Bone morphogenetic protein 4 provides cancer-supportive phenotypes to liver fibroblasts in patients with hepatocellular carcinoma.
Actins
/ genetics
Bone Morphogenetic Protein 4
/ genetics
Carcinoma, Hepatocellular
/ genetics
Cell Line, Tumor
Collagen Type I
/ genetics
Collagen Type I, alpha 1 Chain
Cytokines
/ metabolism
Fibroblasts
/ pathology
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Liver Neoplasms
/ genetics
Neoplasm Invasiveness
Phenotype
Retrospective Studies
Survival Rate
Tumor Microenvironment
Cancer-associated fibroblasts
IL-6
IL-8
Tumor microenvironment
Journal
Journal of gastroenterology
ISSN: 1435-5922
Titre abrégé: J Gastroenterol
Pays: Japan
ID NLM: 9430794
Informations de publication
Date de publication:
Nov 2019
Nov 2019
Historique:
received:
06
08
2018
accepted:
25
03
2019
pubmed:
4
4
2019
medline:
15
8
2020
entrez:
4
4
2019
Statut:
ppublish
Résumé
Cancer-associated fibroblasts (CAFs) are essential constituents of cancer-supportive microenvironments. The high incidence of hepatocellular carcinoma (HCC) in advanced fibrosis patients implies that fibroblasts have a promoting effect on HCC development. We aimed to explore the regulators of phenotypes and function of CAFs in the liver. We established primary cancer-associated fibroblasts (CAFs) and non-cancerous liver fibroblasts (NFs) from 15 patients who underwent HCC resection. We compared phenotypes, capacity of cytokine/chemokine production and gene expression profiles between pairs of CAFs and NFs from the same donors. We examined resected tissue from additional 50 patients with HCC for immunohistochemical analyses. The CAFs expressed more ACTA2 and COL1A1 than the NFs, suggesting that CAFs are more activated phenotype. The CAFs produced larger amounts of IL-6, IL-8 and CCL2 than the NFs, which led to invasiveness of HuH7 in vitro. We found that Bone Morphogenetic Protein-4 (BMP4) is up-regulated in CAFs compared to NFs. The CAF phenotype and function were gained by BMP4 over-expression or recombinant BMP4 given to fibroblasts, all of which decreased with BMP4 knockdown. In tissues obtained from the patients, BMP4-positive cells are mainly observed in encapsulated fibrous lesions and HCC. Positive expression of BMP4 in HCC in resected tissues, not in fibroblasts, was associated with poorer postoperative overall survival in patients with HCC. Endogenous and exogenous BMP4 activate liver fibroblasts to gain capacity of secreting cytokines and enhancing invasiveness of cancer cells in the liver. BMP4 is one of the regulatory factors of CAFs functioning in the microenvironment of HCC.
Sections du résumé
BACKGROUND
BACKGROUND
Cancer-associated fibroblasts (CAFs) are essential constituents of cancer-supportive microenvironments. The high incidence of hepatocellular carcinoma (HCC) in advanced fibrosis patients implies that fibroblasts have a promoting effect on HCC development. We aimed to explore the regulators of phenotypes and function of CAFs in the liver.
METHODS
METHODS
We established primary cancer-associated fibroblasts (CAFs) and non-cancerous liver fibroblasts (NFs) from 15 patients who underwent HCC resection. We compared phenotypes, capacity of cytokine/chemokine production and gene expression profiles between pairs of CAFs and NFs from the same donors. We examined resected tissue from additional 50 patients with HCC for immunohistochemical analyses.
RESULTS
RESULTS
The CAFs expressed more ACTA2 and COL1A1 than the NFs, suggesting that CAFs are more activated phenotype. The CAFs produced larger amounts of IL-6, IL-8 and CCL2 than the NFs, which led to invasiveness of HuH7 in vitro. We found that Bone Morphogenetic Protein-4 (BMP4) is up-regulated in CAFs compared to NFs. The CAF phenotype and function were gained by BMP4 over-expression or recombinant BMP4 given to fibroblasts, all of which decreased with BMP4 knockdown. In tissues obtained from the patients, BMP4-positive cells are mainly observed in encapsulated fibrous lesions and HCC. Positive expression of BMP4 in HCC in resected tissues, not in fibroblasts, was associated with poorer postoperative overall survival in patients with HCC.
CONCLUSION
CONCLUSIONS
Endogenous and exogenous BMP4 activate liver fibroblasts to gain capacity of secreting cytokines and enhancing invasiveness of cancer cells in the liver. BMP4 is one of the regulatory factors of CAFs functioning in the microenvironment of HCC.
Identifiants
pubmed: 30941514
doi: 10.1007/s00535-019-01579-5
pii: 10.1007/s00535-019-01579-5
doi:
Substances chimiques
ACTA2 protein, human
0
Actins
0
BMP4 protein, human
0
Bone Morphogenetic Protein 4
0
Collagen Type I
0
Collagen Type I, alpha 1 Chain
0
Cytokines
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1007-1018Subventions
Organisme : Instituto de Pesquisa Translacional em Saúde e Ambiente na Região Amazônica (BR)
ID : 26-shi-109
Organisme : Grants-in-aid for Research from the National Center for Global Health and Medicine
ID : 26A201
Organisme : the Research Program on Hepatitis from Japan Agency for Medical Research and Development
ID : 17fk0210305h0003
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