Essential role for oncogenic Ras in tumour maintenance Journal Article
| Authors: | Chin, L.; Tam, A.; Pomerantz, J.; Wong, M.; Holash, J.; Bardeesy, N.; Shen, Q.; O'Hagan, R.; Pantginis, J.; Zhou, H.; Horner Ii, J. W.; Cordon-Cardo, C.; Yancopoulos, G. D.; DePinho, R. A. |
| Article Title: | Essential role for oncogenic Ras in tumour maintenance |
| Abstract: | Advanced malignancy in tumours represents the phenotypic end-point 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-Ras(V12G) in a doxycycline-inducible H- Ras(V12G) mouse melanoma model null for the tumour suppressor INK4a. Withdrawal of doxycycline and H-Ras(V12G) 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-Ras(V12G) is important in both the genesis and maintenance of solid tumours. |
| Keywords: | vascular endothelial growth factor a; mutation; nonhuman; animal cell; mouse; animals; mice; melanoma; apoptosis; gene expression; animal experiment; animal model; mice, scid; tumor cells, cultured; angiogenesis; mice, transgenic; oncogenes; cancer genetics; gene expression regulation, neoplastic; genes, ras; tumor growth; doxycycline; oncogene ras; genetic regulation; vascular endothelial growth factors; endothelial growth factors; priority journal; article; lymphokines |
| Journal Title: | Nature |
| Volume: | 400 |
| Issue: | 6743 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 1999-07-29 |
| Start Page: | 468 |
| End Page: | 472 |
| Language: | English |
| DOI: | 10.1038/22788 |
| PUBMED: | 10440378 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 16 August 2016 -- Source: Scopus |
