Figure 2.

Chronic inflammation is responsible for the neoplastic transformation of the biliary epithelial cells. Alterations are due to the presence in the hepatic microenvironment of several molecules, such as peroxinitrites and oxygen free radicals that could induce the accumulation of DNA damage. Nitric oxide (NO) is able to stimulate cell proliferation and escape from apoptosis through the activation of COX2 that stimulates the p38 MAPK/JNK axis to secrete PGE₂, that further transactivates the epidermal growth factor receptor (EGFR); this latter receptor also activates the PI3K/AKT pathway responsible for the proliferation and resistance to apoptosis in cholangiocarcinoma (CCA).