Loss of Apc Allows Phenotypic Manifestation of the Transforming Properties of an Endogenous K-Ras Oncogene in vivo

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-09, Vol.103 (38), p.14122-14127
• Main Authors: Sansom, Owen J., Meniel, Valerie, Wilkins, Julie A., Cole, Alicia M., Oien, Karin A., Marsh, Victoria, Jamieson, Thomas J., Guerra, Carmen, Ashton, Gabrielle H., Barbacid, Mariano, Clarke, Alan R.
• Format: Article
• Language: English
• Subjects: Adenoma; Adenomatous Polyposis Coli Protein - genetics; Adenomatous Polyposis Coli Protein - metabolism; Alleles; Animals; Apoptosis; Biological Sciences; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Proliferation; Cell Transformation, Neoplastic; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Genes, ras; Homeostasis; Humans; Intestines; Intestines - cytology; Intestines - pathology; Intestines - physiology; Kidney - metabolism; Kidney - pathology; Kidneys; Lesions; Male; Mice; Mitogen-Activated Protein Kinase Kinases - metabolism; Mutation; Oligonucleotide Array Sequence Analysis; Phenotype; Phenotypes; raf Kinases - metabolism; ras genes; Rodents; Signal Transduction - physiology; Small intestine; Survival Rate; Tumors; Up regulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0604130103

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.