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 Iwasaki; Thomas 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

doi:10.1136/gutjnl-2020-322493

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

Hematology/Oncology

Research output: Contribution to journal › Article › peer-review

Abstract

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 language	English (US)
Pages (from-to)	185-193
Number of pages	9
Journal	Gut
Volume	71
Issue number	1
DOIs	https://doi.org/10.1136/gutjnl-2020-322493
State	Published - Jan 1 2022

Keywords

cholangiocarcinoma
hepatic fibrosis

ASJC Scopus subject areas

Gastroenterology

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10.1136/gutjnl-2020-322493

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Aoki, S., Inoue, K., Klein, S., Halvorsen, S., Chen, J., Matsui, A., Nikmaneshi, M. R., Kitahara, S., Hato, T., Chen, X., Kawakubo, K., Nia, H. T., Chen, I., Schanne, D. H., Mamessier, E., Shigeta, K., Kikuchi, H., Ramjiawan, R. R., Schmidt, T. C. E., ... Duda, D. G. (2022). Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma. Gut, 71(1), 185-193. https://doi.org/10.1136/gutjnl-2020-322493

Aoki, S, Inoue, K, Klein, S, Halvorsen, S, Chen, J, Matsui, A, Nikmaneshi, MR, Kitahara, S, Hato, T, Chen, X, Kawakubo, K, Nia, HT, Chen, I, Schanne, DH, Mamessier, E, Shigeta, K, Kikuchi, H, Ramjiawan, RR, Schmidt, TCE, Iwasaki, M, Yau, T, Hong, TS, Quaas, A, Plum, PS, Dima, S, Popescu, I, Bardeesy, N, Munn, LL, Borad, MJ, Sassi, S, Jain, RK, Zhu, AX & Duda, DG 2022, 'Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma', Gut, vol. 71, no. 1, pp. 185-193. https://doi.org/10.1136/gutjnl-2020-322493

@article{857681cfbc594a5eaee5b03ea19ae7ff,

title = "Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma",

abstract = "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.",

keywords = "cholangiocarcinoma, hepatic fibrosis",

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

note = "Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2022",

month = jan,

day = "1",

doi = "10.1136/gutjnl-2020-322493",

language = "English (US)",

volume = "71",

pages = "185--193",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

number = "1",

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TY - JOUR

T1 - Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma

AU - Aoki, Shuichi

AU - Inoue, Koetsu

AU - Klein, Sebastian

AU - Halvorsen, Stefan

AU - Chen, Jiang

AU - Matsui, Aya

AU - Nikmaneshi, Mohammad R.

AU - Kitahara, Shuji

AU - Hato, Tai

AU - Chen, Xianfeng

AU - Kawakubo, Kazumichi

AU - Nia, Hadi T.

AU - Chen, Ivy

AU - Schanne, Daniel H.

AU - Mamessier, Emilie

AU - Shigeta, Kohei

AU - Kikuchi, Hiroto

AU - Ramjiawan, Rakesh R.

AU - Schmidt, Tyge C.E.

AU - Iwasaki, Masaaki

AU - Yau, Thomas

AU - Hong, Theodore S.

AU - Quaas, Alexander

AU - Plum, Patrick S.

AU - Dima, Simona

AU - Popescu, Irinel

AU - Bardeesy, Nabeel

AU - Munn, Lance L.

AU - Borad, Mitesh J.

AU - Sassi, Slim

AU - Jain, Rakesh K.

AU - Zhu, Andrew X.

AU - Duda, Dan G.

PY - 2022/1/1

Y1 - 2022/1/1

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

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.

KW - cholangiocarcinoma

KW - hepatic fibrosis

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AN - SCOPUS:85099387425

SN - 0017-5749

VL - 71

SP - 185

EP - 193

JO - Gut

JF - Gut

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ER -

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

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