogenesis. Cell Host Microbe. 2014;15(3):306-16. 32. Gunawardhana N, Jang S, Choi YH, Hong YA, Jeon YE, Kim A, et al. Helicobacter pyloriInduced HB-EGF Upregulates Gastrin Expression via the EGF Receptor, C-Raf, Mek1, and Erk2 in the MAPK Pathway. Front Cell Infect Microbiol. 2017;7:541. 33. Yousefi B, Samadi N, Ahmadi Y. Akt and p53R2, partners that dictate the progression and invasiveness of cancer. DNA repair. 2014;22:24-9. 34. Shimizu T, Marusawa H, Matsumoto Y, Inuzuka T, Ikeda A, Fujii Y, et al. Accumulation of somatic mutations in TP53 in gastric epithelium with Helicobacter pylori infection. Gastroenterology. 2014;147(2):407-17.e3. 35. Capurro M, Greenfield L, Wong H, Robinson L, Jones N. A271 THE HELICOBACTER PYLORI VACA TOXIN IMPAIRS LYSOSOMAL CALCIUM CHANNEL TRPML1 ACTIVITY TO PROMOTE COLONIZATION. Journal of the Canadian Association of Gastroenterology. 2018;1(suppl_2):391-. 36. Nakano M, Hirayama T, Moss J, Yahiro K. Helicobacter pylori VacA Exhibits Pleiotropic Actions in Host Cells. Helicobacter pylori: Springer; 2016. p. 49-66. 37. Su YL, Huang HL, Huang BS, Chen PC, Chen CS, Wang HL, et al. Combination of OipA, BabA, and SabA as candidate biomarkers for predicting Helicobacter pylori-related gastric cancer. Sci Rep. 2016;6:36442. 38. Hanada K, Uchida T, Tsukamoto Y, Watada M, Yamaguchi N, Yamamoto K, et al. Helicobacter pylori infection introduces DNA double-strand breaks in host cells. Infect Immun. 2014;82(10):4182-9. 39. Maeda M, Moro H, Ushijima T. Mechanisms for the induction of gastric cancer by Helicobacter pylori infection: aberrant DNA methylation pathway. Gastric Cancer. 2017;20(Suppl 1):8-15.

