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

Sansom, Owen J. ORCID: https://orcid.org/0000-0001-9540-3010, Meniel, Valerie, Wilkins, Julie Ann, Cole, Alicia M., Oien, Karin A., Marsh Durban, Victoria ORCID: https://orcid.org/0000-0003-1645-1618, Jamieson, Thomas J., Guerra, Carmen, Ashton, Gabrielle H., Barbacid, Mariano and Clarke, Alan Richard ORCID: https://orcid.org/0000-0002-4281-426X 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:	17 Oct 2022 08:46
URI:	https://orca.cardiff.ac.uk/id/eprint/1005

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