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Original research
Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma
  1. Shuichi Aoki1,2,
  2. Koetsu Inoue1,2,
  3. Sebastian Klein1,3,
  4. Stefan Halvorsen4,
  5. Jiang Chen1,5,
  6. Aya Matsui1,
  7. Mohammad R Nikmaneshi1,
  8. Shuji Kitahara1,6,
  9. Tai Hato1,7,
  10. Xianfeng Chen8,
  11. Kazumichi Kawakubo1,
  12. Hadi T Nia1,9,
  13. Ivy Chen1,10,
  14. Daniel H Schanne1,
  15. Emilie Mamessier1,11,
  16. Kohei Shigeta1,12,
  17. Hiroto Kikuchi1,12,
  18. Rakesh R Ramjiawan1,
  19. Tyge CE Schmidt1,
  20. Masaaki Iwasaki1,
  21. Thomas Yau13,
  22. Theodore S Hong14,
  23. Alexander Quaas3,
  24. Patrick S Plum15,
  25. Simona Dima16,
  26. Irinel Popescu16,
  27. Nabeel Bardeesy17,
  28. Lance L Munn1,
  29. Mitesh J Borad8,
  30. Slim Sassi4,18,
  31. Rakesh K. Jain1,
  32. Andrew X Zhu17,19,
  33. Dan G Duda1
  1. 1Radiation Oncology/Steele Laboratories for Tumor Biology, Massachusetts General Hospital, Boston, Massachusetts, USA
  2. 2Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
  3. 3Pathology, University Hospital Cologne, Cologne, Nordrhein-Westfalen, Germany
  4. 4Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA
  5. 5General Surgery, Zhejiang University, Hangzhou, Zhejiang, China
  6. 6Anatomy and Developmental Biology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan
  7. 7Thoracic Surgery, Saitama Medical University, Iruma-gun, Saitama, Japan
  8. 8Oncology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
  9. 9Bioengineering, Boston University, Boston, Massachusetts, USA
  10. 10Research, STIMIT Corporation, Cambridge, Massachusetts, USA
  11. 11Molecular Oncology, Cancer Research Center, Marseille, France
  12. 12Surgery, Keio University Hospital, Shinjuku-ku, Tokyo, Japan
  13. 13Medicine, University of Hong Kong, Hong Kong Special Administrative Region, China
  14. 14Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
  15. 15Department of General, Visceral and Cancer Surgery, University of Cologne, Koln, Nordrhein-Westfalen, Germany
  16. 16Center of Digestive Diseases and Liver Transplantation, Clinical Institute Fundeni, Bucuresti, Romania
  17. 17Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
  18. 18Orthopedics, Massachusetts General Hospital, Boston, Massachusetts, USA
  19. 19Jiahui International Cancer Center, Jiahui Health, Shanghai, China
  1. Correspondence to Dr Dan G Duda, Radiation Oncology/Steele Laboratories for Tumor Biology, Massachusetts General Hospital, Boston, MA 02114-2696, USA; duda{at}


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.


PlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.

  • cholangiocarcinoma
  • hepatic fibrosis

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  • SA and KI contributed equally.

  • Contributors SA designed and performed experiments, analysed the data and wrote the manuscript. KI, SK, JC, AM, MRN, TH, XC, SK, KK, HTN, DHS, EM, KS, HK, RRR, MI and TCES performed experiments, analysed the data and edited the manuscript. SH, IC, MJB and SS analysed the RNA sequencing data and edited the manuscript. PSP, TSH, TY, SD and IP provided human samples and analysed the data. NB provided murine reagents and analysed the data. LLM, RKJ and AXZ analysed the data and edited the manuscript. DGD designed the experiments, analysed the data, obtained funding and wrote the manuscript. All authors approved the final version of the manuscript.

  • Funding DD’s work was supported through NIH grants P01-CA080124, R41-CA213678 and Proton Beam/Federal Share Programme and Department of DefenseDefence grants #W81XWH-19-1-0284 and W81XWH-19-1-0482. RKJ’s work was supported through NIH grants P01-CA080124, R35-CA197743, R01-CA208205 and U01-CA224173, and by the National Foundation for Cancer Research, Harvard Ludwig Cancer Centre, Advanced Medical Research Foundation and Jane’s Trust Foundation. IP’s work was supported by the Romanian Ministry of Research and Innovation, CCCDI–UEFISCDI, project number PN-III-P1-1.2-PCCDI-2017-0797/66PCCDI, within PNCDI III. SA’s research was supported by a Postdoctoral Fellowship from Cholangiocarcinoma Research Foundation, TH received a Postdoctoral Fellowship from Astellas Foundation for Research on Metabolic Disorders, Japan, DS received a Postdoctoral Fellowship from Humboldt Foundation, KS received a Postdoctoral Fellowship from Uehara Memorial Foundation, and EM received a grant from the Philippe Foundation and the Cancéropôle PACA.

  • Competing interests IC is an employee of STIMIT. TY has served in a consulting or advisory role for Bristol Myers Squibb. RKJ received honorarium from Amgen and consultant fees from Chugai, Ophthotech, Merck, SPARC, SynDevRx. RKJ owns equity in Accurius, Enlight, SPARC, and SynDevRx, and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund. AXZ is a consultant/advisory board member for Bayer. DGD received consultant fees from Bayer, Simcere, Surface Oncology and BMS and research grants from Bayer, Exelixis and BMS. No reagents or support from these companies was used for this study.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement 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.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.