This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Farazi, P. A. Articles by DePinho, R. A. Search for Related Content PubMed PubMed Citation Articles by Farazi, P. A. Articles by DePinho, R. A.

Chronic Bile Duct Injury Associated with Fibrotic Matrix Microenvironment Provokes Cholangiocarcinoma in p53-Deficient Mice

¹ Department of Medical Oncology and ² Center for Applied Cancer Science, Dana-Farber Cancer Institute, Departments of ³ Pathology and ⁴ Medicine and Genetics, Brigham and Women's Hospital, ⁵ Center for Matrix Biology, Beth Israel Deaconess Medical Center, ⁶ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School; ⁷ Division of Medical Sciences, Department of Genetics, Harvard University, Boston, Massachusetts and ⁸ Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, Massachusetts

Requests for reprints: Ronald A. DePinho, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street (M413), Boston, MA 02115. Phone: 617-632-6085; Fax: 617-632-6069; E-mail: ron_depinho{at}dfci.harvard.edu or Raghu Kalluri, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Dana Building 514, Boston, MA 02115. Phone: 617-667-0445; Fax: 617-975-5663; E-mail: rkalluri{at}bidmc.harvard.edu.

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. (Cancer Res 2006; 66(13): 6622-7) (Cancer Res 2006; 66(13): 6622-7)

This article has been cited by other articles:

				C. M. Khoo, D. R. Carrasco, M. W. Bosenberg, J.-H. Paik, and R. A. DePinho Ink4a/Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse PNAS, March 6, 2007; 104(10): 3931 - 3936. [Abstract] [Full Text] [PDF]