Review The Role Of Respiratory Microbiota In Lung Cancer

Int. J. Biol. Sci. 2021, Vol. 17and H. pylori [20] infection take part in promoting thedevelopment of lung cancer. Compared with adjacentnormal tissues, the contents of Modestobacter in lungcancer tissues are higher, but Propionibacterium andEnterobacteriaceae are lower [21]. A lower airwaymicrobiome analysis showed that Bradyrhizobiumjaponicum could only be detected in lung cancerpatients, but the genus Acidovorax could be detected innot only patients with lung cancer but also patientswith benign lung disease [22]. Moreover, the numbersof Eubacterium xylanophilum, Eubacterium eligens andClostridium in the human respiratory tract tend tohave a positive correlation with the occurrence ofsmall cell lung cancer (SCLC), and the number ofPrevotella and Pseudobutyrivibrio ruminis may have anegative correlation with the occurrence of SCLC [23].Various microorganisms form a complexregulatory network linked with lung cancer. Differentmicroorganisms in the same type of lung cancer or thesame microorganisms in different types of lung cancermay play different roles. Additional elaboration of thedetailed regulatory network of microorganisms inlung cancer is expected.Pulmonary flora and lung cancerThe opinion of the aseptic lung has beenrepudiated. Many studies have found that thedominant populations in healthy lungs of adults areFirmicutes, Bacteroidetes, Proteobacteria, Actinobacteria,and Fusobacterium [24, 25]. Furthermore, there are alsorelated findings that for healthy adults, the lungmicrobiome has no significant difference in spatialspace [25]. In terms of diversity analysis, there was nosignificant difference in beta diversity betweennonmalignant lung tissue and tumor lung tissues, butthe alpha diversity of the microbial group wassignificantly reduced in tumor lung tissues [26].Lung microorganisms are closely related tocertain lung diseases and health because microbiomedysbiosis may increase tumor susceptibility bychanging metabolism, altering the immune response,promoting inflammation, and increasing toxic effects[27]. Therefore, defining the composition and changesof the microbial group in lung cancer patients isconducive to deepening the understanding of themechanism of lung cancer. At the same time, thisknowledge may provide new ideas for preventinglung cancer or treatment intervention. For example,the epidemiological relationship between M.tuberculosis and lung cancer can be explained by themechanism of chronic inflammation-associatedcarcinogenesis [28].The results of an experimental analysis ofcontralateral bronchoalveolar lavage fluid (BALF)samples via 16S rRNA sequencing showed that the3648number of operational taxonomic units (OTUs) wassignificantly different between the lung cancer groupand the benign mass-like lesion group, whileβ-diversity was still no different. The Chao 1 andShannon indices in the lung cancer group were higherthan those in the normal group. Among the fivedetected phyla and seven detected genera, the phylawith increased relative abundance were Firmicutesand TM7 in the lung cancer group while the mostabundant genera were Eillonella, Megasphaera,Atopobium and Selenomonas. The abundance ofAtopobium and Selenomonas decreased in both groups[29]. These changes may suggest a way to affect nt.In addition, the proportion of Firmicutes/Bacteroidetes in the lung cancer group with smokingwas significantly higher than that in the lung cancergroup with nonsmoking, and the relative abundanceof some bacteria was different from that in thenonsmoker group. Meanwhile, increased TM7 in bothchronic obstructive pulmonary disease (COPD) andlung cancer suggests that TM7 is likely to promote theprogression of COPD to lung cancer. Finally,Megasphaera and Veillonella were identified asbiomarkers for lung cancer, meaning they could beused to predict lung cancer or as microbial therapeutictargets [29].Another study collecting saliva and BALF foundthat the microbial alpha diversity in lung cancerpatients was low, and this difference from the controlgroup was not related to the sampling site. However,certain bacterial groups associated with lung cancerare affected by the sampling site and pathologicaltype, and the same is true for the metabolicdifferences of the microbial population. Via KEGGmetabolic pathway enrichment analysis andfunctional analysis, activated and enriched behaviorsusually include antibiotic resistance and sorting,folding and degradation as well as metabolism ofamino acids and glycans. However, regardless of thesampling site, the microbiota composition differedbetween the two groups. Finally, the study alsosuggests that the good bacterial biomarkers in BALFare Treponema and Filifactor and that Filifactor hasgood resolution in distinguishing between healthycontrols and lung cancer patients [30].However, symbiotic microbial biomarkers oflung cancer or microbial therapies still require furtherlarge-scale studies.Respiratory system fungi, viruses and lungcancerA retrospective study suggested that pulmonarylymphoepithelioma-like carcinoma is closely relatedhttp://www.ijbs.com

