Bacteria-Cancer Interface: Awaiting the Perfect Storm

Abstract

Epidemiological evidence reveal a very close association of malignancies with chronic inflammation as a result of persistent bacterial infection. Recently, more studies have provided experimental evidence for an etiological role of bacterial factors disposing infected tissue towards carcinoma. When healthy cells accumulate genomic insults resulting in DNA damage, they may sustain proliferative signalling, resist apoptotic signals, evade growth suppressors, enable replicative immortality, and induce angiogenesis, thus boosting active invasion and metastasis. Moreover, these cells must be able to deregulate cellular energetics and have the ability to evade immune destruction. How bacterial infection leads to mutations and enriches a tumour-promoting inflammatory response or micro-environment is still not clear. In this review we showcase well-studied bacteria and their virulence factors that are tightly associated with carcinoma and the various mechanisms and pathways that could have carcinogenic properties.

Keywords: DNA damage; bacteria; cancer hallmarks; epithelial mesenchymal transition; inflammation.

Figure 1

Graphical overview of bacteria associated with carcinoma.

Figure 2

Oncogenic pathways activated by H. pylori: VacA can cause apoptosis, resulting in increased cell proliferation or serve as a possible entry point for other possible carcinogens. CagA enters the cell through T4SS and is phosphorylated by Src, causing it to activate SHP-2, resulting in cellular morphological changes. Additionally, CagA can stabilize β-catenin, resulting in increased cell proliferation. Outer membrane protein BabA binds to human Lewis (b) surface epitopes [59,60], thus increasing specific proinflammatory cytokines like CXCL1 [61], that might boost cell proliferation [62]. Outer membrane protein OipA binds to EGFR, leading to activated PI3K-AKT signalling and increased β-catenin.

Figure 3

Oncogenic pathways activated by Salmonella enterica: Salmonella protein AvrA activates Wnt-signalling, stabilizing β-catenin, leading to an increased expression of c-Myc and decreased expression of p53 resulting in increased cell proliferation. AvrA also activates STAT3-signaling, further increasing cell proliferation and inflammatory regulation. Salmonella proteins SopB, SopE and SopE2, injected through type III secretion system activate MAPK/AKT pathway provoking cell transformation and carcinoma.

Figure 4

E. coli, through colibactin, caused cell cycle arrest and double-stranded DNA breaks resulting in genomic instability. Additionally, colibactin was found to increase cell proliferation and induce tumour-promoting inflammation. Colibactin also resulted in increased p53 SUMOylation resulting in emergence of senescent cells. Finally, E. coli downregulated mismatch repair proteins MSH2 and MLH1 leading to further genomic instability.

Figure 5

C. trachomatis downregulates the tumour suppressor P53 leading to increased cell proliferation, while also increasing levels of reactive oxygen species, causing oxidative DNA damage, which together with inhibition of cell DNA repair mechanisms causes genomic instability. C. pneumoniae, through unknown mechanisms, leads to inflammation and dysregulation of replication, transcription, and DNA repair mechanisms.

Figure 6

Pathways activated by F. nucleatum. FadA was found to inhibit E-cadherin, activating β-catenin and increasing cell proliferation. Additionally, increased levels of NF-κB and proinflammatory interleukins IL-6, IL-8, and IL-18 resulted in a possible tumour promoting inflammation. Fap2 showed interactions with the TIGIT immune receptor, causing inhibition of immune cells, and thereby creating an immunosuppressive microenvironment.

Figure 7

S. bovis, through an unknown pathway, increased levels of β-catenin and c-Myc, resulting in increased cell proliferation.

Figure 8

M. hyorhinis increases β-catenin through GSK3β, Wnt-signalling, and activation of LRP6. This resulted in increased cell proliferation. Without LRP6 activation, GSK3β had an inhibitory effect on β-catenin. LRP6 was additionally able to interact with p37, leading to increased levels of cell immortality, cell motility, migration, and invasion.

Figure 9

B. fragilis (ETBF) cleaves E-cadherin, leading to activated β-catenin levels, resulting in increased cell proliferation. ETBF also creates tumour-promoting inflammation through upregulation of the STAT3 pathway, IL-17, and NF-κB.

Figure 10

N. gonorrhoeae, through unclear mechanisms, caused DNA damage and increased the expression of p21 and p27 while decreasing the levels of p53 in non-tumour epithelial cells, resulting in genomic instability and cell cycle dysregulation.

Figure 11

E. faecalis increased intracellular levels of ROS, leading to DNA instability and reduced DNA repair response resulting in genomic instability. E. Faecalis increased NF-κB levels, thereby causing a tumour promoting inflammation. When cocultured with M1 macrophages, β-catenin levels increased, leading to increased cell proliferation. Coculturing with heat-killed E. faecalis EC-12 strain, β-catenin was reduced, showing a possible protective role in CRC.

Figure 12

Mycobacterium tuberculosis (MBT) increased levels of PD-1/PD-L1 resulting in increased tumour metastasis while also inhibiting T cell immune response causing an immunosuppressive microenvironment favourable for potential tumour progression.