Mechanisms of Microbiome Influence on Lung Cancer Pathogenesis: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Karolina Henryka Czarnecka-Chrebelska.

In the process of carcinogenesis, a direct influence of bacteria has been suggested: (1) via regulating oncogenic signaling pathways in epithelial cells, thus leading to cell cycle disorder, mutagenesis, and DNA damage; (2) on the cells of the immune system, triggering an immune response, production and release of cytokines, thus changing the local immune microenvironment of the host; and (3) through MAMPs (microbe-associated molecular patterns), including the effects of bacteriotoxins, TLRs (toll-like receptors) signaling induction, and TNF (tumor necrosis factor) release. These mechanisms interact in the process of carcinogenesis. For example, it has been found that several microorganisms (Acidovorax, Klebsiella, Rhodoferax, Comamonas, and Polarmonas) were more abundant in squamous cell carcinoma with TP53 mutations in smokers. It has been suggested that lung epithelial cells with TP53 mutations due to tobacco smoke can be invaded by species that take advantage of the new microenvironment and may become tumor-foraging bacteria. Whether these bacteria induce mutations in TP53 is currently under investigation. 

  • lung cancer
  • microbiota
  • oncobiome
  • host–microbiota interactions
  • Adaptive Immunity
  • Oxidative stress
  • toxins

