Targeted expression of oncogenic K-ras in intestinal epithelium causes spontaneous tumorigenesis in mice.
OBJECTIVE
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.
Janssen
Klaus-Peter
KP
Cellular Morphogenesis and Signalisation, UMR144, Institut Curie, Paris, France.
el-Marjou
Fatima
F
Pinto
Daniel
D
Sastre
Xavier
X
Rouillard
Dany
D
Fouquet
Coralie
C
Soussi
Thierry
T
Louvard
Daniel
D
Robine
Sylvie
S
D000818:Animals; D002455:Cell Division; D004789:Enzyme Activation; D017491:Genes, APC; D016158:Genes, p53; D011905:Genes, ras / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011230:Precancerous Conditions / Q000209:etiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt
D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases