Cargando…

Proinflammatory and Cancer-Promoting Pathobiont Fusobacterium nucleatum Directly Targets Colorectal Cancer Stem Cells

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, metastas...

Descripción completa

Detalles Bibliográficos
Autores principales: Cavallucci, Virve, Palucci, Ivana, Fidaleo, Marco, Mercuri, Antonella, Masi, Letizia, Emoli, Valeria, Bianchetti, Giada, Fiori, Micol Eleonora, Bachrach, Gilad, Scaldaferri, Franco, Maulucci, Giuseppe, Delogu, Giovanni, Pani, Giovambattista
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9496236/
https://www.ncbi.nlm.nih.gov/pubmed/36139097
http://dx.doi.org/10.3390/biom12091256
_version_ 1784794219351638016
author Cavallucci, Virve
Palucci, Ivana
Fidaleo, Marco
Mercuri, Antonella
Masi, Letizia
Emoli, Valeria
Bianchetti, Giada
Fiori, Micol Eleonora
Bachrach, Gilad
Scaldaferri, Franco
Maulucci, Giuseppe
Delogu, Giovanni
Pani, Giovambattista
author_facet Cavallucci, Virve
Palucci, Ivana
Fidaleo, Marco
Mercuri, Antonella
Masi, Letizia
Emoli, Valeria
Bianchetti, Giada
Fiori, Micol Eleonora
Bachrach, Gilad
Scaldaferri, Franco
Maulucci, Giuseppe
Delogu, Giovanni
Pani, Giovambattista
author_sort Cavallucci, Virve
collection PubMed
description 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.
format Online
Article
Text
id pubmed-9496236
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-94962362022-09-23 Proinflammatory and Cancer-Promoting Pathobiont Fusobacterium nucleatum Directly Targets Colorectal Cancer Stem Cells Cavallucci, Virve Palucci, Ivana Fidaleo, Marco Mercuri, Antonella Masi, Letizia Emoli, Valeria Bianchetti, Giada Fiori, Micol Eleonora Bachrach, Gilad Scaldaferri, Franco Maulucci, Giuseppe Delogu, Giovanni Pani, Giovambattista Biomolecules Article 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. MDPI 2022-09-07 /pmc/articles/PMC9496236/ /pubmed/36139097 http://dx.doi.org/10.3390/biom12091256 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cavallucci, Virve
Palucci, Ivana
Fidaleo, Marco
Mercuri, Antonella
Masi, Letizia
Emoli, Valeria
Bianchetti, Giada
Fiori, Micol Eleonora
Bachrach, Gilad
Scaldaferri, Franco
Maulucci, Giuseppe
Delogu, Giovanni
Pani, Giovambattista
Proinflammatory and Cancer-Promoting Pathobiont Fusobacterium nucleatum Directly Targets Colorectal Cancer Stem Cells
title Proinflammatory and Cancer-Promoting Pathobiont Fusobacterium nucleatum Directly Targets Colorectal Cancer Stem Cells
title_full Proinflammatory and Cancer-Promoting Pathobiont Fusobacterium nucleatum Directly Targets Colorectal Cancer Stem Cells
title_fullStr Proinflammatory and Cancer-Promoting Pathobiont Fusobacterium nucleatum Directly Targets Colorectal Cancer Stem Cells
title_full_unstemmed Proinflammatory and Cancer-Promoting Pathobiont Fusobacterium nucleatum Directly Targets Colorectal Cancer Stem Cells
title_short Proinflammatory and Cancer-Promoting Pathobiont Fusobacterium nucleatum Directly Targets Colorectal Cancer Stem Cells
title_sort proinflammatory and cancer-promoting pathobiont fusobacterium nucleatum directly targets colorectal cancer stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9496236/
https://www.ncbi.nlm.nih.gov/pubmed/36139097
http://dx.doi.org/10.3390/biom12091256
work_keys_str_mv AT cavalluccivirve proinflammatoryandcancerpromotingpathobiontfusobacteriumnucleatumdirectlytargetscolorectalcancerstemcells
AT palucciivana proinflammatoryandcancerpromotingpathobiontfusobacteriumnucleatumdirectlytargetscolorectalcancerstemcells
AT fidaleomarco proinflammatoryandcancerpromotingpathobiontfusobacteriumnucleatumdirectlytargetscolorectalcancerstemcells
AT mercuriantonella proinflammatoryandcancerpromotingpathobiontfusobacteriumnucleatumdirectlytargetscolorectalcancerstemcells
AT masiletizia proinflammatoryandcancerpromotingpathobiontfusobacteriumnucleatumdirectlytargetscolorectalcancerstemcells
AT emolivaleria proinflammatoryandcancerpromotingpathobiontfusobacteriumnucleatumdirectlytargetscolorectalcancerstemcells
AT bianchettigiada proinflammatoryandcancerpromotingpathobiontfusobacteriumnucleatumdirectlytargetscolorectalcancerstemcells
AT fiorimicoleleonora proinflammatoryandcancerpromotingpathobiontfusobacteriumnucleatumdirectlytargetscolorectalcancerstemcells
AT bachrachgilad proinflammatoryandcancerpromotingpathobiontfusobacteriumnucleatumdirectlytargetscolorectalcancerstemcells
AT scaldaferrifranco proinflammatoryandcancerpromotingpathobiontfusobacteriumnucleatumdirectlytargetscolorectalcancerstemcells
AT mauluccigiuseppe proinflammatoryandcancerpromotingpathobiontfusobacteriumnucleatumdirectlytargetscolorectalcancerstemcells
AT delogugiovanni proinflammatoryandcancerpromotingpathobiontfusobacteriumnucleatumdirectlytargetscolorectalcancerstemcells
AT panigiovambattista proinflammatoryandcancerpromotingpathobiontfusobacteriumnucleatumdirectlytargetscolorectalcancerstemcells