期刊
BIOMOLECULES
卷 12, 期 9, 页码 -出版社
MDPI
DOI: 10.3390/biom12091256
关键词
colorectal cancer; cancer stem cells; microbiota; fusobacterium nucleatum; tumor microenvironment; tumor spheroids; carcino-embryonic antigen cell adhesion molecule-1; PTPase; bacterial adhesins
资金
- Italian Ministry of Health [GR-2016-02364891]
- Universita Cattolica del Sacro Cuore [D.1-2020]
Fusobacterium nucleatum (Fn) directly targets colorectal cancer stem cells (CR-CSCs), leading to their attachment and activation, which may contribute to the development and treatment of colorectal cancer.
Intestinal bacterial communities participate in gut homeostasis and are recognized as crucial in bowel inflammation and colorectal cancer (CRC). Fusobacterium nucleatum (Fn), a pathobiont of the oral microflora, has recently emerged as a CRC-associated microbe linked to disease progression, metastasis, and a poor clinical outcome; however, the primary cellular and/or microenvironmental targets of this agent remain elusive. We report here that Fn directly targets putative colorectal cancer stem cells (CR-CSCs), a tumor cell subset endowed with cancer re-initiating capacity after surgery and chemotherapy. A patient-derived CSC line, highly enriched (70%) for the stem marker CD133, was expanded as tumor spheroids, dissociated, and exposed in vitro to varying amounts (range 100-500 MOI) of Fn. We found that Fn stably adheres to CSCs, likely by multiple interactions involving the tumor-associated Gal-GalNac disaccharide and the Fn-docking protein CEA-family cell adhesion molecule 1 (CEACAM-1), robustly expressed on CSCs. Importantly, Fn elicited innate immune responses in CSCs and triggered a growth factor-like, protein tyrosine phosphorylation cascade largely dependent on CEACAM-1 and culminating in the activation of p42/44 MAP kinase. Thus, the direct stimulation of CSCs by Fn may contribute to microbiota-driven colorectal carcinogenesis and represent a target for innovative therapies.
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