Abstract
218 Background: Cholangiocarcinoma (CC) is an aggressive malignancy that often presents in advanced stages with poor response rates to conventional chemotherapy. Recent studies of CC have uncovered several oncogenes and tumor suppressors implicated in the transition from biliary hyperplasia to malignancy. We have developed a mouse model of intrahepatic CC that results from deletion of the phosphatase and tensin homolog (PTEN) gene and the von Hippel Lindau (VHL) gene, a tumor suppressor that regulates hypoxia inducible factor (HIF) expression. Immunohistochemical (IHC) analysis of the liver tumors revealed strong staining of p-AKT and HIF-1α. This study aims to determine the expression of the same downstream targets p-AKT and HIF1α in a dataset of human CC tumors. Methods: Archived samples from 33 CC patients were sectioned and stained via IHC for p-AKT and HIF1α expression. Samples were evaluated using a proportion score (PS) for neoplastic cells on a scale of 0 to 5, and an intensity score (IS) expressed on a scale of 0 to 3. Normal liver samples were used as controls. Results: Using a combined score of at least 5 to determine positive expression, 18% of the 33 evaluated samples displayed positive p-AKT expression and 61% displayed positive HIF1α expression. 15% of cases displayed concomitant expression of both p-AKT and HIF1α, while 39% of evaluated samples had expression of neither protein. Conclusions: Delineating the molecular pathways that lead to CC formation is crucial in developing novel therapeutics for a disease in drastic need of more effective therapies. Our group has developed a mouse model of intrahepatic CC that suggests a synergistic role of PTEN and VHL in the tumorigenesis of CC with upregulation of p-AKT and HIF1α. A modest percentage of a cohort of human samples demonstrates a similar expression pattern, potentially defining a distinct molecular subtype of this cancer with implications for tumor behavior and response to treatment. Future studies will correlate these molecularly-defined subtypes to the clinicopathologic characteristics of the tumors with the ultimate aim of establishing biomarkers of disease prognosis as well as potential predictive indicators of treatment activity. No significant financial relationships to disclose.
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