23

40. Dias-Jacome E, Libanio D, Borges-Canha M, Galaghar A, Pimentel-Nunes P. Gastric microbiota and carcinogenesis: the role of non-Helicobacter pylori bacteria - A systematic review. Rev Esp Enferm Dig. 2016;108(9):530-40. 41. Pachathundikandi SK, Lind J, Tegtmeyer N, El-Omar EM, Backert S. Interplay of the Gastric Pathogen Helicobacter pylori with Toll-Like Receptors. Biomed Res Int. 2015;2015:192420. 42. Kai K, Aishima S, Miyazaki K. Gallbladder cancer: Clinical and pathological approach. World J Clin Cases. 2014;2(10):515-21. 43. Shukla SK, Singh G, Shahi KS, Bhuvan, Pant P. Staging, Treatment, and Future Approaches of Gallbladder Carcinoma. J Gastrointest Cancer. 2018;49(1):9-15. 44. Yousefi B, Samadi N, Baradaran B, Shafiei‐Irannejad V, Zarghami N. Peroxisome proliferator‐ activated receptor ligands and their role in chronic myeloid leukemia: Therapeutic strategies. Chemical biology & drug design. 2016;88(1):17-25. 45. Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol. 2014;6:99-109. 46. Sharma A, Sharma KL, Gupta A, Yadav A, Kumar A. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update. World J Gastroenterol. 2017;23(22):3978-98. 47. Goetze TO. Gallbladder carcinoma: Prognostic factors and therapeutic options. World J Gastroenterol. 2015;21(43):12211-7. 48. Tsuchiya Y, Loza E, Villa-Gomez G, Trujillo CC, Baez S, Asai T, et al. Metagenomics of Microbial Communities in Gallbladder Bile from Patients with Gallbladder Cancer or Cholelithiasis. Asian Pac J Cancer Prev. 2018;19(4):961-7. 49. Gonzalez-Escobedo G, Marshall JM, Gunn JS. Chronic and acute infection of the gall bladder by Salmonella Typhi: understanding the carrier state. Nature Reviews Microbiology. 2011;9(1):9. 50. Vaishnavi C, Singh S, Kochhar R, Bhasin D, Singh G, Singh K. Prevalence of Salmonella enterica serovar Typhi in bile and stool of patients with biliary diseases and those requiring biliary drainage for other purposes. Japanese journal of infectious diseases. 2005;58(6):363. 51. Mohammadzadeh R, Baradaran B, Valizadeh H, Yousefi B, Zakeri-Milani P. Reduced ABCB1 expression and activity in the presence of acrylic copolymers. Advanced pharmaceutical bulletin. 2014;4(3):219. 52. Crawford RW, Gibson DL, Kay WW, Gunn JS. Identification of a bile-induced exopolysaccharide required for Salmonella biofilm formation on gallstone surfaces. Infection and immunity. 2008;76(11):5341-9. 53. Koshiol J, Wozniak A, Cook P, Adaniel C, Acevedo J, Azócar L, et al. Salmonella enterica serovar Typhi and gallbladder cancer: a case–control study and meta‐analysis. Cancer medicine. 2016;5(11):3310-235. 54. Espinoza JA, Bizama C, Garcia P, Ferreccio C, Javle M, Miquel JF, et al. The inflammatory inception of gallbladder cancer. Biochim Biophys Acta. 2016;1865(2):245-54. 55. Van Dyke AL, Kemp TJ, Corbel AF, Zhu B, Gao YT, Wang BS, et al. Lipopolysaccharidepathway proteins are associated with gallbladder cancer among adults in Shanghai, China with mediation by systemic inflammation. Ann Epidemiol. 2016;26(10):704-9. 56. Di Domenico EG, Cavallo I, Pontone M, Toma L, Ensoli F. Biofilm Producing Salmonella Typhi: Chronic Colonization and Development of Gallbladder Cancer. Int J Mol Sci. 2017;18(9). 57. Majidinia M, Yousefi B. DNA repair and damage pathways in breast cancer development and therapy. DNA repair. 2017;54:22-9. 58. Nagaraja V, Eslick GD. Systematic review with meta-analysis: the relationship between chronic Salmonella typhi carrier status and gall-bladder cancer. Aliment Pharmacol Ther. 2014;39(8):745-50. 59. Iyer P, Barreto SG, Sahoo B, Chandrani P, Ramadwar MR, Shrikhande SV, et al. Non-typhoidal Salmonella DNA traces in gallbladder cancer. Infect Agent Cancer. 2016;11:12. 60. Murphy G, Michel A, Taylor PR, Albanes D, Weinstein SJ, Virtamo J, et al. Association of seropositivity to Helicobacter species and biliary tract cancer in the ATBC study. Hepatology. 2014;60(6):1963-71. 24

