3-nitrotyrosine and Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (CCA) is a lethal malignancy of the biliary epithelium associated with p53 mutations, bile duct injury, inflammation, and fibrosis. Here, to validate these processes in CCA, we developed a liver cirrhosis model driven by chronic intermittent toxin exposure, which provokes bile duct injury/necrosis and proliferation, fibroblast recruitment, and progressive extracellular matrix (ECM) changes. Fibrotic changes in the matrix microenvironment, typified by increased type I and III collagens and fibroblast recruitment, were shown to stimulate biliary epithelium hyperplasia with subsequent progression to malignant intrahepatic CCA only in mice harboring a p53 mutant allele. These murine CCAs bear histologic and genetic features of human intrahepatic CCA, including dense peritumoral fibrosis, increased inducible nitric oxide synthase, nitrotyrosine, and cyclooxygenase-2 expression, c-Met activation, cErbB2 overexpression, down-regulation of membrane-associated E-cadherin, and p53 codon 248 mutation. Thus, p53 deficiency, chronic bile duct injury/proliferation, and the fibrotic matrix microenvironment cooperate to induce intrahepatic CCA, highlighting the key role of the ECM microenvironment in this common liver cancer.

Topics: Animals; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cadherins; Carbon Tetrachloride Poisoning; Cholangiocarcinoma; Cyclooxygenase 2; Extracellular Matrix; Female; Fibrosis; Germ-Line Mutation; Hyperplasia; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type II; Proto-Oncogene Proteins c-met; Receptor, ErbB-2; Tumor Suppressor Protein p53; Tyrosine