Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma.
cholangiocarcinoma
hepatic fibrosis
Journal
Gut
ISSN: 1468-3288
Titre abrégé: Gut
Pays: England
ID NLM: 2985108R
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
09
07
2020
revised:
21
12
2020
accepted:
27
12
2020
pubmed:
13
1
2021
medline:
11
1
2022
entrez:
12
1
2021
Statut:
ppublish
Résumé
Intrahepatic cholangiocarcinoma (ICC)-a rare liver malignancy with limited therapeutic options-is characterised by aggressive progression, desmoplasia and vascular abnormalities. The aim of this study was to determine the role of placental growth factor (PlGF) in ICC progression. We evaluated the expression of PlGF in specimens from ICC patients and assessed the therapeutic effect of genetic or pharmacologic inhibition of PlGF in orthotopically grafted ICC mouse models. We evaluated the impact of PlGF stimulation or blockade in ICC cells and cancer-associated fibroblasts (CAFs) using in vitro 3-D coculture systems. PlGF levels were elevated in human ICC stromal cells and circulating blood plasma and were associated with disease progression. Single-cell RNA sequencing showed that the major impact of PlGF blockade in mice was enrichment of quiescent CAFs, characterised by high gene transcription levels related to the Akt pathway, glycolysis and hypoxia signalling. PlGF blockade suppressed Akt phosphorylation and myofibroblast activation in ICC-derived CAFs. PlGF blockade also reduced desmoplasia and tissue stiffness, which resulted in reopening of collapsed tumour vessels and improved blood perfusion, while reducing ICC cell invasion. Moreover, PlGF blockade enhanced the efficacy of standard chemotherapy in mice-bearing ICC.
Identifiants
pubmed: 33431577
pii: gutjnl-2020-322493
doi: 10.1136/gutjnl-2020-322493
pmc: PMC8666816
doi:
Substances chimiques
Antibodies, Monoclonal
0
Placenta Growth Factor
144589-93-5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
185-193Subventions
Organisme : NCI NIH HHS
ID : P01 CA261669
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA221073
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA080124
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA208205
Pays : United States
Organisme : NCI NIH HHS
ID : R41 CA213678
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197743
Pays : United States
Informations de copyright
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: IC is an employee of STIMIT. TY has served in a consulting or advisory role for Bristol Myers Squibb. RKJ received honorarium from Amgen and consultant fees from Chugai, Ophthotech, Merck, SPARC, SynDevRx. RKJ owns equity in Accurius, Enlight, SPARC, and SynDevRx, and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund. AXZ is a consultant/advisory board member for Bayer. DGD received consultant fees from Bayer, Simcere, Surface Oncology and BMS and research grants from Bayer, Exelixis and BMS. No reagents or support from these companies was used for this study.
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