Bacterial infections and cancer

Abstract

Infections are estimated to contribute to 20% of all human tumours. These are mainly caused by viruses, which explains why a direct bacterial contribution to cancer formation has been largely ignored. While epidemiological data link bacterial infections to particular cancers, tumour formation is generally assumed to be solely caused by the ensuing inflammation responses. Yet, many bacteria directly manipulate their host cell in various phases of their infection cycle. Such manipulations can affect host cell integrity and can contribute to cancer formation. We here describe how bacterial surface moieties, bacterial protein toxins and bacterial effector proteins can induce host cell DNA damage, and thereby can interfere with essential host cell signalling pathways involved in cell proliferation, apoptosis, differentiation and immune signalling.

Keywords: bacteria; cancer; effectors; infection; signalling.

Figure 1. Bacterial outer‐surface components that manipulate host cell signalling cascades involved in cellular malignancy

(A) Helicobacter pylori CagL binds β5‐integrin and induces downstream signalling of Raf, MEK and ERK pathways that play a central role in H. pylori‐induced gastrin production and cellular transformation. (B) H. pylori OipA activates EGFR and stimulates Akt and β‐catenin signalling, causing cell proliferation. (C) H. pylori BabA binds human Lewis(b) surface epitopes which increases levels of CCL5, IL‐8, CDX2 and MUC2, causing cell proliferation. (D) Fusobacterium nucleatum FadA binds to E‐cadherin, which releases β‐catenin that activates transcription factor Tcf/LEF which controls the transcription of genes involved in apoptosis, cell proliferation and transformation.

Figure 2. Host cell signalling pathways involved in cell growth and transformation manipulated by bacterial toxins

(A) The CdtB subunit of the CDT toxin is delivered to the nucleus where it causes DSBs and impairs DNA DDR sensor functionality. At the same time, NET1 and RhoA are activated which ensure upregulation of MAPK and cellular survival. (B) Bacteroides fragilis BFT binds to E‐cadherin and involved in cellular signalling, proliferation and transformation via activation of the β‐catenin/Wnt and NF‐κβ signalling pathways.

Figure 3. Examples of bacterial effector proteins involved in cellular transformation

(A) Salmonella Enteritidis AvrA stabilizes β‐catenin, which results in proliferative Wnt signalling. At the same time, AvrA inhibits JNK and NF‐κβ signalling pathways involved in inflammation and apoptosis. (B) The effector proteins SopB, SopE and SopE2 of Salmonella typhimurium activate the small GTPases RhoG, Rac1 and Cdc42 and activate members of the PAK that phosphorylate members of the Abl kinase family, leading to the activation the cytoplasmic transcription factor STAT3, which contributes to cellular transformation. The effector proteins SopB, SopE, SopE2 and SptP of S. typhimurium additionally mediate activation of the MAPK and Akt pathways, which transforms premutated fibroblasts and gallbladder organoids.