1. Bacterial Toxins and Metabolites as Inflammatory Mediators of Lung Carcinogenesis

Certain bacterial toxins and metabolites lead to genetic mutations that promote uncontrolled cell growth and the formation of cancerous cells or create an environment conducive to tumor growth and a vicious cycle. Moreover, the molecules produced by bacteria might hinder the immune system’s capacity to detect and destroy cancer cells, which enables the cancer to evade immune surveillance and continue to grow [34][1]. One of the first bacterial infections linked to lung cancer was chronic chlamydiosis. Prolonged pneumocyte infection caused by Chlamydia pneumoniae has been linked to a 1.6 times higher risk of lung cancer development [60,80][2][3]. An in silico analysis demonstrated that C. pneumoniae proteins can target the mitochondria of host cells, causing its dysfunction. A study by Alshamsan et al. [81][4] found that 183 out of 1112 of these proteins target the mitochondria, while 513 target the cytoplasmic cellular processes. This, in turn, can disrupt normal cellular growth, alter apoptosis, and trigger lung carcinogenesis. These proteins can also be incorporated into intracellular organelles, forming a host cell proteome [82][5]. The C. pneumoniae oncogenic activity may be mediated by an endotoxin-like protein—the chlamydial heat shock protein-60 (cHSP60)—produced even during the chlamydia dormancy phase [83][6]. Heat shock proteins are a family of proteins found in all cells, highly conserved across species, including prokaryotes and eukaryotes, that play a crucial role in cellular stress responses. In the case of Chlamydia, cHSPs may resemble human HSPs, triggering autoimmune responses by activating the toll-like receptor 4 (TLR4) and inducing IL-6, TNF-α, and IL-1β production [82,83][5][6].
An example of a bacterial genotoxin is a cytolethal distending toxin (CDT) produced by various gram-negative bacteria, such as Actinobacillus. This bacterial toxin can directly cause DNA damage and trigger mutations [84,85][7][8]. It has been found in the human lung adenocarcinoma A549 cell line when a CDT induces apoptosis [86][9]. Another bacterial genotoxin is colibactin, produced by Escherichia coli, which can lead to double-strand breaks, resulting in a loss of genomic integrity and further cytotoxicity [84][7]. Among several Pseudomonas aeruginosa - identified toxins, the ExoS exhibits a genotoxin activity. An increased activity of the base excision repair enzyme OGG1 was observed in mice lung epithelial cells infected by P. aeruginosa. Additionally, it was proposed that ExoS, which has GTPase-activating and ADP ribosyl transferase activities, can directly cause DNA strand breaks via the phosphorylation of histone H2AX [84,87][7][10].
Cytotoxin-associated antigen A (CagA) is a virulence factor produced by Helicobacter pylori that, in the host epithelium, can modify various cellular signaling pathways and stimulate the toll-like receptors mediated response, i.e., the production of pro-inflammatory cytokines (IFN-α, IL-1, IL-2, IL-8) and chemokines leading to chronic inflammation. While H. pylori infection and CagA are primarily associated with stomach-related conditions (gastritis, peptic ulcers, and an increased risk of gastric cancer), studies demonstrated H. pylori’s presence in BALF and lung biopsies [88][11]. Another Helicobacter toxin, vacuolating cytotoxin A (VacA), named for its ability to form large, vacuole-like structures within the host cell, has immunomodulatory properties but also leads to mitochondrial membrane damage. The VacA exotoxin was detected in the bronchial epithelial cells of patients with interstitial pneumonia, where it activated the secretion of interleukins 6 and 8 [82,89][5][12]. Streptococcus pneumoniae is an opportunistic pathogen that produces a pneumolysin (PLY) toxin, which is a cholesterol-dependent cytolysin and a genotoxin. In the host tissue, PLY enables pore formation in the cell membrane, which can cause damage to the lung endothelium, as well as the nasal and tracheobronchial epithelium [90][13]. Targeting the host cell mitochondrial membrane, PLY can cause dysfunction and a loss of the mitochondrial membrane potential [91][14]. Moreover, the S. pneumoniae toxin can induce double-strand breaks in the DNA, thereby directly promoting genome instability and accelerating oncogenesis [92][15].
Through advanced sequencing techniques, scientists have discovered phyla and previously undetected species in human tissue, particularly in the lungs. A significant example was the detection of the Cyanobacteria phylum in lung cancer tissue, which is a gram-negative photosynthesizing bacterium [68][16]. It produces microcystin (MC)—a cyclic peptide toxin—that can induce mutations as predominantly large deletions, interfere with DNA damage repair processes, and finally contribute to genetic instability [93][17]. The increased expression of poly (ADP-ribose) polymerase 1 (PARP1) was linked to a Cyanobacteria presence in the lung, and the PARP1 expression was significantly increased in the adenocarcinoma lesion infected with Cyanobacteria compared to neighboring non-cancerous tissues [68][16]. PARP1, via the scavenger receptor CD36, can mediate inflammatory pathways that contribute to inflammation-associated lung carcinogenesis [68][16].
When pathogens and their metabolites interact with the host tissues, they can trigger inflammation by boosting the production of specific cytokines and inflammatory mediators, such as IL-1, IL-23, TNF, and IL-17. This happens through MAMPs, which then activate the critical downstream signaling pathways, like STAT3 and NF-kB pathways, as well as the ERK and PI3K pathways—regulating cell proliferation, survival, and differentiation—which are upregulated in lung cancer patients [94][18]. The evidence of the inflammation-associated carcinogenesis comes from the study of Tsay et al. [60][2], who found that the genera present in the respiratory tract, i.e., Veillonella and Streptococcus were associated with the upregulation of the ERK and PI3K signaling pathways in the airways of the patients with lung cancer. In the case of Cyanobacteria infection, the inflammation response included the secretion and activation of TNF, IL-1β, IL-4, and oncostatin M [68][16].
