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

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the biliary tree and a risk factor for development of cholangiocarcinoma (CCA). The pathogene-sis of PSC-related CCA is largely unclear, although it is assumed that chronic inflam-matory 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 signifi-cantly 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)-1 beta, 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.