The molecular pathogenesis of cholangiocarcinoma: The majority of risk factors for cholangiocarcinoma cause chronic inflammation and/or cholestasis. Inflammatory mediators such as IL-6 and TNFɑ activate a number of pathways such as JAK-STAT, p38 MAPK and Akt resulting in increased cell growth, survival and proliferation. Macrophages secrete ligands that activate the Wnt/β-catenin pathway, leading to TCF/LEF-mediated gene transcription. Although cholestasis causes inflammation, prolonged exposure of bile acids can have direct cellular effects leading to upregulation of COX-2 and Mcl-1 resulting in resistance to apoptosis. Liver flukes can also have direct effects on cholangiocytes via activation of the Akt pathway and upregulation of iNOS, increasing cell survival and proliferation. A number of microRNAs are up- or downregulated in cholangiocarcinoma. All these alterations lead to well-established oncogenic mechanisms; genetic mutations, increased cell growth, survival, and apoptotic resistance. For a full description of the depicted pathways, please refer to the article text.