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Cougnoux and colleagues1 report a new mechanism by which select bacteria can drive colon cancer. Specifically, they discovered that colobactin-producing E. coli strains can activate growth-arrested (ie, senescent) cells to produce growth factors that drive tumor growth. These findings may, in part, underlie the association of such bacteria with carcinomas and could result in novel strategies to slow tumor growth.
Approximately 20% of cancers are considered to be a consequence of infection by bacteria and/or viruses typically classified as pathogens. Moreover, many cancers occur in tissues with high exposure to microbiota, such as colorectal cancers (CRC), suggesting microbes not typically thought of as pathogens in promoting carcinogenesis. For example, mucosa-associated Escherichia coli are present more frequently in colon tissue from patients with adenocarcinomas than in control subjects. While E. coli are typically present in the intestine of healthy persons, various strains of E. coli have ‘pathogen-like features’ and associate with disease resulting in them being referred to as pathobionts. That such pathobionts have also been associated with inflammatory bowel disease, which, itself, has long been associated with an increased risk for colon cancer, suggested that inflammation might be the common thread by which such bacteria promote both IBD and carcinogenesis. However, recent work has demonstrated that the means by which pathobionts can promote cancer goes beyond merely driving inflammation.2 Moreover, the paper provides mechanistic insight into how such bacteria can promote tumour growth.1
Some pathobiont E. coli can have procarcinogenic features associated with the down-regulation of DNA mismatch repair proteins,3 making them particularly good candidates for tumour initiation/progression-associated bacteria. E. coli strains harbouring the pks island (pks+ E. coli) are associated with human colorectal tumours, and were previously reported to have carcinogenic effects in mice.2 ,4 ,5
The pks island encodes enzymes responsible for the synthesis of colibactin, which is is a non-ribosomal genotoxin that has been proposed to mediate DNA damage that might initiate cancer.6 Colibactin-positive E. coli has been found in 50–60% of human colorectal tumours versus 20% in control patients,2 ,5 and were previously reported to induce DNA damage, cell cycle arrest, mutations and chromosomal instability;6 and a recent study demonstrated that such genotoxic activity of colibactin-producing E. coli initiate development of cancerous cells independent of inflammation.2 However, the extent to which pks E. coli might drive tumour growth has been poorly defined.
In this study, Cougnoux et al 1 first confirmed that colibactin-producing E. coli were able to enhance tumour growth in xenograft and azoxymethane/dextran sodium sulfate models. They next investigated the mechanism that sustained tumour growth and found a central role played by the emergence of senescent cells with a secretory phenotype, that act as an intermediate between colibactin-producing E. coli and proliferation of cancer cells. Cellular senescence is a mechanism linked to cell cycle arrest that can occur as a direct consequence of small ubiquitin-like modifier (SUMO)-conjugated p53 accumulation, and the emergence of this cell’s population after colibactin-producing E. coli infection was associated with the production of human growth factor (HGF). This HGF production by senescent cells was found by the authors to be sufficient to induce the proliferation of uninfected cells both in vitro and in vivo. Even a short time (3 h) of contact between tumour cells and colibactin-producing E. coli was found to be sufficient to stimulate tumour growth in their xenograft model, suggesting that even a transient colonisation could affect tumour fate. Hence, in the presence of colibactin-producing E. coli, senescent cells are not in blissful slumber but, rather, can be thought of as having been hypnotised to serve the needs of the tumour.
The underlying mechanisms of colibactin-induced senescence involve an upregulation of microRNA-20a-5p expression through c-Myc transcription factor activation in response to infection. This microRNA-20a-5p is then able to bind to SENP1 mRNA 3′untranslated region (UTR), resulting in the downregulation of SENP1, which is a negative regulator of p53 SUMOylation, leading to the accumulation of SUMO-conjugated p53, finally resulting in the emergence of senescent cells. Interestingly, pks+ E. coli-induced senescence was also observed in p53−/− cells, suggesting that there could be other pathways in addition to p53 involved in the senescence process. Importantly, the analysis of expression of SENP1, microRNA-20a-5p and HGF in human colon cancer biopsies colonised by pks+ E. coli nicely corroborate with these previous findings.
These data revealed new important pieces in understanding carcinogenesis, in which colobactin-producing E. coli strains can activate growth-arrested (ie, senescent) cells to produce growth factors that drive tumour growth. The authors proposed that targeting colibactin production may be a strategy to restrain the production of pro-tumorigenic factors.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.
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