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

Abstract

Oncogenic mutations in the K-ras gene occur in Ϸ50% 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 Raf͞MEK͞ERK 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 Kras 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 Raf͞MEK͞ERK 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.colorectal cancer ͉ renal carcinoma ͉ Wnt signaling

Many roads lead to oncogene-induced senescence

“…For example, in the process of generating a mouse model of intestinal tumors, Sansom et al (2006) showed that the expression of a single, activated K-ras allele was insufficient to trigger AKT or ERK activation in the intestine and reported that negative feedback pathways were responsible for attenuating the Ras signal. In contrast, in the same mouse strain, this single K-ras allele resulted in potent ERK and AKT activation in the kidney and potently cooperated with APC Figure 1 Negative regulators of the Ras pathway.…”

“…Mechanisms of oncogene-induced senescence S Courtois-Cox et al mutations to drive renal cell carcinoma, illustrating an inherent difference in 'sensitivity' between these two cell types in vivo (Sansom et al, 2006). It is now becoming more generally apparent that many mouse tissues designed to express this single K-ras allele do not exhibit much if any ERK and AKT activation (Kim et al, 2005).…”

Myc heterozygosity attenuates the phenotypes of APC deficiency in the small intestine

“…We have previously shown that AhCre þ Apc fl/ þ mice develop intestinal adenomas associated with the loss of the remaining Apc allele and a clear nuclear accumulation of b-catenin within the adenomas (Sansom et al, 2006). To assess the consequences of Myc heterozygosity on this phenotype, we generated cohorts of experimental AhCre þ Apc fl/ þ Myc fl/ þ and control AhCre þ Apc fl/ þ Myc þ / þ mice.…”

“…To assess the consequences of Myc heterozygosity on this phenotype, we generated cohorts of experimental AhCre þ Apc fl/ þ Myc fl/ þ and control AhCre þ Apc fl/ þ Myc þ / þ mice. The mice were injected with 3 Â 80 mg/kg b-naphthoflavone in a single day to induce maximal cre-mediated recombination within the intestinal epithelium (Sansom et al, 2006) and aged until they developed symptoms of intestinal disease. These included paling of feet because of anaemia caused by intestinal polyposis, hunching and weight loss.…”

Lymph node-independent liver metastasis in a model of metastatic colorectal cancer

“…Moreover, these adenomas primarily localize to the small intestine, with relatively few adenomas manifesting in the colon 7 . Introduction of oncogenic Kras to the mutant Apc background promotes intestinal adenoma multiplicity 8,9 and accelerates progression to invasiveness 8,10,11 , with a marked enhancement of tumour development in the relevant anatomical location of the colon 9 . Development of intestinal lymph node metastases, however, has not been observed in Apc/Kras compound mutant mice 8,12 , with distant liver metastases only detected in 20-27% of Apc/Kras compound mutant mice by transgene RT-PCR 8 or gross observation 12 .…”