Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance.
Oncogene
; 38(11): 1951-1965, 2019 03.
Article
em En
| MEDLINE
| ID: mdl-30390075
ABSTRACT
Cancer stem cells (CSCs) are inherently resistant to chemotherapy, and CSCs in chemotherapy-failed recurrent tumors are enriched; however, the cellular origin of chemotherapy-induced CSC enrichment remains unclear. Communication with stromal fibroblasts may induce cancer cell dedifferentiation into CSCs through secreted factors. We recently demonstrated that fibroblast-derived exosomes promote chemoresistance in colorectal cancer (CRC). Here, we report that fibroblasts confer CRC chemoresistance via exosome-induced reprogramming (dedifferentiation) of bulk CRC cells to phenotypic and functional CSCs. At the molecular level, we provided evidence that the major reprogramming regulators in fibroblast-exosomes are Wnts. Exosomal Wnts were found to increase Wnt activity and drug resistance in differentiated CRC cells, and inhibiting Wnt release diminished this effect in vitro and in vivo. Together, our results indicate that exosomal Wnts derived from fibroblasts could induce the dedifferentiation of cancer cells to promote chemoresistance in CRC, and suggest that interfering with exosomal Wnt signaling may help to improve chemosensitivity and the therapeutic window.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Neoplásicas
/
Neoplasias Colorretais
/
Resistencia a Medicamentos Antineoplásicos
/
Desdiferenciação Celular
/
Exossomos
/
Via de Sinalização Wnt
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Oncogene
Assunto da revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
China