61. Hassan EH, Gerges SS, El-Atrebi KA, El-Bassyouni HT. The role of H. pylori infection in gall bladder cancer: clinicopathological study. Tumour Biol. 2015;36(9):7093-8. 62. Murata H, Tsuji S, Tsujii M, Fu H, Tanimura H, Tsujimoto M, et al. Helicobacter bilis infection in biliary tract cancer. Alimentary pharmacology & therapeutics. 2004;20:90-4. 63. Mashayekhi F, Moghny M, Faramarzpoor M, Yahaghi E, Khodaverdi Darian E, Tarhriz V, et al. Molecular characterization and antimicrobial resistance of uropathogenic Escherichia coli. Iranian Journal of Biotechnology. 2014;12(2):32-40. 64. Wu S, Rhee K-J, Albesiano E, Rabizadeh S, Wu X, Yen H-R, et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nature medicine. 2009;15(9):1016. 65. Martin HM, Campbell BJ, Hart CA, Mpofu C, Nayar M, Singh R, et al. Enhanced Escherichia coli adherence and invasion in Crohn’s disease and colon cancer. Gastroenterology. 2004;127(1):80-93. 66. Masseret E, Boudeau J, Colombel J, Neut C, Desreumaux P, Joly B, et al. Genetically related Escherichia colistrains associated with Crohn's disease. Gut. 2001;48(3):320-5. 67. McCoy W. Enterococcal endocarditis associated with carcinoma the sigmoid. J Med Assoc State Ala. 1951;21:162-5. 68. Reynolds JG, Silva E, McCormack WM. Association of Streptococcus bovis bacteremia with bowel disease. Journal of clinical microbiology. 1983;17(4):696-7. 69. Bayliss R, Clarke C, Oakley C, Somerville W, Whitfield A, Young S. The bowel, the genitourinary tract, and infective endocarditis. Heart. 1984;51(3):339-45. 70. Burns CA, McCaughey R, Lauter CB. The association of Streptococcus bovis fecal carriage and colon neoplasia: possible relationship with polyps and their premalignant potential. American Journal of Gastroenterology. 1985;80(1). 71. Gold JS, Bayar S, Salem RR. Association of Streptococcus bovis bacteremia with colonic neoplasia and extracolonic malignancy. Archives of Surgery. 2004;139(7):760-5. 72. Biarc J, Nguyen IS, Pini A, Gosse F, Richert S, Thierse D, et al. Carcinogenic properties of proteins with pro-inflammatory activity from Streptococcus infantarius (formerly S. bovis). Carcinogenesis. 2004;25(8):1477-84. 73. Müller MF, Ibrahim AE, Arends MJ. Molecular pathological classification of colorectal cancer. Virchows Archiv. 2016;469(2):125-34. 74. Liu Z, Xu X, Chen L, Li W, Sun Y, Zeng J, et al. Helicobacter pylori CagA inhibits the expression of Runx3 via Src/MEK/ERK and p38 MAPK pathways in gastric epithelial cell. Journal of cellular biochemistry. 2012;113(3):1080-6. 75. Kumar R, Herold JL, Schady D, Davis J, Kopetz S, Martinez-Moczygemba M, et al. Streptococcus gallolyticus subsp. gallolyticus promotes colorectal tumor development. PLoS pathogens. 2017;13(7):e1006440. 76. Aymeric L, Donnadieu F, Mulet C, du Merle L, Nigro G, Saffarian A, et al. Colorectal cancer specific conditions promote Streptococcus gallolyticus gut colonization. Proceedings of the National Academy of Sciences. 2018;115(2):E283-E91. 77. Yu T, Guo F, Yu Y, Sun T, Ma D, Han J, et al. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell. 2017;170(3):548-63. e16. 78. Pasquereau-Kotula E, Martins M, Aymeric L, Dramsi S. Significance of Streptococcus gallolyticus subsp. gallolyticus association with colorectal cancer. Frontiers in microbiology. 2018;9:614. 79. Montazami N, Kheir Andish M, Majidi J, Yousefi M, Yousefi B, Mohamadnejad L, et al. siRNA-mediated silencing of MDR1 reverses the resistance to oxaliplatin in SW480/OxR colon cancer cells. Cellular and molecular biology (Noisy-le-Grand, France). 2015;61(2):98-103. 80. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International journal of cancer. 2015;136(5):E359-E86. 81. Greathouse KL, White JR, Vargas AJ, Bliskovsky VV, Beck JA, von Muhlinen N, et al. Interaction between the microbiome and TP53 in human lung cancer. Genome biology. 2018;19(1):123. 25

