TY - JOUR T1 - Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma JF - Gut JO - Gut DO - 10.1136/gutjnl-2020-322493 SP - gutjnl-2020-322493 AU - Shuichi Aoki AU - Koetsu Inoue AU - Sebastian Klein AU - Stefan Halvorsen AU - Jiang Chen AU - Aya Matsui AU - Mohammad R Nikmaneshi AU - Shuji Kitahara AU - Tai Hato AU - Xianfeng Chen AU - Kazumichi Kawakubo AU - Hadi T Nia AU - Ivy Chen AU - Daniel H Schanne AU - Emilie Mamessier AU - Kohei Shigeta AU - Hiroto Kikuchi AU - Rakesh R Ramjiawan AU - Tyge CE Schmidt AU - Masaaki Iwasaki AU - Thomas Yau AU - Theodore S Hong AU - Alexander Quaas AU - Patrick S Plum AU - Simona Dima AU - Irinel Popescu AU - Nabeel Bardeesy AU - Lance L Munn AU - Mitesh J Borad AU - Slim Sassi AU - Rakesh K. Jain AU - Andrew X Zhu AU - Dan G Duda Y1 - 2021/01/11 UR - http://gut.bmj.com/content/early/2021/01/11/gutjnl-2020-322493.abstract N2 - 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. ER -