A systems biology perspective on cholangiocellular carcinoma development: Focus on MAPK-signaling and the extracellular environment

Background/Aims: Multiple genes have been implicated in cholangiocellular carcinoma (CCC) development. However, the overall neoplastic risk is likely associated with a much lower number of critical physiological pathways. Methods: To investigate this hypothesis, we extracted all published genetic associations for the development of CCC from PubMed (genetic association studies, but also studies associating genes and CCC in general, i.e. functional studies in cell lines, genetic studies in humans, knockout mice etc.) and integrated CCC microarray data. Results: We demonstrated the MAPK pathway was consistently enriched in CCC. Comparing our data to genetic associations in HCC often successfully treated by a multityrosine kinase inhibitor, sorafenib, we demonstrated a similar overrepresentation of MAPK. In contrast, most cancer-related genetic studies focusing on genes related to transcription and cell cycle control, we consistently found genes coding for products in the extracellular environment to be significantly enriched. Thus, CCC must be regarded as developing in the context of an altered extracellular environment. Conclusions: Our study suggests the liver microenvironment holds essential functions and structures key to CCC progression. Furthermore, we identified the MAPK signaling pathway consistently enriched, pointing towards a critical role in CCC development. These data may provide a rationale for treatment of CCC with sorafenib. [Copyright &y& Elsevier]