The role played by bacterial infections in the onset and metastasis of cancer

Abstract

Understanding various responses of cells towards change in their external environment, presence of other species and is important in identifying and correlating the mechanisms leading to malignant transformations and cancer development. Although uncovering and comprehending the association between bacteria and cancer is highly challenging, it promises excellent perspectives and approaches for successful cancer therapy. This review introduces various bacterial species, their virulence factors, and their role in cell transformations leading to cancer (particularly gastric, oral, colon, and breast cancer). Bacterial dysbiosis permutates host cells, causes inflammation, and results in tumorigenesis. This review explored bacterial-mediated host cell transformation causing chronic inflammation, immune receptor hyperactivation/absconding immune recognition, and genomic instability. Bacterial infections downregulate E-cadherin, leading to loosening of epithelial tight junction polarity and triggers metastasis. In addition to understanding the role of bacterial infections in cancer development, we have also reviewed the application of bacteria for cancer therapy. The emergence of bacteriotherapy combined with conventional therapies led to new and effective ways of overcoming challenges associated with available treatments. This review discusses the application of bacterial minicells, microswimmers, and outer cell membrane vesicles (OMV) for drug delivery applications.

Keywords: Bacterial infections; Bacteriotherapy; Chronic inflammation; Genomic instability; Immune response modulation; Metastasis.

Graphical abstract

Fig. 1

Schematic showing the role of bacteria in the induction and inhibition of cancer.

Fig. 2

Bacterial dysbiosis causes chronic inflammation leading to cancer. Infected host immune cells produces inflammatory signalling molecules like TNF-α (tumour necrosis factor alpha), IL-1 (interleukin-1), IL-8, IL23, STAT-3 (signal transducer & activator of transcription 3), NF-κβ (nuclear factor kappa-light-chain-enhancer of activated B cells), ROS (reactive oxygen species), RNS (reactive nitrogen species), which causes chronic inflammation and leads to progression of cancer.

Fig. 3

Bacterial infections manipulate host immune response and stimulates pathogenesis. Bacterial LPS (lipopolysaccharides) binds to TLR (toll like receptor), activate dendritic cells, helps bacteria in bypassing the immune detection and trigger the production of interleukins, TGF-β (tumour growth factor beta), VEGF (vascular endothelial growth factor) which in turn induces cellular proliferation, inhibits apoptosis and cancer progression.

Fig. 4

Bacterial genotoxins mediated DNA double stranded damage leading to cancer. CDT (cytolethal distending toxin) enters the nucleus and disrupts the DNA double helix structure. The DNA damage response intensifies MAPK (mitogen-activated protein kinase) function by activating NET 1 (neuroepithelial cell-transforming gene one protein), GTPase RhoA (guanosine triphosphatase Ras homologue family member A) protein which prolongs the cell survival.

Fig. 5

Various cancers associated with bacterial infections. Bacteria infects the host cell and ensure their prolonged survival by modulating the host cell machinery; NF-kβ (nuclear factor kappa-light-chain-enhancer of activated B cells), IL (interleukins), ROS (reactive oxygen species), STAT-3 (signal transducer and activator of transcription 3).

Fig. 6

Cytotoxin-associated gene A (Cag A) and peptidoglycan of H. pylori triggers signalling pathways leading to cancer progression. Cag A, phosphorylated by Abl and Src tyrosine kinase on tyrosine motif EPIYA (glutamate-proline-isoleucine-tyrosine-alanine) induces cellular proliferation. Peptidoglycan induces proliferations, metastasis, inhibition of apoptosis by activation of NOD1- NF-kβ (nucleotide-binding oligomerization domain-containing protein one- nuclear factor kappa light chain enhancer activated B cells), PI3K-PKB/Akt(phosphoinositide-3-kinase–protein kinase B/Akt), Src-EGFR (epidermal growth factor receptor) signalling pathway.

Fig. 7

Bacterial infections downregulate epithelial tight junction proteins leading to cancer-metastasis. Multiple kinase-mediated signalling pathways like TGFβ−1 (tumour growth factor beta one) /Smad2/3 (intracellular mediator, translocate TGF-β from cytoplasm to nucleus), GSK-3 (Glycogen synthase kinase three) are activated which downregulates the tight junction proteins E-cadherin and promotes EMT (epithelial mesenchymal transition).

Fig. 8

Bacteria derived vehicles for targeted drug delivery. Bacterial microswimmer, membrane coated vesicles, minicell delivers anticancer drug to hypoxic core of tumour microenvironment and prevent the tumour reoccurrence.

Fig. 9

Bacteria mediated immune cell activation promotes the lysis of tumour cells. Drug loaded EDVs (EnGeneIC Dream Vector)/OMVs (outer membrane vesicles) activates the host immune cells like DCs (dendritic cells), NK (natural killer) cells, CTLs (cytotoxic T lymphocytes and stimulate secretion of perforins/granzymes, TNFs (tumour necrosis factors), ILs (interleukins) causing lysis of tumour cells.

Fig. 10

Therapeutic benefits of combinational therapy. Bacteria therapy combined with chemo/radiotherapy prevents the multidrug resistance and tumour regrowth by inhibiting the phosphorylation, activation of kinase like P-mTOR (phospho-mammalian targets of rapamycin), P-p70s6K (phospho-p70 ribosomal s6 kinase) which are the main regulator of p-glycoprotein (protein responsible for drug resistance) expression.