Colorectal cancer-derived extracellular vesicles induce transformation of fibroblasts into colon carcinoma cells.
Animals
Apoptosis
/ genetics
BRCA1 Protein
/ genetics
Biological Transport
Biomarkers, Tumor
Cell Line, Tumor
Cell Movement
/ genetics
Cell Transformation, Neoplastic
/ genetics
Colorectal Neoplasms
/ genetics
Disease Models, Animal
Extracellular Vesicles
/ metabolism
Female
Fibroblasts
/ metabolism
Gene Expression Profiling
Gene Knockdown Techniques
Humans
Mice
Neoplasm Metastasis
Phenotype
Polymorphism, Genetic
Transcriptome
Colorectal Cancer
Extracellular vesicles
Genetic material
Horizontal transfer
Metastasis
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
14 Jun 2019
14 Jun 2019
Historique:
received:
02
04
2019
accepted:
27
05
2019
entrez:
16
6
2019
pubmed:
16
6
2019
medline:
18
12
2019
Statut:
epublish
Résumé
We reported that horizontal transfer of malignant traits to target cells is a potential pathway to explain cancer dissemination. Although these results were encouraging, they were never corroborated by data showing the molecular mechanisms responsible for the observed phenomenon. In the present study, we exposed BRCA1-KO fibroblasts to extracellular vesicles (EVs) isolated from a colon cancer cell line (HT29) and from sera of patients with colorectal cancer. Three weeks after exposure, fibroblasts were injected subcutaneously into NOD-SCID mice. Whole genome sequencing, transcriptome analysis and RNA sequencing of cancer EVs and fibroblasts prior and after exposure to cancer EVs were performed. Phenotypical transformation of the fibroblasts into colon cancer cells was confirmed by histopathological study of the xenotransplants. We observed that EV-mediated transfer of cancer microRNAs was responsible for the transition from a mesenchymal to an epithelial phenotype (MET) in the treated fibroblasts as well as activation of cell cycle progression and cell survival pathways. DNA and RNA sequencing suggested that cancer DNA was transferred and possibly transcribed in target cells. Furthermore, injection of colon cancer EVs in the tail vein of NOD-SCID mice determined neoplastic transformation and metastases in the lungs of the mice confirming for the first time the hypothesis that transfer of malignant epithelial cancer traits to distant target cells is a concept applicable to in vivo models. These discoveries shed new light into the molecular mechanisms behind the horizontal transfer of malignant traits and confirm the notion that metastatic disease might be reproduced through transfer of circulating genetic material.
Sections du résumé
BACKGROUND
BACKGROUND
We reported that horizontal transfer of malignant traits to target cells is a potential pathway to explain cancer dissemination. Although these results were encouraging, they were never corroborated by data showing the molecular mechanisms responsible for the observed phenomenon.
METHODS
METHODS
In the present study, we exposed BRCA1-KO fibroblasts to extracellular vesicles (EVs) isolated from a colon cancer cell line (HT29) and from sera of patients with colorectal cancer. Three weeks after exposure, fibroblasts were injected subcutaneously into NOD-SCID mice. Whole genome sequencing, transcriptome analysis and RNA sequencing of cancer EVs and fibroblasts prior and after exposure to cancer EVs were performed.
RESULTS
RESULTS
Phenotypical transformation of the fibroblasts into colon cancer cells was confirmed by histopathological study of the xenotransplants. We observed that EV-mediated transfer of cancer microRNAs was responsible for the transition from a mesenchymal to an epithelial phenotype (MET) in the treated fibroblasts as well as activation of cell cycle progression and cell survival pathways. DNA and RNA sequencing suggested that cancer DNA was transferred and possibly transcribed in target cells. Furthermore, injection of colon cancer EVs in the tail vein of NOD-SCID mice determined neoplastic transformation and metastases in the lungs of the mice confirming for the first time the hypothesis that transfer of malignant epithelial cancer traits to distant target cells is a concept applicable to in vivo models.
CONCLUSIONS
CONCLUSIONS
These discoveries shed new light into the molecular mechanisms behind the horizontal transfer of malignant traits and confirm the notion that metastatic disease might be reproduced through transfer of circulating genetic material.
Identifiants
pubmed: 31200749
doi: 10.1186/s13046-019-1248-2
pii: 10.1186/s13046-019-1248-2
pmc: PMC6567673
doi:
Substances chimiques
BRCA1 Protein
0
BRCA1 protein, human
0
Biomarkers, Tumor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
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