82. Dean AG, Kreis R. Understanding Lung Cancer: Presentation, Screening, and Treatment Advances. The Journal for Nurse Practitioners. 2018;14(4):316-22. 83. Apostolou P, Tsantsaridou A, Papasotiriou I, Toloudi M, Chatziioannou M, Giamouzis G. Bacterial and fungal microflora in surgically removed lung cancer samples. Journal of cardiothoracic surgery. 2011;6(1):137. 84. Huang Q, Duan L, Qian X, Fan J, Lv Z, Zhang X, et al. IL-17 Promotes Angiogenic Factors IL-6, IL-8, and Vegf Production via Stat1 in Lung Adenocarcinoma. Sci Rep. 2016;6:36551. 85. Faden AA. The potential role of microbes in oncogenesis with particular emphasis on oral cancer. Saudi medical journal. 2016;37(6):607. 86. Jobin C. The microbiome and cancer. Nat Rev Cancer. 2013;13:800-12. 87. Garn H, Neves JF, Blumberg RS, Renz H. Effect of barrier microbes on organ-based inflammation. Journal of Allergy and Clinical Immunology. 2013;131(6):1465-78. 88. Mao Q, Jiang F, Yin R, Wang J, Xia W, Dong G, et al. Interplay between the lung microbiome and lung cancer. Cancer letters. 2018;415:40-8. 89. Vanacore D, Boccellino M, Rossetti S, Cavaliere C, D'Aniello C, Di Franco R, et al. Micrornas in prostate cancer: an overview. Oncotarget. 2017;8(30):50240-51. 90. Caraglia M, Alaia C, Grimaldi A, Boccellino M, Quagliuolo L. MiRNA as prognostic and therapeutic targets in tumor of male urogenital tract. Molecular Targets and Strategies in Cancer Prevention: Springer; 2016. p. 151-71. 91. Stark T, Livas L, Kyprianou N. Inflammation in prostate cancer progression and therapeutic targeting. Transl Androl Urol. 2015;4(4):455-63. 92. Sfanos KS, De Marzo AM. Prostate cancer and inflammation: the evidence. Histopathology. 2012;60(1):199-215. 93. Hayes RB, Pottern LM, Strickler H, Rabkin C, Pope V, Swanson GM, et al. Sexual behaviour, STDs and risks for prostate cancer. Br J Cancer. 2000;82(3):718-25. 94. Hernández-Luna MA, Lagunes-Servin HE, Lopez-Briones S. The role of Escherichia coli in the development and progression of cancer. ARC Journal of Cancer Science. 2016;3(1):1-11. 95. Muenzner P, Kengmo Tchoupa A, Klauser B, Brunner T, Putze J, Dobrindt U, et al. Uropathogenic E. coli Exploit CEA to Promote Colonization of the Urogenital Tract Mucosa. PLoS Pathog. 2016;12(5):e1005608. 96. Feng W, Han Z, Zhu R, Liu P, Liu S. Association of p16 gene methylation with prostate cancer risk: a meta-analysis. J buon. 2015;20(4):1074-80. 97. Tolg C, Sabha N, Cortese R, Panchal T, Ahsan A, Soliman A, et al. Uropathogenic E. coli infection provokes epigenetic downregulation of CDKN2A (p16INK4A) in uroepithelial cells. Laboratory investigation. 2011;91(6):825. 98. Simons BW, Durham NM, Bruno TC, Grosso JF, Schaeffer AJ, Ross AE, et al. A human prostatic bacterial isolate alters the prostatic microenvironment and accelerates prostate cancer progression. The Journal of pathology. 2015;235(3):478-89. 99. Rennebeck G, Martelli M, Kyprianou N. Anoikis and survival connections in the tumor microenvironment: is there a role in prostate cancer metastasis? Cancer research. 2005;65(24):11230-5. 100. Stallone G, Cormio L, Netti GS, Infante B, Selvaggio O, Fino GD, et al. Pentraxin 3: a novel biomarker for predicting progression from prostatic inflammation to prostate cancer. Cancer Res. 2014;74(16):4230-8. 101. Ginsburg O, Bray F, Coleman MP, Vanderpuye V, Eniu A, Kotha SR, et al. The global burden of women's cancers: a grand challenge in global health. Lancet. 2017;389(10071):847-60. 102. Hillemanns P, Soergel P, Hertel H, Jentschke M. Epidemiology and Early Detection of Cervical Cancer. Oncol Res Treat. 2016;39(9):501-6. 103. Yue XA, Chen P, Tang Y, Wu X, Hu Z. The dynamic changes of vaginal microecosystem in patients with recurrent vulvovaginal candidiasis: a retrospective study of 800 patients. Arch Gynecol Obstet. 2015;292(6):1285-94.

