Journal
GUT
Volume 71, Issue 1, Pages 185-193Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2020-322493
Keywords
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Funding
- NIH [P01-CA080124, R35-CA197743, R01-CA208205, U01-CA224173, R41-CA213678]
- Department of DefenseDefence grants [W81XWH-19-1-0284, W81XWH-19-1-0482]
- National Foundation for Cancer Research
- Jane's Trust Foundation
- Romanian Ministry of Research and Innovation, CCCDI-UEFISCDI within PNCDI III [PN-III-P1-1.2-PCCDI-2017-0797/66PCCDI]
- Cholangiocarcinoma Research Foundation
- Astellas Foundation for Research on Metabolic Disorders, Japan
- Humboldt Foundation
- Uehara Memorial Foundation
- Philippe Foundation
- Canceropole PACA
- Proton Beam/Federal Share Programme
- Harvard Ludwig Cancer Centre
- Advanced Medical Research Foundation
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Elevated levels of placental growth factor (PIGF) in human ICC stromal cells and circulating blood plasma were associated with disease progression. Inhibition of PIGF led to reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity, and increased survival in mice-bearing aggressive ICC.
Objective 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 (PIGF) in ICC progression. Design We evaluated the expression of PIGF in specimens from ICC patients and assessed the therapeutic effect of genetic or pharmacologic inhibition of PIGF in orthotopically grafted ICC mouse models. We evaluated the impact of PIGF stimulation or blockade in ICC cells and cancer-associated fibroblasts (CAFs) using in vitro 3-D coculture systems. Results PIGF 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 PIGF blockade in mice was enrichment of quiescent CAFs, characterised by high gene transcription levels related to the Akt pathway, glycolysis and hypoxia signalling. PIGF blockade suppressed Akt phosphorylation and myofibroblast activation in ICC-derived CAFs. PIGF 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, PIGF blockade enhanced the efficacy of standard chemotherapy in mice-bearing ICC. Conclusion PIGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.
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