Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma

Shuichi Aoki, Koetsu Inoue, Sebastian Klein, Stefan Halvorsen, Jiang Chen, Aya Matsui, Mohammad R. Nikmaneshi, Shuji Kitahara, Tai Hato, Xianfeng Chen, Kazumichi Kawakubo, Hadi T. Nia, Ivy Chen, Daniel H. Schanne, Emilie Mamessier, Kohei Shigeta, Hiroto Kikuchi, Rakesh R. Ramjiawan, Tyge C.E. Schmidt, Masaaki IwasakiThomas Yau, Theodore S. Hong, Alexander Quaas, Patrick S. Plum, Simona Dima, Irinel Popescu, Nabeel Bardeesy, Lance L. Munn, Mitesh J. Borad, Slim Sassi, Rakesh K. Jain, Andrew X. Zhu, Dan G. Duda

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)185-193
Number of pages9
Issue number1
Publication statusPublished - 2022 Jan 1


  • cholangiocarcinoma
  • hepatic fibrosis


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