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Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K-ras oncogene in vivo

Sansom, Owen J., Meniel, Valerie, Wilkins, Julie Ann, Cole, Alicia M., Oien, Karin A., Marsh Durban, Victoria, Jamieson, Thomas J., Guerra, Carmen, Ashton, Gabrielle H., Barbacid, Mariano and Clarke, Alan Richard 2006. Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K-ras oncogene in vivo. Proceedings of the National Academy of Sciences 103 (38) , pp. 14122-14127. 10.1073/pnas.0604130103

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Abstract

Oncogenic mutations in the K-ras gene occur in ?50% of human colorectal cancers. However, the precise role that K-ras oncogenes play in tumor formation is still unclear. To address this issue, we have conditionally expressed an oncogenic K-ras V12 allele in the small intestine of adult mice either alone or in the context of Apc deficiency. We found that expression of K-ras V12 does not affect normal intestinal homeostasis or the immediate phenotypes associated with Apc deficiency. Mechanistically we failed to find activation of the Raf/MEK/ERK pathway, which may be a consequence of the up-regulation of a number of negative feedback loops. However, K-ras V12 expression accelerates intestinal tumorigenesis and confers invasive properties after Apc loss over the long term. In renal epithelium, expression of the oncogenic K-ras V12 allele in the absence of Apc induces the rapid development of renal carcinoma. These tumors, unlike those of intestinal origin, display activation of the Raf/MEK/ERK and Akt signaling pathways. Taken together, these data indicate that normal intestinal and kidney epithelium are resistant to malignant transformation by an endogenous K-ras oncogene. However, activation of K-ras V12 after Apc loss results in increased tumorigenesis with distinct kinetics. Whereas the effect of K-ras oncogenes in the intestine can been observed only after long latencies, they result in rapid carcinogenesis in the kidney epithelium. These data imply a window of opportunity for anti-K-ras therapies after tumor initiation in preventing tumor growth and invasion.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords: Colorectal cancer ; Renal carcinoma ; Wnt signaling
ISSN: 0027-8424
Last Modified: 15 Dec 2017 08:35
URI: http://orca.cf.ac.uk/id/eprint/1005

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