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  • Review Article
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Collateral damage: insights into bacterial mechanisms that predispose host cells to cancer

Subjects

Key Points

  • Infections with bacteria, viruses and parasites are responsible for about 20% of all human malignancies, but only one bacterium is formally recognized as a class I carcinogen. Accumulative evidence supports the involvement of bacterial pathogens in the development of cancer.

  • Bacteria can manipulate the biology of the cell directly through bacterial effectors that are capable of subverting oncogenic pathways or indirectly by the immune response and microbial metabolites.

  • Genomic instability is an important hallmark of cancer cells and constitutes a first step towards tumour initiation. Bacteria can secrete toxins that induce DNA breaks in host cells and cause genomic instability.

  • As part of their infection cycle, bacteria activate various host pathways that are also activated in cancer. These include the β-catenin, mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K-AKT) and nuclear factor-κB (NF-κB) pathways. Activating these pathways may be a step in the process of cell transformation.

  • Bacteria can promote local or systemic tumour-promoting effects through the modulation of the inflammatory response by, for example, producing radicals and secondary carcinogenic metabolites.

  • Pathogenic infections or microbiota colonization increase the risk of tumour initiation by targeting several pathways at the same time. A better definition of bacterial contributions to cancer development may lead to strategies to prevent or control tumours.

Abstract

Infections are estimated to contribute to 20% of all human tumours. Viruses are known to induce cell transformation, but evidence has also linked bacteria, such as Helicobacter pylori and Salmonella enterica subsp. enterica serovar Typhi, to different cancer types. In addition, Chlamydia trachomatis, Fusobacterium nucleatum and Bacteroides fragilis are associated with the development of cancer, although a causal relationship has not yet been established. Bacterial effectors such as colibactin and the virulence factor cytotoxin-associated gene A (CagA) can promote cancer directly by influencing host cell signalling cascades, such as the WNT and ataxia-telangiectasia mutated (ATM) pathways, or indirectly by inducing tissue damage and inflammatory responses. In this Review, we discuss how bacterial pathogens interact with host cells to contribute to the development of cancer.

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Figure 1: Cellular response to bacterial genotoxins.
Figure 2: Bacterial modulation of p53 expression and of the DNA damage response.
Figure 3: Bacterial diversion of the β-catenin signalling pathway.
Figure 4: Cell signalling pathways that are targeted by bacterial effectors and toxins.
Figure 5: Overview of host pathways that are manipulated by bacteria with oncogenic consequences.

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Acknowledgements

This work was supported by a grant from The Foundation of Medical Research (FRM) to J.-P.G., a grant from the Dutch Society of Cancer Research K.W.F. and a European Research Council Adv grant to J.N. Grants from the French Cancer Research Association (ARC), the Cancéropôle Provence Alpes Côte d'Azur (PACA) and the French National Institute against Cancer (INCa)/AVIESAN alliance were received by B.N.

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Glossary

Marginal zone-derived lymphoma

(MZL). A group of indolent non-Hodgkin lymphomas that arise from the marginal zone, including extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, splenic B-cell marginal zone lymphoma and nodal marginal zone lymphoma.

Neoplastic initiation

The first event in the multistep process of malignant transformation. This can be driven by cell-intrinsic or cell-extrinsic factors.

Genomic instability

Genetic alterations, including point mutations and chromosome rearrangements, that arise during DNA repair, chromosome duplication or recombination, which can be promoted by genotoxic agents such as reactive oxygen species and ionizing irradiation.

DNA damage response

(DDR). The protein machinery networks that control DNA damage checkpoints and carry out DNA repair.

Tumour suppressors

Genes that negatively regulate oncogenic pathways, opposing the activity of oncogenes. Tumour suppressors are often disrupted in cancer.

Oncogenes

Genes, the protein products of which positively regulate oncogenic pathways. Oncogene mutations are generally gain-of-function mutations in cancer, either through over-activation or expression at an illegitimate differentiation stage or tissue (ectopic expression). The same gene can be an oncogene in one cancer subtype and a tumour suppressor in another.

Genomic island

A chromosomal region that is present in some, but not all, bacterial strains of the same species that is likely to have been acquired through horizontal gene transfer. These islands are often associated with specific functions, including pathogenicity, and can encode toxins.

Polyketide synthases

Multifunctional enzymes or enzyme complexes that synthesize polyketides, which are important secondary metabolites in bacteria, fungi and plants.

Ataxia telangiectasia mutated

(ATM). A serine/threonine kinase that is recruited to DNA double-strand breaks by the MRE11–RAD50–NSB1 (MRN) complex. ATM controls the activation of the DNA damage checkpoint, resulting in cell cycle arrest and DNA repair.

γH2AX

A form of histone H2AX that is phosphorylated at the serine residue that is four amino acids from the carboxyl terminus and that is required for the DNA damage response. It is often used to mark DNA double-strand breaks.

Senescent cells

Cells that undergo an irreversible cell cycle arrest in late G1 phase in response to excessive stress that does not cause cell death. Such cells acquire phenotypic characteristics such as a senescence-associated secretory phenotype with pro-inflammatory characteristics.

Endoplasmic reticulum-associated protein degradation

A cellular pathway that enables the elimination of misfolded or unassembled proteins from the endoplasmic reticulum. The selected targets are transported into the cytoplasm for degradation by the proteasome.

Inside-out activation

Intracellular signals that induce conformational changes in integrins, activating them to bind to extracellular ligands.

Anchorage-independent cell growth

The ability of cells to survive and grow independently from anchorage to the extracellular matrix and in the absence of neighbouring cells. It is a hallmark of many cancer cells and strongly correlates with invasiveness and metastatic potential.

Type III secretion system

(T3SS). An assembly of bacterial proteins that are anchored in bacterial membranes that form a needle-like extension through which bacterial effectors are translocated directly from the bacterial interior into the cytoplasm of the target cell. This type of secretion apparatus is found in Salmonella, Pseudomonas and Shigella species.

MRE11–RAD50–NSB1

(MRN). A protein complex that binds to the end of broken DNA and initiates the DNA damage response and checkpoint pathways.

Pentose phosphate pathway

(PPP). A metabolic pathway that represents the main antioxidant cellular defence mechanism. The oxidative branch of PPP generates NADPH and ribonucleotides that serve as precursors for nucleotide biosynthesis and redox control; the non-oxidative branch of PPP generates pentose phosphate.

Warburg effect

A shift in cellular metabolism in cancer cells, which often produce energy from glycolysis using lactic acid fermentation instead of mitochondrial oxidative phosphorylation.

Type IV secretion system

(T4SS). A large protein complex that traverses the envelope in many bacteria, forming a secretion apparatus that is involved in the translocation of proteins or DNA into the host cell cytoplasm. Many Gram-negative bacteria, such as Helicobacter pylori, Brucella spp. or Legionella pneumophila, use T4SS to translocate virulence effectors directly into the host cell.

Nucleotide excision repair

A DNA repair mechanism involving helicases and endonucleases that resolves bulky DNA lesions (mostly pyrimidine dimers).

DNA mismatch repair

(MMR). A highly conserved pathway that corrects base–base and insertion–deletion mismatches that arise during DNA replication or damage. It is a multistep process that involves proteins such as MSH2, MLH1, MSH3, MSH6 and PMS2.

Microsatellite instability

Extension or shortening of the length of tandem repeated DNA sequences that are found throughout the genome. This can result in frameshift and missense mutations.

Conserved repeat responsible for phosphorylation independent activity

(CRPIA). A conserved motif that is located at the carboxy-terminal region of cytotoxin-associated gene A (CagA). It is involved in the activity of non-phosphorylated CagA.

EPIYA repeats

An amino-acid sequence (Glu-Pro-Ile-Tyr-Ala) that is located in the carboxy-terminal variable region of cytotoxin-associated gene A (CagA). This motif is important for its phosphorylation-dependent biological activity.

Claudin 7

A transmembrane protein that is involved in the formation of tight junctions, which are important for maintaining cell-to-cell adhesion and cell polarity.

Epithelial–mesenchymal transition

The transdifferentiation of epithelial cells into mesenchymal cells. This phenomenon is characterized by the loss of cellular junctions and polarity, and an increase in cell motility that is involved in the development of an invasive phenotype.

T helper 17 cell responses

Immune responses that are associated with the T helper 17 subset of CD4+ T cells that are responsible for the secretion of interleukin-17 (IL-17), IL-22 and IL-26, all of which regulate host defence against fungal and extracellular bacterial infection, as well as granulopoiesis.

Nucleotide binding and oligomerization domain 1

(NOD1). An intracellular sensor located mainly in the cytosol. NOD1 ligands are peptides, such as γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP), which are derived from peptidoglycan, a bacterial cell wall component.

Gastric pits

Narrow depressions of the gastric mucosa that are located between villous folds of the stomach, into which the gastric glands discharge their secretion.

BCL2-associated athanogene 1

(BAG1). Binds to BCL-2 to enhance its anti-apoptotic effects.

Spermine oxidase

(SMO). An enzyme from the polyamine metabolic pathway that is responsible for the conversion of spermine into spermidine. This enzymatic reaction yields hydrogen peroxide.

Polyamine

A polycationic amino acid that contains two or more amine chemical groups (NH2) that has the ability to modulate different cellular functions, such as apoptosis or cytokine secretion.

Deoxycholic acid

(DCA). A secondary bile acid that is produced by enteric bacteria from primary bile acids such as cholic acid and chenodeoxycholic acid, which are produced by the liver for assisting fat digestion.

T helper 1 cell response

An immune response that is associated with the T helper 1 subset of CD4+ T cells, which secrete interferon-γ and tumour necrosis factor, and are crucial for fighting intracellular pathogens and triggering cellular immunity.

Immune checkpoints

Mechanisms that keep immune cells in check by preventing their activation.

Immune checkpoint inhibitors

Monoclonal antibody therapies that are directed against negative immune checkpoints. The best characterized are the anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) antibody (ipilimumab) and anti-programmed cell death protein 1 (PD1) antibodies (nivolumab, pembrolizumab and others) for the treatment of melanoma and other immunogenic tumours.

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Gagnaire, A., Nadel, B., Raoult, D. et al. Collateral damage: insights into bacterial mechanisms that predispose host cells to cancer. Nat Rev Microbiol 15, 109–128 (2017). https://doi.org/10.1038/nrmicro.2016.171

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