Chronic bile duct injury associated with fibrotic matrix microenvironment provokes cholangiocarcinoma in p53-deficient mice.
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.
Farazi
Paraskevi A
PA
Department of Medical Oncology and Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Zeisberg
Michael
M
Glickman
Jonathan
J
Zhang
Yan
Y
Kalluri
Raghu
R
DePinho
Ronald A
RA
D000818:Animals; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000096:biosynthesis; D002252:Carbon Tetrachloride Poisoning / Q000473:pathology; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005355:Fibrosis; D018095:Germ-Line Mutation; D006965:Hyperplasia; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis
D015820:Cadherins; D051546:Cyclooxygenase 2; D052247:Nitric Oxide Synthase Type II; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; D014443:Tyrosine; C002744:3-nitrotyrosine; C496317:Nos2 protein, mouse