Essential role for oncogenic Ras in tumour maintenance.
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.
Chin
L
L
Adult Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA. lynda_chin@dfci.harvard.edu
Tam
A
A
Pomerantz
J
J
Wong
M
M
Holash
J
J
Bardeesy
N
N
Shen
Q
Q
O'Hagan
R
R
Pantginis
J
J
Zhou
H
H
Horner
J W
JW
Cordon-Cardo
C
C
Yancopoulos
G D
GD
DePinho
R A
RA
D000818:Animals; D017209:Apoptosis; D004318:Doxycycline / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D011905:Genes, ras; D008222:Lymphokines / Q000378:metabolism; D008545:Melanoma / Q000098:blood supply / Q000235:genetics* / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009857:Oncogenes; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004318:Doxycycline