Int. J. Biol. Sci. 2021, Vol. 173649to Epstein-Barr virus (EBV) infection, and EBV latentinfection is the main state of pulmonarylymphoepithelioma-like carcinoma [31]. sitive pulmonary lymphoepithelioma-likecarcinoma (LELC) cases, latent membrane protein1(LMP1) and viral capsid antigen (VCA) areexpressed in approximately half and a quarter of thesecases, respectively. Many recent related studiesconfirm that lymphoid-specific helicase (LSH) canaffect the occurrence and development of non-smallcell lung cancer (NSCLC) in cancer metabolism andepigenetics through different mechanisms or asintermediate products. For example, Go, Ichi, Nii, andSan complex subunit 4 (GINS4) is highly expressed inNSCLC and contributes to tumorigenesis. LSHincreases GINS4 expression by binding to the3'-untranslated region [32]. Moreover, LSH promoteslipid metabolism-related genes and becomes a vitalinhibitor of ferroptosis in carcinogenesis in vitro or invivo. The increased expression of LSH is regulated byEGLN1 and c-Myc [33]. The overexpression of LSH innasopharyngeal carcinoma is linked to EBV infection,and LSH becomes a cancer driver by suppressing theactivity of fumarate hydratase [34, 35].cumulative incidence of lung cancer amongHIV-infected groups continues to rise. In addition to areduction in all-cause mortality, immunosuppression,pulmonary inflammation, and systemic inflammationare all specific risk factors for increased risk [38].There are studies that suggest that direct viraloncogenesis is a mechanism of lung cancer in HIVinfection, but there is no exact support for direct HIVoncogenesis in the lungs. Only some early studieshave shown some direct oncogenic activity amongHIV virus proteins. Studies evaluating antiretroviraltreatment did not lead to a higher risk of cancer. Inaddition, the hypothesis that P450 cytochromeinhibitors may affect the metabolism of lung cancercarcinogens has not been found in The FrenchHospital Database [39].In short, the types and quantities of humanmicroorganisms are very large. Although the HumanMicrobiome Project (HMP) does not use the lung asan organ of research, the traditional view that the lungis sterile has been overthrown, and the study of themicrobiome in the lung has developed rapidly as anew field. There are still many areas worth exploring.Table 1. Representative bacteria in different circumstancesNormalRespiratory Tract ①,②Phylum and class:Proteobacteria, Firmicutes, Fusobacteria,Bacteroidetes.Genus:Pseudomonas, Streptococcus, Prevotella,Veillonella, Haemophilus, Neisseria.Propionibacterium, Enterobacteriaceae,Prevotella, Pseudobutyrivibrio, onasMore M.tuberculosis, Helicobacter, Pylori,Phylum:Actinomyces, Peptostreptococcus,FirmicutesStreptococcus, Wechsler, Modestobacter, TM7Eubacterium xylanophilum, EubacteriumGenus:Eligens, Clostridium.Veillonella,Megasphaera FilifactorSelenomonasCancer LessA clinical study across Taiwan showed that ahigh risk of lung cancer involved being exposed toinfluenza and that there was more risk aftercumulative exposure to flu. However, the mechanismis currently unknown [36]. In samples from patientswith lung adenocarcinoma, the prevalence of JohnCunningham virus (JC virus) and whether virus waspresent in metastatic lymph nodes were evaluated,suggesting that JC virus may be involved in lungcancer [37].The data show that the incidence of lung cancerin human immunodeficiency virus (HIV)-infectedpatients is higher than that in uninfected patients. TheFigure 1. Representative bacteria in different circumstances. In the normalrespiratory tract, the representative phyla and classes are Proteobacteria andFirmicutes, and the representative genera are Pseudomonas and Streptoccus,respectively. In the respiratory tract with lung cancer, some bacteria tend to be lessabundant, such as Propionibacterium and Enterobacteriaceae, and some tend to be moreabundant, such as M.tuberculosis and Helicobacter. In the lungs of healthy people, themost common bacterial microorganisms are Firmicutes, Bacteroidetes, Proteobacteria,Actinobacteria, and Fusobacterium. In the lungs of patients with lung cancer, Atopobiumand Selenomonas were obviously decreased. In contrast, additional microorganismswere Firmicutes, TM7, Veillonella, Megasphaera, Filifactor and Selenomonas.http://www.ijbs.com

Int. J. Biol. Sci. 2021, Vol. 17Lung cancer-related microorganisms in othertumorsThe carcinogenesis of H. pylori, throughHelicobacter pylori toxin such as CageA, may also bea way for H. pylori to induce lung cancer [40, 41]. HPVis not only related to cervical cancer and breast cancerbut is also a risk factor for lung cancer [41, 42].Clearly, a healthy commensal microbiome istightly related to immune cell functioning. The studyof Rea Bingula et al. on the gut-lung axis mainly usedthe gut as an example and tracked the effects ofintestinal immune stimulation on the lung tospeculate that the situation originating from the lungmucosa and lymph nodes is also similar [43]. The two“cooperate” and influence each other.The lung cancer-related microorganismssummarized above have also been found in