26

104. Di Paola M, Sani C, Clemente AM, Iossa A, Perissi E, Castronovo G, et al. Characterization of cervico-vaginal microbiota in women developing persistent high-risk Human Papillomavirus infection. Sci Rep. 2017;7(1):10200. 105. Mikamo H, Izumi K, Ito K, Watanabe K, Ueno K, Tamaya T. Internal bacterial flora of solid uterine cervical cancer. Kansenshogaku Zasshi. 1993;67(11):1057-61. 106. Audirac-Chalifour A, Torres-Poveda K, Bahena-Roman M, Tellez-Sosa J, Martinez-Barnetche J, Cortina-Ceballos B, et al. Cervical Microbiome and Cytokine Profile at Various Stages of Cervical Cancer: A Pilot Study. PLoS One. 2016;11(4):e0153274. 107. Mikamo H, Sato Y, Hayasaki Y, Kawazoe K, Izumi K, Ito K, et al. Intravaginal bacterial flora in patients with uterine cervical cancer. High incidence of detection of Gardnerella vaginalis. J Infect Chemother. 1999;5(2):82-5. 108. Pavic N. Is there a local production of nitrosamines by the vaginal microflora in anaerobic vaginosis/trichomoniasis? Med Hypotheses. 1984;15(4):433-6. 109. Biswal BM, Singh KKB, Ismail MB, Jalal MIBA, Safruddin EISBE. Current Concept of Bacterial Vaginosis in Cervical Cancer. Journal of Clinical Gynecology and Obstetrics. 2014;3(1):1-7. 110. Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2010;10(1):9-22. 111. Badgwell D, Bast Jr RC. Early detection of ovarian cancer. Disease markers. 2007;23(5, 6):397410. 112. Momenimovahed Z, Tiznobaik A, Taheri S, Salehiniya H. Ovarian cancer in the world: epidemiology and risk factors. International journal of women's health. 2019;11:287. 113. Xie X, Yang M, Ding Y, Chen J. Microbial infection, inflammation and epithelial ovarian cancer. Oncology letters. 2017;14(2):1911-9. 114. Ka W. Berman sM, Centers for Disease Control and Prevention. sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. 2006;55:1-94. 115. Edgar RC. UNOISE2: improved error-correction for Illumina 16S and ITS amplicon sequencing. BioRxiv. 2016:081257. 116. Amir A, McDonald D, Navas-Molina JA, Kopylova E, Morton JT, Xu ZZ, et al. Deblur rapidly resolves single-nucleotide community sequence patterns. MSystems. 2017;2(2):e00191-16. 117. Eren AM, Morrison HG, Lescault PJ, Reveillaud J, Vineis JH, Sogin ML. Minimum entropy decomposition: unsupervised oligotyping for sensitive partitioning of high-throughput marker gene sequences. The ISME journal. 2015;9(4):968. 118. Yu Y, Champer J, Beynet D, Kim J, Friedman AJ. The role of the cutaneous microbiome in skin cancer: lessons learned from the gut. Journal of drugs in dermatology: JDD. 2015;14(5):461-5. 119. Ye W, Held M, Lagergren J, Engstrand L, Blot WJ, McLaughlin JK, et al. Helicobacter pylori infection and gastric atrophy: risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia. Journal of the National Cancer Institute. 2004;96(5):388-96. 120. Kostic AD, Gevers D, Pedamallu CS, Michaud M, Duke F, Earl AM, et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome research. 2012;22(2):292-8. 121. Luu TH, Michel C, Bard J-M, Dravet F, Nazih H, Bobin-Dubigeon C. Intestinal proportion of Blautia sp. is associated with clinical stage and histoprognostic grade in patients with early-stage breast cancer. Nutrition and cancer. 2017;69(2):267-75. 122. Fernández MF, Reina-Pérez I, Astorga JM, Rodríguez-Carrillo A, Plaza-Díaz J, Fontana L. Breast cancer and its relationship with the microbiota. International journal of environmental research and public health. 2018;15(8):1747. 123. Rea D, Coppola G, Palma G, Barbieri A, Luciano A, Del Prete P, et al. Microbiota effects on cancer: from risks to therapies. Oncotarget. 2018;9(25):17915. 124. Sampson JN, Falk RT, Schairer C, Moore SC, Fuhrman BJ, Dallal CM, et al. Association of estrogen metabolism with breast cancer risk in different cohorts of postmenopausal women. Cancer research. 2017;77(4):918-25.

