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- Title
Essential role for oncogenic Ras in tumour maintenance.
- Authors
Chin, L; Tam, A; Pomerantz, J; Wong, M; Holash, J; Bardeesy, N; Shen, Q; O'Hagan, R; Pantginis, J; Zhou, H; Horner, J W, 2nd; Cordon-Cardo, C; Yancopoulos, G D; DePinho, R A
- Abstract
Advanced malignancy in tumours represents the phenotypic endpoint of successive genetic lesions that affect the function and regulation of oncogenes and tumour-suppressor genes. The established tumour is maintained through complex and poorly understood host-tumour interactions that guide processes such as angiogenesis and immune sequestration. The many different genetic alterations that accompany tumour genesis raise questions as to whether experimental cancer-promoting mutations remain relevant during tumour maintenance. Here we show that melanoma genesis and maintenance are strictly dependent upon expression of H-RasV12G in a doxycycline-inducible H-Ras12G mouse melanoma model null for the tumour suppressor INK4a. Withdrawal of doxycycline and H-RasV12G down-regulation resulted in clinical and histological regression of primary and explanted tumours. The initial stages of regression involved marked apoptosis in the tumour cells and host-derived endothelial cells. Although the regulation of vascular endothelial growth factor (VEGF) was found to be Ras-dependent in vitro, the failure of persistent endogenous and enforced VEGF expression to sustain tumour viability indicates that the tumour-maintaining actions of activated Ras extend beyond the regulation of VEGF expression in vivo. Our results provide genetic evidence that H-RasV12G is important in both the genesis and maintenance of solid tumours.
- Publication
Nature, 1999, Vol 400, Issue 6743, p468
- ISSN
0028-0836
- Publication type
Journal Article
- DOI
10.1038/22788