Abstract
Background and Aims: avb6 integrin is markedly upregulated in liver fibrosis and human cholangiocarcinoma (CC), and its genetic and pharmaceutical inhibition revealed potent antifibrotic activity in experimental liver fibrosis. Whether avb6 integrin inhibition may interfere with cholangiocarcinogenesis is unknown. Methods: To induce experimental CC, male Sprague-Dawley rats were treated with thioacetamide (TAA) for 22 weeks, followed by specific non-peptidic avb6 integrin inhibitor EMD527040 at 60mg/kg/day i.p. after 9 weeks of TAA. Besides mortality and tumor incidence, expression of avb6 integrin was evaluated by immunohistochemistry and RT-PCR. In vitro, 3D culture cell invasion assay was used to evaluate cholangiocarcinoma TFK-1 cells spheroid formation and invasive capacities. Human liver specimens of patients with cirrhosis, cholangiocarcinoma and normal liver tissues were analyzed by EMT RT ProfilerTM PCR Array (Qiagen). Results: TAA administration in rats induced CC in 80% of animals with no mortality, and an upregulation of avb6 integrin by 15-fold. Treatment with EMD527040 reduced the incidence of CC by 50%, and caused a significant down-regulation of avb6 mRNA expression. In vitro, 10mM EMD527040 completely prevented spheroid formation of cholangiocarcinoma cells TFK-1 in 3D system cultivation, whereas no matrix invasion with this cell type was observed. Microarrays in human CC samples detected a significant upregulation of 4 genes related to EMT: COL1A2, COL3A1, KRT19 and VCAN (p < 0.05), while there was a significant 5-fold downregulation of the EGFR, ESR1, F11R, IL1RN, NUDT13, PPPDE2 and WNT11 genes. Conclusions: Pharmaceutical targeting of avb6 integrin reduces tumor burden in an experimental model of CC, possibly by inhibiting tumor dissemination.
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