27

125. Vogtmann E, Goedert JJ. Epidemiologic studies of the human microbiome and cancer. British journal of cancer. 2016;114(3):237. 126. Thompson KJ, Ingle JN, Tang X, Chia N, Jeraldo PR, Walther-Antonio MR, et al. A comprehensive analysis of breast cancer microbiota and host gene expression. PloS one. 2017;12(11):e0188873. 127. Wang H, Altemus J, Niazi F, Green H, Calhoun BC, Sturgis C, et al. Breast tissue, oral and urinary microbiomes in breast cancer. Oncotarget. 2017;8(50):88122. 128. Morgan LL. The epidemiology of glioma in adults: a “state of the science” review. Neurooncology. 2015;17(4):623-4. 129. Almairac F, Frenay M, Paquis P. Genetic diseases and glioblastomas. Neuro-Chirurgie. 2010;56(6):455-8. 130. Florian I, Ungureanu G, Berce C. Risk factors for gliomas. An extensive review. Romanian Neurosurgery. 2013;20(1):5-21. 131. Hochhalter CB, Carr C, O'Neill BE, Ware ML, Strong MJ. The association between human cytomegalovirus and glioblastomas: a review. Neuroimmunol Neuroinflammation. 2017;4:96. 132. Pagano JS, Blaser M, Buendia M-A, Damania B, Khalili K, Raab-Traub N, et al., editors. Infectious agents and cancer: criteria for a causal relation. Seminars in cancer biology; 2004: Elsevier. 133. Schuman LM, Choi N, Gullen W. Relationship of central nervous system neoplasms to Toxoplasma gondii infection. American Journal of Public Health and the Nations Health. 1967;57(5):848-56. 134. Bitnun A, Richardson SE. Mycoplasma pneumoniae: innocent bystander or a true cause of central nervous system disease? Current infectious disease reports. 2010;12(4):282-90. 135. Zhang B, Izadjoo M, Horkayne-Szakaly I, Morrison A, Wear DJ. Medulloblastoma and brucellosis-molecular evidence of Brucella sp in association with central nervous system cancer. Journal of Cancer. 2011;2:136. 136. Aviles-Jimenez F, Yu G, Torres-Poveda K, Madrid-Marina V, Torres J. On the search to elucidate the role of microbiota in the genesis of cancer: the cases of gastrointestinal and cervical cancer. Archives of medical research. 2017;48(8):754-65. 137. Liu Y, O’Brien JL, Ajami NJ, Scheurer ME, Amirian ES, Armstrong G, et al. Lung tissue microbial profile in lung cancer is distinct from emphysema. American journal of cancer research. 2018;8(9):1775. 138. Yang Y, Dong J, Sun K, Zhao L, Zhao F, Wang L, et al. Obesity and incidence of lung cancer: a meta‐analysis. International journal of cancer. 2013;132(5):1162-9.

