Peptostreptococcus anaerobius promotes colorectal carcinogenesis and modulates tumour immunity
| العنوان: | Peptostreptococcus anaerobius promotes colorectal carcinogenesis and modulates tumour immunity |
|---|---|
| المؤلفون: | Anthony W.H. Chan, Joseph J.Y. Sung, Francis K.L. Chan, Li Tong, Chun Ho Szeto, Olabisi Oluwabukola Coker, Eagle S. H. Chu, Xiaohang Long, Chi Chun Wong, Minne Y. Y. Go, Jun Yu |
| المصدر: | Nature Microbiology. 4:2319-2330 |
| بيانات النشر: | Springer Science and Business Media LLC, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Microbiology (medical), Immunology, ved/biology.organism_classification_rank.species, Integrin, Cell, Inflammation, medicine.disease_cause, Applied Microbiology and Biotechnology, Microbiology, 03 medical and health sciences, Genetics, medicine, Receptor, 030304 developmental biology, 0303 health sciences, biology, 030306 microbiology, ved/biology, Cell growth, Chemistry, Peptostreptococcus anaerobius, Cell Biology, medicine.anatomical_structure, biology.protein, Cancer research, medicine.symptom, Signal transduction, Carcinogenesis |
| الوصف: | Emerging evidence implicates a role of the gut microbiota in colorectal cancer (CRC). Peptostreptococcus anaerobius (P. anaerobius) is an anaerobic bacterium selectively enriched in the faecal and mucosal microbiota from patients with CRC, but its causative role and molecular mechanism in promoting tumorigenesis remain unestablished. We demonstrate that P. anaerobius adheres to the CRC mucosa and accelerates CRC development in ApcMin/+ mice. In vitro assays and transmission electron microscopy revealed that P. anaerobius selectively adheres to CRC cell lines (HT-29 and Caco-2) compared to normal colonic epithelial cells (NCM460). We identified a P. anaerobius surface protein, putative cell wall binding repeat 2 (PCWBR2), which directly interacts with colonic cell lines via α2/β1 integrin, a receptor frequently overexpressed in human CRC tumours and cell lines. Interaction between PCWBR2 and integrin α2/β1 induces the activation of the PI3K–Akt pathway in CRC cells via phospho-focal adhesion kinase, leading to increased cell proliferation and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. NF-κB in turn triggers a pro-inflammatory response as indicated by increased levels of cytokines, such as interleukin-10 and interferon-γ in the tumours of P. anaerobius-treated ApcMin/+ mice. Analyses of tumour-infiltrating immune cell populations in P. anaerobius-treated ApcMin/+ mice revealed significant expansion of myeloid-derived suppressor cells, tumour-associated macrophages and granulocytic tumour-associated neutrophils, which are associated with chronic inflammation and tumour progression. Blockade of integrin α2/β1 by RGDS peptide, small interfering RNA or antibodies all impair P. anaerobius attachment and abolish P. anaerobius-mediated oncogenic response in vitro and in vivo. Collectively, we show that P. anaerobius drives CRC via a PCWBR2-integrin α2/β1-PI3K–Akt–NF-κB signalling axis and identify the PCWBR2-integrin α2/β1 axis as a potential therapeutic target for CRC. Peptostreptococcus anaerobius is enriched in the gut microbiota of patients with colorectal cancer (CRC). Here, the authors show that it can selectively bind to tumours and CRC cell lines and trigger downstream responses, resulting in chronic inflammation and tumour progression in a mouse model of CRC. |
| تدمد: | 2058-5276 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::ddfac65c99ce6a382bcea0e942771552 https://doi.org/10.1038/s41564-019-0541-3 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi...........ddfac65c99ce6a382bcea0e942771552 |
| قاعدة البيانات: | OpenAIRE |
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