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

Aoki, Shuichi; Inoue, Koetsu; Klein, Sebastian; Halvorsen, Stefan; Chen, Jiang; Matsui, Aya; Nikmaneshi, Mohammad R; Kitahara, Shuji; Hato, Tai; Chen, Xianfeng; Kawakubo, Kazumichi; Nia, Hadi T; Chen, Ivy; Schanne, Daniel H; Mamessier, Emilie; Shigeta, Kohei; Kikuchi, Hiroto; Ramjiawan, Rakesh R; Schmidt, Tyge Ce; Iwasaki, Masaaki; ... (2022). Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma. Gut, 71(1), pp. 185-193. BMJ Publishing Group 10.1136/gutjnl-2020-322493

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology

UniBE Contributor:

Schanne, Daniel Hendrik

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0017-5749

Publisher:

BMJ Publishing Group

Language:

English

Submitter:

Beatrice Scheidegger

Date Deposited:

11 Jan 2022 14:35

Last Modified:

05 Dec 2022 15:55

Publisher DOI:

10.1136/gutjnl-2020-322493

PubMed ID:

33431577

Uncontrolled Keywords:

cholangiocarcinoma hepatic fibrosis

BORIS DOI:

10.48350/161986

URI:

https://boris.unibe.ch/id/eprint/161986

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