Triggering inflammation is even more visible in the case of well-known pathogenic factors, like Mycobacterium tuberculosis. In a systematic review by Liang et al., it was demonstrated that pre-existing tuberculosis is associated with a significantly increased lung cancer risk, particularly for the adenocarcinoma subtype [95][19]. Infections with M. tuberculosis activate the immune response mediated by the secretion of the interleukins IL-1,2,12, TNF-α, and INF-γ, and also trigger the neutrophils’ generation of reactive oxygen species. In turn, ROS can cause DNA breaks or interfere with mitochondria complexes, both contributing to cancer formation [82,96][5][20]. There was an association between EGFR mutation occurrence and lung AD in patients with pulmonary tuberculosis history [97][21].
Other bacteria that may affect lung cancer growth through the activation of inflammatory signaling is Staphylococcus aureus. S. aureus produces lipoteichoic acid (LTA) that induces a significant increase in cellular proliferation in NSCLC cell lines (A549 and H226), even at low concentrations [98][22]. LTA activates /increases the IL-8 mRNA expression by binding to TLR-2, leading to cell proliferation. This finding suggests that S. aureus pulmonary infections may have a direct pro-proliferative effect on lung cancer growth. [94][18]. Another species of bacteria linked to lung cancer is gram-positive cocci Granulicatella adiacens, a bacteria previously considered part of the normal flora in the oral, intestinal, and respiratory tract. G. adiacens was significantly enriched in lung cancer patients’ sputum samples compared to healthy controls, suggesting its role in early NSCLC development [99][23]. The analysis of G. adiacens extracellular vesicles (EVs) proteome revealed the presence of many putative virulence factors, but not many associated with direct DNA damage. However, the presence of thioredoxin, which plays a crucial role in cellular redox regulation, may link G. adiacens to carcinogenesis in the lungs. Furthermore, the EVs of G. adiacens were found to be potent inducers of proinflammatory cytokines [100][24].
Reactive forms of oxygen (ROS) and nitrogen (RNS) are also compounds produced by the metabolism of bacteria. Free radicals contain unpaired electrons that enable the transfer of electrons to other molecules, harming amino acids, fatty acids, or even nucleic acids. If ROS and RNS accumulate excessively, they can cause biomolecules to undergo excessive oxidation, resulting in changes to protein structures and functions and further cellular damage and inflammation [37,101][25][26]. By directly damaging DNA or modifying cell signaling pathways, they create an environment favorable for carcinogenesis. Additionally, the inflammatory cells stimulated by dysbiosis can release reactive oxygen and nitrogen species, thus increasing their number and influence on angiogenesis and carcinogenesis [102,103][27][28]. Chronic C. pneumoniae infection may induce oncogenesis, also via the production and liberation of ROS, particularly nitric oxide during inflammation, thus leading to DNA damage [60][2]. The body’s inflammatory response to C. pneumoniae is associated with the production of cytokines such as IL-8, IL-10, and TNF in human alveolar macrophages and peripheral blood mononuclear cells [82,104][5][29]. It was demonstrated that Cyanobacteria toxin–microcystin also induces an excessive formation of reactive oxygen and nitrogen species, resulting in DNA damage [93][17]. The studies analyzing the bacterial toxin activity in lung oncogenesis are compiled in Table 21.
Table 21.
The summary of toxins directly related to the lung carcinogenesis process.
Identified Bacteria Toxin/ROS Biological Effect Ref.
Actinobacillus CDT Direct DNA damage and triggering mutations [84,85][7][8]
Chlamydia pneumoniae ROS Oxidative stress, DNA damage, mutagenesis [60,80][2][3]
? Targeting mitochondria, cellular redox regulation [81,82][4][5]
cHSP60 Triggering autoimmune responses by activating the toll-like receptor 4 [82,83,104][5][6][29]
Cyanobacteria MC Generation of reactive oxygen species, DNA damage, mutagenesis [93][17]
Contributing to the inflammation-associated lung carcinogenesis—activation of TNF, IL-1β, IL-4, and oncostatin M [68][16]
Escherichia coli Colibactin Direct DNA damage (double-strand breaks) promoting genome instability [84][7]
Granulicatella adiacens ? Activation of proinflammatory cytokines secretion [99,100][23][24]
Thioredoxin/ROS Targeting mitochondria, oxidative stress, and cellular redox regulation [100][24]
Helicobacter pylori CagA Triggering autoimmune responses by activating the toll-like receptor, increased secretion of pro-inflammatory cytokines and chemokines [88][11]
VacA Increased secretion of IL-6 and Il-8 [89][12]
Targeting mitochondria, cellular redox regulation [82][5]
Mycobacterium tuberculosis ROS Oxidative stress, DNA damage, mutagenesis [96,97][20][21]
? Increased secretion of cytokines, IL1,2.3,4,10,12,14, 17, IFN-γ and TNF-α [82][5]
Pseudomonas aeruginosa ExoS Direct DNA damage (double-strand breaks) promoting genome instability [84,87][7][10]
Staphylococcus aureus LTA Triggering autoimmune responses by activating the toll-like receptor 2, leading to cell proliferation [98][22]
Streptococcus pneumoniae Ply Activation of the ERK and PI3K signaling pathways [60,90][2][13]
Direct DNA damage (double-strand breaks) promoting genome instability [91][14]
Targeting mitochondria, cellular redox regulation [92][15]
Veillonella ? Activation of the ERK and PI3K signaling pathways [60][2]
CagA—Cytotoxin-associated antigen A; CDT—Cytolethal distending toxin; cHSP60—Chlamydial heat shock protein-60; ExoS—Exotoxin S; LTA—Lipoteichoic acid; MC—Microcystin; Ply—Pneumolysin; ROS—Reactive oxygen species; VacA—Vacuolating cytotoxin A.

