Essential role for oncogenic Ras in tumour maintenance

Advanced malignancy in tumours represents the phenotypic endpoint of succes sive genetic lesions that affect the function and regulation of oncogenes a nd tumour-suppressor genes(1). The established tumour is maintained through complex and poorly understood host-tumour interactions that guide processe s such as angiogenesis and immune sequestration. The many different genetic alterations that accompany tumour genesis raise questions as to whether ex perimental cancer-promoting mutations remain relevant during tumour mainten ance. Here we show thar melanoma genesis and maintenance are strictly depen dent upon expression of H-Ras(V12G) in a doxycycline-inducible H-Ras mouse melanoma model null for the tumour suppressor INK4a. Withdrawal of doxycycl ine and H-Ras(V12G) down-regulation resulted in clinical and histological r egression of primary and explanted tumours. The initial stages of regressio n involved marked apoptosis in the tumour cells and host-derived endothelia l cells. Although the regulation of vascular endothelial growth factor (VEG F) was found td be Ras-dependent in vitro, the failure of persistent endoge nous and enforced VEGF expression to sustain tumour viability indicates tha t the tumour-maintaining actions of activated Ras extend beyond the regulat ion of VEGF expression in vivo. Our results provide genetic evidence that H -Ras(V12G) is important in both the genesis and maintenance of solid tumour s.