Cholangiocarcinoma cell proliferation is enhanced in primary sclerosing cholangitis: A role for IL-17A

Ruby Lieshout, Eline J C A Kamp, Monique M A Verstegen*, Michail Doukas, Winand N M Dinjens, Kübra Köten, Jan N M IJzermans, Marco J Bruno, Maikel P Peppelenbosch, Luc J W van der Laan, Annemarie C de Vries

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the biliary tree and a risk factor for development of cholangiocarcinoma (CCA). The pathogenesis of PSC-related CCA is largely unclear, although it is assumed that chronic inflammatory environment plays a pivotal role. We aimed to investigate the effect of inflammation-related cytokines in PSC on the proliferation rate of cancer cells. For this, the proliferation index in PSC-CCA and sporadic CCA was determined by Ki-67 immunohistochemistry. The percentage of Ki-67 positivity in cancer cells was significantly higher in PSC-CCA than in sporadic CCA (41.3% ± 5.7% vs 25.8% ± 4.1%; P = .038). To assess which cytokines in the inflammatory environment have the potential to stimulate cancer cell proliferation, patient-derived CCA organoids (CCAOs) were exposed to five cytokines related to PSC (Interleukin (IL)-1β, IL-6, IL-17A, interferon gamma and tumor necrosis factor alpha). Only IL-17A showed a significant stimulatory effect on cell proliferation in CCAOs, increasing organoid size by 45.9% ± 16.4% (P < .01) and proliferation rate by 38% ± 16% (P < .05). IL-17A immunohistochemistry demonstrated that PSC-CCA might express more IL-17A than sporadic CCA. Moreover, correlation analysis in sporadic CCA and PSC-CCA found a significant correlation between IL-17A expression and proliferation. In conclusion, tumor cell proliferation is increased in PSC-CCA cells compared with sporadic CCA cells. IL-17A increases CCA cell proliferation in vitro and may contribute to the high proliferation rate in PSC-CCA in situ. Therefore, IL-17A represents a new potential therapeutic target in (PSC-)CCA, to be tested in future trials.

Original languageEnglish
JournalInternational Journal of Cancer
DOIs
Publication statusE-pub ahead of print - 8 Nov 2022

Bibliographical note

FUNDING INFORMATION
Investigators in this study received financial support from the Erasmus MC Human Disease Model Award (HDMA grant-380801), the Netherlands Organization for Health Research and Development (ZonMw) (InnoSysTox grant 114027003), the Dutch Digestive Foundation (MLDS-Diagnostics project number D16-26) and the Dutch Cancer Society (KWF) (project number 10496).

© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

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