Essential role for oncogenic Ras in tumour maintenance

Lynda Chin (), Alice Tam, Jason Pomerantz, Michelle Wong, Jocelyn Holash, Nabeel Bardeesy, Qiong Shen, Ronan O'Hagan, Joe Pantginis, Hao Zhou, James W. Horner, Carlos Cordon-Cardo, George D. Yancopoulos and Ronald A. DePinho# ()
Additional contact information
Lynda Chin: Adult Oncology, Dana Farber Cancer Institute
Alice Tam: Adult Oncology, Dana Farber Cancer Institute
Jason Pomerantz: Albert Einstein College of Medicine
Michelle Wong: Albert Einstein College of Medicine
Jocelyn Holash: Regeneron Pharmaceuticals
Nabeel Bardeesy: Adult Oncology, Dana Farber Cancer Institute
Qiong Shen: Adult Oncology, Dana Farber Cancer Institute
Ronan O'Hagan: Adult Oncology, Dana Farber Cancer Institute
Joe Pantginis: Regeneron Pharmaceuticals
Hao Zhou: Regeneron Pharmaceuticals
James W. Horner: Adult Oncology, Dana Farber Cancer Institute
Carlos Cordon-Cardo: Memorial Sloan Kettering Cancer Center
George D. Yancopoulos: Regeneron Pharmaceuticals
Ronald A. DePinho#: Adult Oncology, Dana Farber Cancer Institute

Nature, 1999, vol. 400, issue 6743, 468-472

Abstract: 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 genes1. 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-RasV12G 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.

Date: 1999
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DOI: 10.1038/22788

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