RT Journal Article
SR Electronic
T1 Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 185
OP 193
DO 10.1136/gutjnl-2020-322493
VO 71
IS 1
A1 Shuichi Aoki
A1 Koetsu Inoue
A1 Sebastian Klein
A1 Stefan Halvorsen
A1 Jiang Chen
A1 Aya Matsui
A1 Mohammad R Nikmaneshi
A1 Shuji Kitahara
A1 Tai Hato
A1 Xianfeng Chen
A1 Kazumichi Kawakubo
A1 Hadi T Nia
A1 Ivy Chen
A1 Daniel H Schanne
A1 Emilie Mamessier
A1 Kohei Shigeta
A1 Hiroto Kikuchi
A1 Rakesh R Ramjiawan
A1 Tyge CE Schmidt
A1 Masaaki Iwasaki
A1 Thomas Yau
A1 Theodore S Hong
A1 Alexander Quaas
A1 Patrick S Plum
A1 Simona Dima
A1 Irinel Popescu
A1 Nabeel Bardeesy
A1 Lance L Munn
A1 Mitesh J Borad
A1 Slim Sassi
A1 Rakesh K. Jain
A1 Andrew X Zhu
A1 Dan G Duda
YR 2022
UL http://gut.bmj.com/content/71/1/185.abstract
AB 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.Data are available on reasonable request. Data are available on reasonable request from the corresponding author DGD. The authors used deidentified participant data at Fundeni Clinical Institute, Bucharest, Romania, University Hospital Cologne, Germany, and Massachusetts General Hospital, Boston, USA.