othertumors.Alterations in these changing microorganisms inthe microenvironment of other tumors have also beenreported by other papers. For example, Atopobiummay not only lead to a high risk of esophagealsquamous cell carcinoma [44] but also increase therisk of endometrial cancer in the uterus [45].Firmicutes was found to be more abundant in the urineof bladder cancer patients, and Veillonella was moreabundant in the healthy control group than in thebladder cancer group [48]. Filifactor in the oral cavityis positively related to oral squamous cell carcinoma[126, 127] and is overrepresented in the tonguecoating of pancreatic head carcinoma patients [128].Selenomonas is overrepresented in the stool ofcolorectal cancer patients [129] and is more abundantin left colorectal cancer patients compared to rightcolorectal cancer patients [130].The high risk of esophageal squamous cellcarcinoma may be related to Atopobium, a kind ofmicroorganism that is reduced in lung cancer [44]. Anin vitro experiment found that Atopobium vaginae(which becomes less abundant in lung cancer) inducesproinflammatory cytokine expression in endometrialcells and may lead to significant endometrial cancer ifPorphyromonas somerae also exists [45].In addition, Propionibacterium in the lung rium in the prostate is positivelycorrelated with prostate cancer [46, 47]. For bladdercancer, the most abundant phylum in both groupswas Firmicutes, which became more abundant in lungswith lung cancer than in healthy lungs. However,Veillonella, suggested as a lung cancer marker, is morecommon in healthy urine [48].The progress and relationship of lungcancer-related microorganisms and other tumorsneeds further research and discovery.3650The influence of pulmonarymicroorganism on lung cancerAt present, the understanding of the influence ofthe microbiota on tumors is still insufficient. Theinfluence of microorganisms on tumors involvesmany aspects, such as canceration, angiogenesis, andtherapy.The possible mechanism of the influence ofpulmonary microorganisms on lung cancercancerationIn the process of cancer occurrence,microecology deviates from the normal steady-statestructure and gradually forms the microenvironmentof promoting cancer to induce a series of chainreactions, finally causing canceration. An imbalancein the lung microecology may affect the canceration oflung cancer through inflammation, immunity,metabolism and genotoxicity.InflammationChronic lung inflammation is a critical risk factorfor lung cancer [49], and proinflammatory cytokines,adhesion molecules, and growth factors can provide afavorable microenvironment to promote the survivaland proliferation of tumor cells [50]. Microbialorganisms are confirmed to be important causativeagents of cancer-inducing inflammation [51].Membrane receptors play a vital role in cancercaused by microorganisms through the process ofinflammation. Membrane receptors such as patternrecognition receptor (PRR), cluster of designation(CD), and TLR proteins can recognize microorganisms and their production, proinflammatorycytokines and some other signaling molecules,leading to effects on apoptosis and cellularproliferation [52]. In COPD patients, infection withnontypeable Haemophilus influenzae (NTHi) can induceepithelial cells to express IL-17C and neutrophils topromote tumors [53]. Interleukin-6 (IL-6) also exerts asignificant function in lung cancer by inducing aCOPD-like inflammatory response [54].ImmunityA small number of cancer cells in the body canbe eliminated by the antitumor immune mechanism,which may malfunction with the growth of cancercells [55]. The regulation of the cancer immuneresponse by microbiota has also received moreattention.Commensal bacteria are involved in maintainingimmune homeostasis against cancer through γδT17responses [56]. Lung immunity after antibiotictreatment tends to be defective, thus creating a morefavorable environment for the occurrence of cancer.http://www.ijbs.com

Int. J. Biol. Sci. 2021, Vol. 17However, another study suggested that the localmicrobiota could activate lung-resident γδ T cells topromote inflammation associated with lungadenocarcinoma and tumor cell proliferation [9].Commensal bacteria also regulate the antitumorresponse in the lung through alveolar macrophages,maintaining their low level of CCL24 secretion [57].Although it is unknown and difficult to definewhether the immune environment is regulated byspecific bacteria with dedicated functions in the lung,the role of some bacteria has been proposed.Morganella morganii and Escherichia fergusonii, twoubiquitous opportunistic pathogens from theProteobacteria phylum in the lung, can mulatory effect [58]. NSCLC patients reactto Streptococcus salivarius and Streptococcus agalactiaewith significantly higher frequencies of T helper type17 (Th17) and Th1 cells than healthy controls [59].Recently, a study revealed that Pasteurella has apositive correlation with cytotoxic CD8 TILs and anegative correlation with M2 macrophages. There is aceae and M2 macrophages and a negativecorrelation with CD8 cells [60]. Together, theseimmune reactions