Aoki, Shuichi, Inoue, Koetsu, Klein, Sebastian ORCID: 0000-0002-2188-9377, Halvorsen, Stefan, Chen, Jiang, Matsui, Aya, Nikmaneshi, Mohammad R., Kitahara, Shuji ORCID: 0000-0002-2904-0319, Hato, Tai ORCID: 0000-0002-1319-505X, Chen, Xianfeng ORCID: 0000-0002-7531-5862, Kawakubo, Kazumichi ORCID: 0000-0002-8979-9474, Nia, Hadi T., Chen, Ivy, Schanne, Daniel H., Mamessier, Emilie ORCID: 0000-0002-3516-0093, Shigeta, Kohei ORCID: 0000-0003-1596-4200, Kikuchi, Hiroto, Ramjiawan, Rakesh R., Schmidt, Tyge C. E., Iwasaki, Masaaki, Yau, Thomas, Hong, Theodore S., Quaas, Alexander, Plum, Patrick S. ORCID: 0000-0002-8165-4553, Dima, Simona, Popescu, Irinel, Bardeesy, Nabeel, Munn, Lance L., Borad, Mitesh J., Sassi, Slim, Jain, Rakesh K., Zhu, Andrew X. and Duda, Dan G. (2022). Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma. Gut, 71 (1). S. 185 - 194. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-3288

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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 (PIGF) in ICC progression. Design We evaluated the expression of PIGF in specimens from ICC patients and assessed the therapeutic effect of genetic or pharmacologic inhibition of PIGF in orthotopically grafted ICC mouse models. We evaluated the impact of PIGF stimulation or blockade in ICC cells and cancer-associated fibroblasts (CAFs) using in vitro 3-D coculture systems. Results PIGF 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 PIGF blockade in mice was enrichment of quiescent CAFs, characterised by high gene transcription levels related to the Akt pathway, glycolysis and hypoxia signalling. PIGF blockade suppressed Akt phosphorylation and myofibroblast activation in ICC-derived CAFs. PIGF 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, PIGF blockade enhanced the efficacy of standard chemotherapy in mice-bearing ICC. Conclusion PIGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Aoki, ShuichiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Inoue, KoetsuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, SebastianUNSPECIFIEDorcid.org/0000-0002-2188-9377UNSPECIFIED
Halvorsen, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, JiangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Matsui, AyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nikmaneshi, Mohammad R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kitahara, ShujiUNSPECIFIEDorcid.org/0000-0002-2904-0319UNSPECIFIED
Hato, TaiUNSPECIFIEDorcid.org/0000-0002-1319-505XUNSPECIFIED
Chen, XianfengUNSPECIFIEDorcid.org/0000-0002-7531-5862UNSPECIFIED
Kawakubo, KazumichiUNSPECIFIEDorcid.org/0000-0002-8979-9474UNSPECIFIED
Nia, Hadi T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, IvyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schanne, Daniel H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mamessier, EmilieUNSPECIFIEDorcid.org/0000-0002-3516-0093UNSPECIFIED
Shigeta, KoheiUNSPECIFIEDorcid.org/0000-0003-1596-4200UNSPECIFIED
Kikuchi, HirotoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramjiawan, Rakesh R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, Tyge C. E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iwasaki, MasaakiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yau, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hong, Theodore S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Quaas, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plum, Patrick S.UNSPECIFIEDorcid.org/0000-0002-8165-4553UNSPECIFIED
Dima, SimonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Popescu, IrinelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bardeesy, NabeelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Munn, Lance L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borad, Mitesh J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sassi, SlimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jain, Rakesh K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhu, Andrew X.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duda, Dan G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-602938
DOI: 10.1136/gutjnl-2020-322493
Journal or Publication Title: Gut
Volume: 71
Number: 1
Page Range: S. 185 - 194
Date: 2022
Publisher: BMJ PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1468-3288
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HEPATOCELLULAR-CARCINOMA; GENE-EXPRESSION; INHIBITS GROWTH; CANCER; FIBROBLASTS; THERAPY; ANGIOGENESIS; CELLS; THROMBOSPONDIN-1; DIFFERENTIATIONMultiple languages
Gastroenterology & HepatologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60293

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