KITAHARA Shuji    Department   Research Institutes and Facilities, Research Institutes and Facilities    Position   Associate Professor (Fixed Term)
Article types	Original article
Language	English
Peer review	Peer reviewed
Title	Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma.
Journal	Formal name：Gut Abbreviation：Gut ISSN code：14683288/00175749
Domestic / Foregin	Foregin
Volume, Issue, Page	e(e),pp.e-e
Author and coauthor	Aoki Shuichi, Inoue Koetsu, Klein Sebastian, Halvorsen Stefan, Chen Jiang, Matsui Aya, Nikmaneshi Mohammad R, Kitahara Shuji, Hato Tai, Chen Xianfeng, Kawakubo Kazumichi, Nia Hadi T, Chen Ivy, Schanne Daniel H, Mamessier Emilie, Shigeta Kohei, Kikuchi Hiroto, Ramjiawan Rakesh R, Schmidt Tyge Ce, Iwasaki Masaaki, Yau Thomas, Hong Theodore S, Quaas Alexander, Plum Patrick S, Dima Simona, Popescu Irinel, Bardeesy Nabeel, Munn Lance L, Borad Mitesh J, Sassi Slim, Jain Rakesh K, Zhu Andrew X, Duda Dan G
Publication date	2021/01/11
Summary	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.ConclusionPlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.
DOI	10.1136/gutjnl-2020-322493
PMID	33431577