Nature 1999 Jul 29;400(6743):468-72
Essential role for oncogenic Ras in tumour maintenance.
Chin L, Tam A, Pomerantz J, Wong M, Holash J, Bardeesy N, Shen Q, O'Hagan R, Pantginis J, Zhou H, Horner
JW 2nd, Cordon-Cardo C, Yancopoulos GD, DePinho RA
Adult Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA. lynda_chin@dfci.harvard.edu
[Medline record in process]
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.
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