Concurrent Activation of Kras and Canonical Wnt Signaling Induces Premalignant Lesions That Progress to Extrahepatic Biliary Cancer in Mice.

Autor:	Nagao M; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Fukuda A; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Omatsu M; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Namikawa M; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Sono M; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Fukunaga Y; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.; Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Masuda T; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Araki O; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Yoshikawa T; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Ogawa S; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Masuo K; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Goto N; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Hiramatsu Y; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Muta Y; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Tsuda M; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Maruno T; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Nakanishi Y; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Taketo MM; Kitano Hospital, The Tazuke Kofukai Medical Research Institute, Kita-ku, Osaka, Japan.; iACT, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan., Ferrer J; Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.; CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Spain.; Genetics and Genomics Section, Department of Metabolism, Digestion and Reproduction, National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, Imperial College London, London, United Kingdom., Tsuruyama T; Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Nakanuma Y; Department of Diagnostic Pathology, Fukui Prefecture Saiseikai Hospital, Fukui, Japan., Taura K; Division of Hepatobiliary Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Uemoto S; Division of Hepatobiliary Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Seno H; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2022 May 03; Vol. 82 (9), pp. 1803-1817.
DOI:	10.1158/0008-5472.CAN-21-2176
Abstrakt:	Biliary cancer has long been known to carry a poor prognosis, yet the molecular pathogenesis of carcinoma of the extrahepatic biliary system and its precursor lesions remains elusive. Here we investigated the role of Kras and canonical Wnt pathways in the tumorigenesis of the extrahepatic bile duct (EHBD) and gall bladder (GB). In mice, concurrent activation of Kras and Wnt pathways induced biliary neoplasms that resembled human intracholecystic papillary-tubular neoplasm (ICPN) and biliary intraepithelial neoplasia (BilIN), putative precursors to invasive biliary cancer. At a low frequency, these lesions progressed to adenocarcinoma in a xenograft model, establishing them as precancerous lesions. Global gene expression analysis revealed increased expression of genes associated with c-Myc and TGFβ pathways in mutant biliary spheroids. Silencing or pharmacologic inhibition of c-Myc suppressed proliferation of mutant biliary spheroids, whereas silencing of Smad4/Tgfbr2 or pharmacologic inhibition of TGFβ signaling increased proliferation of mutant biliary spheroids and cancer formation in vivo. Human ICPNs displayed activated Kras and Wnt signals and c-Myc and TGFβ pathways. Thus, these data provide direct evidence that concurrent activation of the Kras and canonical Wnt pathways results in formation of ICPN and BilIN, which could develop into biliary cancer. Significance: This work shows how dysregulation of canonical cell growth pathways drives precursors to biliary cancers and identifies several molecular vulnerabilities as potential therapeutic targets in these precursors to prevent oncogenic progression. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz: