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Establishment and characterization of a new intrahepatic cholangiocarcinoma cell line resistant to gemcitabine

ABSTRACT: Intrahepatic cholangiocarcinoma (ICC) is one of the most lethal liver cancers. The late diagnosis as well as the resistance to chemotherapy concurred to the scarce outfit of this malignancy. Even the improvement of the knowledge and, as consequence, of the broad spectrum of alternative therapies available (i.e. targeted, immune checkpoint inhibitors), the survival and the quality of life remain poor. The phenomenon of resistance is not still clear. Here, we established one gemcitabine, GEM, (the standard therapy in ICC) resistant cell line, named MTCHC01R1.5, obtained by a gradual exposure to GEM for 9 months (up to 1.5 µM) of the sensible counterpart MT-CHC01. We biologically and molecularly characterized this cell line comparing its behavior with its parental cell line. The drug resistance is irreversible, even if cells are treated with high doses of GEM. They grew slowly, both in vitro and in vivo, and no differences are highlighted in terms of migration and invasion. GEM resistance promoted a multi drug resistance development, but the drug prediction analysis showed that paclitaxel and doxycycline could overcome GEM resistance, as confirmed by cell viability assay. There is a global enrichment of up-regulated genes involved in the regulation of cell cycle and in DNA related process. The down-regulated genes are involved in response to stimuli, and xenobiotic metabolism, and angiogenesis. A deregulation of more than 20 genes related to drug resistance and epithelial to mesenchymal transition (EMT) was found. The trend in expression of 9 genes related to resistance is confirmed in a primary cell culture. In conclusion, we characterized a new Italian GEM resistance ICC model which could be exploited either to study the mechanism of resistance or to explore new therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE116118 | GEO | 2019/05/30

REPOSITORIES: GEO

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Project description:Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary cancer in the liver. ICC is an aggressive cancer with poor prognosis and limited therapeutic strategies. The identification of new drug targets and prognostic biomarkers is an important clinical challenge for ICC. The presence of an abundant stroma is a histological hallmark of ICC. Given the well established role of the stromal compartment in the progression of cancer diseases, we hypothesized that relevant biomarkers could be identified by analyzing the stroma of ICC. By combining laser capture microdissection and gene expression profiling we demonstrated that ICC stromal cells exhibit dramatic genomic changes. We identified a signature of 1,073 non-redundant genes that significantly discriminate the tumor stroma from non tumor fibrous tissue. Functional analysis of differentially expressed genes demonstrated that up-regulated genes in the stroma of ICC were related to cell cycle, extracellular matrix and Transforming Growth Factor beta (TGFM-NM-2) pathways. Tissue microarray analysis using an independent cohort of 40 ICC patients validated at a protein level the increase expression of Collagen 4, Laminin, Osteopontin/SPP1, KIAA0101 and TGFM-NM-22 genes in the stroma of ICC. Statistical analysis of clinical and pathological features demonstrated that the expression of Osteopontin, TGFM-NM-22 and Laminin in the stroma of ICC was significantly correlated with patient overall survival. More importantly, multivariate analysis demonstrated that the stromal expression of Osteopontin was an independent prognostic marker for overall and disease-free survival. Conclusion: The study identifies clinically relevant genomic alterations in the stroma of ICC, including candidates biomarkers for prognosis, supporting the idea that tumor stroma is an important factor for ICC onset and progression. 20 RNA samples were analyzed, from 10 patients with ICC. For each patient, RNA were isolated from laser capture microdissected (LCM) stroma from tumor and non tumor areas.

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Establishment and characterization of a new intrahepatic cholangiocarcinoma cell line resistant to gemcitabine

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