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Table 1. Current findings of relationship between lung microbiota and lung disease Infection agents Common LC Mycobacterium tuberculosis Capnocytophaga Megasphaera Granulicatella Abiotrophia Haemophilus influenza Enterobacter sp. Escherichia coli Streptococcus Capnocytophaga Selenomonas Neisseria Fusobacterium nucleatum Veillonella Thermus Ralstonia Actinobacter Acidovorax Prevotella Bifidobacterium Diaphorobacter Sphingomonas Ruminococcus Aggregatibacter Limnobacter Finegoldia Akkermansia Methylobacterium Blautia Pantoea Dialister Sarcina Anaerostipes Paracoccus Asthma infection agents Haemophilus spp . Streptococcus spp. Moraxella Neisseria Fusobacterium Porphyromonas

references

(88, 136-138)

(138)

Cystic fibrosis infection agents Prevotella Haemophilus Porphyromonas Veillonella Staphylococcus Burkholderia Streptococcus Pseudomonas Stenotrophomonas Achromobacter

(138)

lung transplantation agents Pseudomonas aeruginosa

(138)

29

Staphylococcus aureus Chronic obstructive pulmonary disease agents

Cancer type

The main bacteria associated with the cancer

Host –related responses

Pseudomonas Streptococcus Prevotella Haemophilus Ochrobactrum Stenotrophomonas Propionibacterium Lactobacillus Leptotrichia Fusobacterium Corynebacterium Moraxella Porphyromonas Veillonella

Bacterial factors

Reference

(88)

Idiopathic pulmonary fibrosis Streptococcus Prevotella Staphylococcus Veillonella Haemophilus Pseudomonas

(88)

Table 2. The main bacteria associated with the cancer, host –related responses and oncological mechanisms of bacteria in the promotion of cancers

30

E. coli

Bacterial components such Increasing of TLR 1-3, 6, 7 as lipopeptides, RNA, and 9 signaling pathways DNA

(15)

Increasing of chemokines genes such as CCL20

Bacterial components such as cell wall

(16)

Activation of both innate and adaptive immune response mainly CD4 Th1cell response

CagA BabA Peptidoglycan VacA Urease Oxidative radicals

(30)

inflammation following increasing of LBP and CD14

LPS CDT bacterial glucoronidase, secondary bile acids and nitroso compounds

(53)

Esophageal cancer Fusobacterium nucleatum H. pylori

Gastric cancer

S. Typhi Gallbladder cancer

Bacteroides fragilis strains, including nontoxigenic B. fragilis and enterotoxigenic. B. fragilis Colorectal cancer

E. coli

S. bovis

lung cancer

Prostate cancer

Ovarian cancer Breast cancer

increasing the levels of Th17 and Treg cells

Inflammation Inflammation by releasing chemokines such as IL-8 and prostaglandin E2

Induced bone morphogenetic protein (BMP) 2 overexpression Releasing tumor necrosis factor, interleukin-7, interleukin-2, RANTES, E. coli and macrophage inflammatory protein-1, Th17 responses Inflammation due to Chlamydia releasing of (IFN)-γ, GMtrachomatis, CSF IL-6, IL-8, IL-10 and Mycoplasma genitalium IL-12 Clostridia, Inflammation, Ruminococcaceae

metalloprotease toxin of Bacteroides fragilis

CDT CNF wall extracted antigens (WEA), cell-associated proteins such as S300 bacteriocin

Mycoplasma

31

(64)

(66)

(71, 72, 76)

(88)

Bacterial components such as lipopeptides, RNA, DNA, Afa/Dr adhesion molecule

(94, 95)

Bacterial components

(132, 135)

estrogen-metabolizing enzymes such as β-

(120, 122)

families

glucuronidase

32

Figure 1. H. pylori can exert its oncogenic effects through a variety of mechanisms.

33

Figure 1. Carcinogenic pathways of S. Typhi in GBC.

34

Microbial infections as the most common infectious agents are reported to be emerging players in the establishment of malignant cells. World Health Organization (WHO) describes bacterium as class I carcinogens and several bacterial infections have been reported in association with prevalent cancers. In this review, we will summarize the role of known bacterial infections in the initiation of the main common cancers. Examining the microbiomes in cancer patients is important and necessary to better understand the pathogenesis of this disease and also to plan therapeutic interventions.