2. Modulation of the Adaptive Immunity by the Microbiota

Chronic inflammation is a known contributing factor to carcinogenesis. The underlying mechanisms include the induction of genomic instability, alterations in epigenetic events and subsequent aberrant gene expression, enhanced cell proliferation, and resistance to apoptosis (e.g., due to smoking). There is increasing evidence about the role of lung microbiota in lower airway inflammation. Additionally, molecules produced by bacteria might hinder the immune system’s capacity to detect and destroy cancer cells, which enables the cancer to evade immune surveillance and continue to grow [105][30]. As found in LC patients, lung microbiota from BALF enriched with supraglottic taxa was associated with a pro-inflammatory profile and the stimulation of Th17 cells, thus showing a pro-tumorigenic effect [25,46,60][2][31][32]. It was also confirmed by the more recent study by Tsay et al. [106][33], who showed that dysbiosis in the lower respiratory tract contributed to the inflammation of the tumor microenvironment characterized by an increased share of the Th1 and Th17 phenotypes.
IL-17-producing CD4 helper T cells (Th17 cells) are principal adaptive immune cells generated in the lung during inflammation. Th17 cells play a critical role in promoting chronic tissue inflammation through the upregulation of proinflammatory cytokines and chemokines in epithelial cells, where they are efficiently recruited upon inflammation [107][34]. As revealed by Chang et al. [108][35], in a mouse model of lung cancer, the role of Th17 cell-mediated inflammation was critical in tumorigenesis during the early stages of pulmonary adenocarcinoma. IL-17 accelerated cancer development, at least in part, by recruiting myeloid cells and promoting inflammation. The study of Wang et al. [109][36] revealed that Th17 cell-derived IL-17A played an essential role in the tumor progression of NSCLC via STAT3/NF-kB/Notch1 signaling. The authors clearly indicated that the levels of Th17 cells and IL-17A mRNA were increased in NSCLC patients (both in blood and cancerous lung tissue), and in vitro studies revealed that IL-17A could promote the invasion, migration, and cancer stem cell-like properties of NSCLC cells [109][36].
In NSCLC, the Janus kinase/signal transducers and activators of the transcription (JAK/STAT) pathway are crucial for promoting cellular survival and growth. The STAT protein family consists of seven transcription factors, including STAT3 and STAT5A/B, which have oncogenic properties both in vitro and in vivo [110][37]. While direct evidence linking dysbiosis and the STAT3 protein is limited, the activation through IL-17 may explain the interaction between dysbiosis, immune responses, and the activation of the activity of transcription factors like STAT3. Jin et al. [79][38], using germ-free preclinical lung cancer models, demonstrated that the lung commensal microbiome can induce the activation and proliferation of γδ T cells by stimulating myeloid cells to produce Myd88-dependent IL-23, IL-1β, and IL-17, and lead to a pro-inflammatory state that induces tumor proliferation. Another process linking dysbiosis to tumor cell proliferation is mediated by IL-22, whose production is activated in many infectious and inflammatory disorders. In mice lung cancer models, the presence of the Kras mutation led to the activation of the NF-κB pathway and to the secretion of IL-6 and IL-17, which was related to the increase in the IL-22 secretion [111][39]. CD4+ T helper lymphocytes (Th17, Th22, and Th1), natural killer T cells (NKT), innate lymphoid cells (ILC), and γδ T cells are all capable of producing cytokine IL-22 [112][40]. The dual action of IL-22 has already been proven in colorectal cancers, where IL-22 increases inflammation during the acute phase. Then, in the silencing phase, IL-22 promotes tissue repair, which can lead to the development of neoplastic lesions [113][41]. What is important is that cytokine IL-22 acts only on non-hematopoietic stromal cells, keratinocytes, hepatocytes, and particularly epithelial cells, i.e., in lungs and alveoli [112][40]. IL-22 operates through the heterodimer complex protein formed by the IL-22R1 and IL-10R2 coreceptors that phosphorylate the Stat3 protein, leading to the activation of the STAT3 pathway downstream effectors [114][42]. The protein Stat3 plays a crucial role in the differentiation of Th17 and the production of T cell-dependent IgG responses. It also contributes to maintaining epithelial homeostasis, promoting wound healing, and producing antimicrobial factors such as β-defensins in response to infections caused by Staphylococcus and Candida [115][43]. Nevertheless, the IL-22 pro-inflammatory properties can also lead to harmful consequences, particularly when IL-22 is released alongside other pro-inflammatory cytokines, particularly IL-17 [112][40].
 

