Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma
Open Access
- 11 January 2021
- Vol. 71 (1), 185-193
- https://doi.org/10.1136/gutjnl-2020-322493
Abstract
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 (PlGF) in ICC progression. Design 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. Results 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. Conclusion PlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.Keywords
Funding Information
- Cholangiocarcinoma Research Foundation (Postdoctoral Fellowship)
- Harvard Ludwig Cancer Center (Grant)
- U.S. Department of Defense (W81XWH-19-1-0284, W81XWH-19-1-0482)
- Canceropôle PACA (Grant)
- Romanian Ministry of Research and Innovation, CCCDI–UEFISCDI (PN-III-P1-1.2-PCCDI-2017-0797/66PCCDI)
- Alexander von Humboldt-Stiftung (Postdoctoral Fellowship)
- Advanced Medical Research Foundation (Grant)
- Jane’s Trust Foundation (Grant)
- National Cancer Institute (P01-CA080124, Proton Beam/Federal Share Program, R01-CA208205, R35-CA197743, R41-CA213678, U01-CA224173)
- National Foundation for Cancer Research (Fellow)
- Astellas Foundation for Research on Metabolic Disorders (Postdoctoral Fellowship)
- Uehara Memorial Foundation (Postdoctoral Fellowship)
This publication has 58 references indexed in Scilit:
- Current Therapy and Future Directions in Biliary Tract MalignanciesCurrent Treatment Options in Oncology, 2013
- Platelet-derived growth factor-D and Rho GTPases regulate recruitment of cancer-associated fibroblasts in cholangiocarcinomaJournal of Hepatology, 2013
- KrasG12D and p53 Mutation Cause Primary Intrahepatic CholangiocarcinomaCancer Research, 2012
- Myofibroblast-derived PDGF-BB promotes hedgehog survival signaling in cholangiocarcinoma cellsJournal of Hepatology, 2011
- HRG Inhibits Tumor Growth and Metastasis by Inducing Macrophage Polarization and Vessel Normalization through Downregulation of PlGFCancer Cell, 2011
- Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract CancerThe New England Journal of Medicine, 2010
- Further Pharmacological and Genetic Evidence for the Efficacy of PlGF Inhibition in Cancer and Eye DiseaseCell, 2010
- Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-κB-Dependent MannerCancer Cell, 2010
- αPlGF: A New Kid on the Antiangiogenesis BlockCell, 2007
- Enhanced expression of thrombospondin-1 and hypovascularity in human cholangiocarcinomaJournal of Hepatology, 1998