BACKGROUND & AIMS: Ras oncoproteins are mutated in about 50% of human colorectal cancers, but their precise role in tumor initiation or progression is still unclear. METHODS: This study presents transgenic mice that express K-ras(V12G), the most frequent oncogenic mutation in human tumors, under control of the murine villin promoter in epithelial cells of the large and small intestine. RESULTS: More than 80% of the transgenic animals displayed single or multiple intestinal lesions, ranging from aberrant crypt foci (ACF) to invasive adenocarcinomas. Expression of K-ras(V12G) caused activation of the MAP kinase cascade, and the tumors were frequently characterized by deregulated cellular proliferation. Unexpectedly, we obtained no evidence of inactivating mutations of the tumor suppressor gene Apc, the "gatekeeper" in colonic epithelial proliferation. However, spontaneous mutation of the tumor-suppressor gene p53, a frequent feature in the human disease, was found in 3 of 7 tumors that were tested. CONCLUSIONS: This animal model recapitulates the stages of tumor progression as well as a part of the genetic alterations found in human colorectal cancer. Furthermore, it indicates that activation of K-ras in concert with mutations in p53 may constitute a route to digestive tumor formation and growth, underlining the fact that the pathway to intestinal cancer is not necessarily a single road.
BACKGROUND & AIMS: Ras oncoproteins are mutated in about 50% of humancolorectal cancers, but their precise role in tumor initiation or progression is still unclear. METHODS: This study presents transgenic mice that express K-ras(V12G), the most frequent oncogenic mutation in humantumors, under control of the murine villin promoter in epithelial cells of the large and small intestine. RESULTS: More than 80% of the transgenic animals displayed single or multiple intestinal lesions, ranging from aberrant crypt foci (ACF) to invasive adenocarcinomas. Expression of K-ras(V12G) caused activation of the MAP kinase cascade, and the tumors were frequently characterized by deregulated cellular proliferation. Unexpectedly, we obtained no evidence of inactivating mutations of the tumor suppressor gene Apc, the "gatekeeper" in colonic epithelial proliferation. However, spontaneous mutation of the tumor-suppressor gene p53, a frequent feature in the human disease, was found in 3 of 7 tumors that were tested. CONCLUSIONS: This animal model recapitulates the stages of tumor progression as well as a part of the genetic alterations found in humancolorectal cancer. Furthermore, it indicates that activation of K-ras in concert with mutations in p53 may constitute a route to digestive tumor formation and growth, underlining the fact that the pathway to intestinal cancer is not necessarily a single road.
Authors: Paola Alberici; Emma de Pater; Joana Cardoso; Mieke Bevelander; Lia Molenaar; Jos Jonkers; Riccardo Fodde Journal: Am J Pathol Date: 2007-01 Impact factor: 4.307
Authors: Jin C Kim; In H Ka; Yoo M Lee; Kum H Koo; Hee C Kim; Chang S Yu; Se J Jang; Yong S Kim; Han I Lee; Kang H Lee Journal: Virchows Arch Date: 2007-01-25 Impact factor: 4.064
Authors: Marybeth A Pysz; Olga V Leontieva; Nicholas W Bateman; Joshua M Uronis; Kathryn J Curry; David W Threadgill; Klaus-Peter Janssen; Sylvie Robine; Anna Velcich; Leonard H Augenlicht; Adrian R Black; Jennifer D Black Journal: Exp Cell Res Date: 2009-02-14 Impact factor: 3.905
Authors: Tobias Gutting; Christian A Weber; Philip Weidner; Frank Herweck; Sarah Henn; Teresa Friedrich; Shuiping Yin; Julia Kzhyshkowska; Timo Gaiser; Klaus-Peter Janssen; Wolfgang Reindl; Matthias P A Ebert; Elke Burgermeister Journal: Oncoimmunology Date: 2018-02-01 Impact factor: 8.110