3. Modulation of the Innate Immunity by the Microbiota

The accumulating evidence indicates that bacterial MAMPs and TLRs contribute to carcinogenesis. Bacteria and their metabolites activate the TLR receptors on immune and epithelial cells, and thus induce inflammation. The cells of the innate immune response, as well as epithelial cells, express various receptors, such as TLRs, which inform about the invasion of pathogens. TLRs react to exogenous infectious ligands, such as cell wall elements, including LPS of gram-negative bacteria, lipoteichoic acids of gram-positive bacteria, motility systems, single- and double-stranded RNA, and DNA of microorganisms. The receptors of the TLR1 subfamily (TLR1, 2, 6, 10), TLR4, and TLR5 are found mainly in the cell membrane. They recognize the elements of cell walls, capsules, and movement apparatuses of pathogenic microorganisms. TLR3, TLR7-9, and TLR11-13 are found in intracellular organelles, such as endosomes, and are mainly involved in recognizing pathogen nucleic acids. Signal cascades are activated when the appropriate ligands are bound to the TLRs [117][44]. The activation of adaptive proteins begins, leading to the kinase cascades’ activation. The main signaling kinases are IRAK (interleukin-1 receptor-associated kinase), TRAF (TNF receptor-associated factor), MAPK (mitogen-activated protein kinase) and IKK (IκB kinase). The signal pathways triggered by TLRs lead to the activation of the transcription factors, such as NFκB (nuclear factor κ-light chain-enhancer of activated B cells) and AP-1 (activator protein-1) [117,118][44][45].
The above processes stimulate the expression and secretion of pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1beta chemokines. Several studies have indicated NFκB signaling as a mechanistic link between inflammation and lung cancer [119,120,121][46][47][48]. It has also been found that the expression of TLR4 was higher in lung cancer tissue than in paracancerous tissue [122][49], thus supporting the role of this receptor signaling in cancerogenesis [123,124][50][51]. Additionally, it has been clearly shown that IL-6 plays an essential role in lung cancer promotion [125][52], and its blockade significantly inhibits lung cancer development, STAT3 activation in tumor cells, tumor cell proliferation, and angiogenesis markers [126][53].
It is known that an upregulation of the ERK and PI3K pathways plays a central role in cell proliferation, survival, and tissue invasion at an early stage of lung cancerogenesis [94,127][18][54]. Their importance is enhanced by the possibility of being considered a therapeutic target [128,129][55][56]. The PI3K/AKT pathway is an intracellular signaling pathway that regulates various cellular functions, including cell survival, metabolism, and growth. Upon the binding of extracellular signaling molecules, the membrane receptor activation activates intracellular PI3K, which converts PIP2 lipids to PIP3. Then, AKT binds to PIP3, which can be phosphorylated by PDK1 and mTOR at two different sites, thus resulting in the full activation of AKT. pAKT phosphorylates several downstream molecules (BAD, IKK, CREB, FOXO1, and mTORC1), which regulate numerous cellular processes. The dysfunction of this pathway can lead to its over-activation and is associated with numerous pathological processes, including tumorigenesis [94][18]. As mentioned earlier, Streptococcus and Veillonella—found to be enriched in the lower airways of patients with lung cancer—are associated with an upregulation of the ERK and PI3K signaling pathways, and it was confirmed in vitro by the exposure of the airway epithelial cells to Veillonella, Prevotella, and Streptococcus [60,106][2][33]. The analysis showed that these oral taxa were associated with the upregulation of the PI3K/PTEN, ERK/MAPK, IL-6/IL-8, and p53 mutation pathways, thus indicating the mechanism linking the microorganisms and a cascade of events leading to lung cancer development.

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