affect the occurrence anddevelopment of lung tumors.These results suggest that the microbiota in therespiratory system has an important influence on theoccurrence of lung cancer, which may establish apermissive environment for lung cancer.MetabolismMicroorganisms have been proven to participatein regulating host metabolism, detoxification, vitaminlevels and nutritional status [61].Changes in microorganisms are related to theproduction of carcinogens such as acetaldehyde [62]and deoxycholic acid [63]. This metabolic imbalancemay result in the formation of carcinogens in the lungor lead to the secondary processing of foreigncarcinogens. The lung microbiota is considered to beconnected with specific insults related to lung cancervia CD36, which regulates the treatment ofcyanobacteria-derived microcystin residues in thelung alveoli, upregulating the expression of poly(ADP-ribose) polymerase 1 (PARP1) [64].Microorganisms may also play an anticancer roleby influencing metabolism. Short-chain fatty acids, asproducts of intestinal bacteria, exert antiinflammatory and antiproliferation functions [65].Moreover, butyrate treatment could lead to anupregulation of miR-3935 and an inhibition of theproliferation and migration of A549 cells [66].3651GenotoxicityHost DNA damage can cause cell death andaffect the expression of tumor suppressor genes oroncogenes. Some bacterial molecules have beenrevealed to be related to genotoxicity. For instance,Bacteroides fragilis toxin and Escherichia coli toxin havebeen found to be related to inducing double-strandedDNA damage [67, 68]. Chemicals produced bybacteria such as reactive oxygen species (ROS)produced by Porphyromonas, hydrogen sulfideproduced by Clostridium cholephilum and superoxidedismutase produced by some bacteria are alsoresponsible for genomic instability [69-71], increasingthe probability of cancer. In addition, microorganismscan also play a carcinogenic role through theintegration of their DNA and host genome.The possible mechanism of the influence ofpulmonary microorganisms on the metastasisof lung cancerMicroorganisms also play an irreplaceable rolein the metastasis of lung cancer. Oral taxa that are richin the lower airway of lung cancer patients, such ion, invasion and metastasis of lung cancercells by activating the ERK and PI3K pathways inairway epithelial cells [18]. Ubiquitin molecules inhost cells can activate protein tyrosine phosphatase A(PTPA) secreted by M. tuberculosis, which promotesthe proliferation and migration of the human lungadenocarcinoma cell line A549 [72]. Additionally, themetastasis of lung cancer can be affected bymicroorganisms through inflammatory mechanisms.The stimulation of gram-negative bacteria with TLR4,a receptor that mediates inflammation, increasesadhesion, migration, and metastatic spreading ofNSCLC cells [73]. Similarly, gram-positive pneumoniaaugments NSCLC metastasis via TLR2 activation [74].Inflammation also causes crosstalk between bacteriaand tumor cells through quorum sensing peptides topromote tumor metastasis [75]. In terms of immunity,a decrease in bacterial load is linked with reducedregulatory T cells and enhanced T cell and naturalkiller (NK) cell activation, which contributes to aresultful reduction in lung metastases [58].Angiogenesis is an intermediary betweenmicroorganisms and tumorsHuman microbiota can affect angiogenesis [75,76]. An important possible reason is thatinflammatory factors related to microbiota-inducedinflammation affect angiogenesis. Angiogenesis hasan effect on infection, tumors and other pathologicalprocesses. In recent decades, many scholars havestudied how angiogenesis affects tumor growth andhttp://www.ijbs.com

Int. J. Biol. Sci. 2021, Vol. 17metastasis. There are many clinical data to prove thatantiangiogenic drugs are effective in cancer patients.Therefore, the effect of the microbiome onangiogenesis makes it possible to manipulate thehuman microbiome to change angiogenesis in thedisease process.Accepted mechanisms of neovascularizationinclude sprouting angiogenesis, vasculogenesis,vasculogenic mimicry and vascular intussusception,and the above four mechanisms are thought to act onpathological neovascularization at the same time.Among them, sprouting angiogenesis models havebeen extensively studied (Figure 2). To avoid necrosisthat is due to hypoxia, cells in hypoxic regions secretevascular endothelial growth factors (VEGF). VEGFpromotes endothelial cells (ECs) to secrete matrixmetalloproteases (MMPs), which can degrade theirbasement membrane (BM) and extracellular matrix(ECM) [77]. BM is located on the basal surface of ECsand has a supporting, connecting and fixing effect onendothelial cells. When the stability of BM isdisrupted, endothelial cells gain the ability to

The respiratory system is an important part of the human body connecting the outside world with the body. omplex and diverse microbial C communities in the respiratory tract [13] play unique roles in biological processes. Respiratory micro-organisms are of great importance in a variety of diseases. Studying the structure of human respiratory