Commensal bacteria drive endogenous transformation and tumour stem cell marker expression through a bystander effect
Open accessAbstract
Objective: Commensal bacteria and innate immunity play a major role in the development of colorectal cancer (CRC). We propose that selected commensals polarise colon macrophages to produce endogenous mutagens that initiate chromosomal instability (CIN), lead to expression of progenitor and tumour stem cell markers, and drive CRC through a bystander effect. Design: Primary murine colon epithelial cells were repetitively exposed to Enterococcus faecalis-infected macrophages, or purified trans-4-hydroxy-2-nonenal (4-HNE)—an endogenous mutagen and spindle poison produced by macrophages. CIN, gene expression, growth as allografts in immunodeficient mice were examined for clones and expression of markers confirmed using interleukin (IL) 10 knockout mice colonised by E. faecalis. Results: Primary colon epithelial cells exposed to polarised macrophages or 4-hydroxy-2-nonenal developed CIN and were transformed after 10 weekly treatments. In immunodeficient mice, 8 of 25 transformed clones grew as poorly differentiated carcinomas with 3 tumours invading skin and/or muscle. All tumours stained for cytokeratins confirming their epithelial cell origin. Gene expression profiling of clones showed alterations in 3 to 7 cancer driver genes per clone. Clones also strongly expressed stem/progenitor cell markers Ly6A and Ly6E. Although not differentially expressed in clones, murine allografts positively stained for the tumour stem cell marker doublecortin-like kinase 1. Doublecortin-like kinase 1 and Ly6A/E were expressed by epithelial cells in colon biopsies for areas of inflamed and dysplastic tissue from E. faecalis-colonised IL-10 knockout mice. Conclusions: These results validate a novel mechanism for CRC that involves endogenous CIN and cellular transformation arising through a microbiome-driven bystander effect.
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A small number of specific pathobionts have now been linked with adenomas and colorectal cancer, including Streptococcus gallolyticus, Enterococcus faecalis and B. fragilis.
“a small number of specific pathobionts have now been linked with adenomas and CRC including Streptococcus gallolyticus,94 Enterococcus faecalis95 and B. fragilis.84”
From The gut microbiota and host health: a new clinical frontier (2016) · cites this paper as [95]
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- Authors
- Wang, X., Yang, Y., & Huycke, M. M.
- Affiliations
- Veterans Health Administration (US)
- The Muchmore Laboratories for Infectious Diseases Research, Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA
- Corresponding author
- Huycke, Mark M
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2014-06-06
- Volume
- 64
- Issue
- 3
- Pages
- 459-468
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC4345889
- OpenAlex
- W2154896150
- Cited by
- 122
- References
- 51
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 17 · 2023: 9 · 2022: 17 · 2021: 15 · 2020: 10 · 2019: 7 · 2018: 9 · 2017: 13 · 2016: 4 · 2015: 7
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Gut (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- University of Oklahoma
- Oklahoma Center for the Advancement of Science and Technology (HR10-032)
- Oklahoma Medical Research Foundation
- National Institutes of Health (GM103639)
- University of Oklahoma Health Sciences Center
- Stephenson Cancer Center
- National Cancer Institute (R01CA127893, CA127893)
- National Institute of General Medical Sciences (P20GM103639)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- colorectal cancer, commensal bacteria, Enterococcus faecalis, bystander effect, chromosomal instability, endogenous mutagens, macrophage polarization, cancer stem cells, DCLK1, IL-10 knockout mice, gut microbiota
- MeSH terms
- Aldehydes, Animals, Cell Line, Cell Transformation, Neoplastic, Colon, Colonic Neoplasms, Female, Humans, Intestinal Mucosa, Macrophages, Neoplasm Transplantation, Enterococcus faecalis, Neoplastic Stem Cells, Mice, Inbred NOD, Gram-Positive Bacterial Infections, In Situ Hybridization, Fluorescence, Bystander Effect, HCT116 Cells, Mice
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