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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. (Cancer Res 2006; 66(13): 6622-7) (Cancer Res 2006; 66(13): 6622-7)<\/jats:p>","DOI":"10.1158\/0008-5472.can-05-4609","type":"journal-article","created":{"date-parts":[[2006,7,6]],"date-time":"2006-07-06T12:44:31Z","timestamp":1152189871000},"page":"6622-6627","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":80,"title":["Chronic Bile Duct Injury Associated with Fibrotic Matrix Microenvironment Provokes Cholangiocarcinoma in p53-Deficient Mice"],"prefix":"10.1158","volume":"66","author":[{"given":"Paraskevi A.","family":"Farazi","sequence":"first","affiliation":[{"name":"1Department of Medical Oncology and"},{"name":"7Division of Medical Sciences, Department of Genetics, Harvard University, Boston, Massachusetts and"}]},{"given":"Michael","family":"Zeisberg","sequence":"additional","affiliation":[{"name":"5Center for Matrix Biology, Beth Israel Deaconess Medical Center,"}]},{"given":"Jonathan","family":"Glickman","sequence":"additional","affiliation":[{"name":"3Pathology and"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology and"}]},{"given":"Raghu","family":"Kalluri","sequence":"additional","affiliation":[{"name":"5Center for Matrix Biology, Beth Israel Deaconess Medical Center,"},{"name":"6Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School;"},{"name":"8Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, Massachusetts"}]},{"given":"Ronald A.","family":"DePinho","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology and"},{"name":"2Center for Applied Cancer Science, Dana-Farber Cancer Institute, Departments of"},{"name":"4Medicine and Genetics, Brigham and Women's Hospital,"}]}],"member":"1086","published-online":{"date-parts":[[2006,7,3]]},"reference":[{"key":"2022061622125243800_B1","doi-asserted-by":"crossref","unstructured":"Okuda K, Nakanuma Y, Miyazaki M. 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