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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bishop, J. M. Molecular themes in oncogenesis. Cell 64, 235–248 (1991).
Gossen, M.et al. Transcriptional activation by tetracyclines in mammalian cells. Science 268, 1766–1769 (1995).
Fasano, O., Taparowsky, E., Fiddes, J., Wigler, M. & Goldfarb, M. Sequence and structure of the coding region of the human H-ras-1 gene from T24 bladder carcinoma cells. J. Mol. Appl. Genet. 2, 173–180 (1983).
Kistner, A.et al. Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc. Natl Acad. Sci. USA 93, 10933–10938 ( 1996).
Chin, L.et al. Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes Dev. 11, 2822– 2834 (1997).
Thomson, T. M.et al. Differentiation antigens of melanocytes and melanoma: analysis of melanosome and cell surface markers of human pigmented cells with monoclonal antibodies. J. Invest. Dermatol. 90, 459 –466 (1988).
Gause, P. R.et al. Chromosomal and genetic alterations of 7,12-dimethylbenz[a]anthracene-induced melanoma from TP-ras transgenic mice. Mol. Carcin. 20, 78–87 (1997).
Shirasawa, S., Furuse, M., Yokoyama, N. & Sasazuki, T. Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science 260, 85–88 ( 1993).
Doherty, P. C., Tripp, R. A. & Sixbey, J. W. Evasion of host immune responses by tumours and viruses. Ciba Found. Symp. 187, 245– 256 (1994).
Bird, I. N., Spragg, J. H., Ager, A. & Matthews, N. Studies of lymphocyte transendothelial migration: analysis of migrated cell phenotypes with regard to CD31 (PECAM-1), CD45RA and CD45RO. Immunology 80 , 553–560 (1993).
Traweek, S. T., Kandalaft, P. L., Mehta, P. & Battifora, H. The human hematopoietic progenitor cell antigen (CD34) in vascular neoplasia. Am. J. Clin. Pathol. 96, 25– 31 (1991).
Rak, J.et al. Oncogenes as inducers of tumor angiogenesis. Cancer Metastasis Rev. 14, 263–277 ( 1995).
Arbiser, J. L.et al . Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways. Proc. Natl Acad. Sci. USA 94, 861–866 (1997).
Okada, F.et al. Impact of oncogenes in tumor angiogenesis: mutant K-ras up-regulation of vascular endothelial growth factor/vascular permeability factor is necessary, but not sufficient for tumorigenicity of human colorectal carcinoma cells. Proc. Natl Acad. Sci. USA 95, 3609– 3614 (1998).
Shweiki, D., Itin, A., Soffer, D. & Keshet, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359, 843–845 (1992).
Mazure, N. M., Chen, E. Y., Yeh, P., Laderoute, K. R. & Giaccia, A. J. Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth factor expression. Cancer Res. 56, 3436–3440 (1996).
Goldberg, M. A. & Schneider, T. J. Similarities between the oxygen-sensing mechanisms regulating the expression of vascular endothelial growth factor and erythropoietin. J. Biol. Chem. 269, 4355–4359 (1994).
Mukhopadhyay, D.et al . Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation. Nature 375, 577–581 (1995).
Rak, J.et al. Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res. 55 , 4575–4580 (1995).
Grugel, S., Finkenzeller, G., Weindel, K., Barleon, B. & Marme, D. Both v-Ha-Ras and v-Raf stimulate expression of the vascular endothelial growth factor in NIH 3T3 cells. J. Biol. Chem. 270, 25915–25919 (1995).
Larcher, F.et al. Up-regulation of vascular endothelial growth factor/vascular permeability factor in mouse skin carcinogenesis correlates with malignant progression state and activated H-ras expression levels. Cancer Res. 56, 5391–5396 ( 1996).
Ganss, R., Montoliu, L., Monaghan, A. P. & Schutz, G. Acell-specific enhancer far upstream of the mouse tyrosinase gene confers high level and copy number-related expression in transgenic mice. EMBO J. 13, 3083–3093 ( 1994).
Valenzuela, D. M.et al. Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscule, at the neuromuscular junction, and after injury. Neuron 15, 573– 584 (1995).
Schreiber-Agus, N.et al. Role of Mxi1 in ageing organ systems and the regulation of normal and neoplastic growth. Nature 393, 483–487 (1998).
Gavrieli, Y., Sherman, Y. & Ben-Sasson, S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J. Cell Biol. 119, 493–501 ( 1992).
Cheng, L., Fu, J., Tsukamoto, A. & Hawley, R. G. Use of green fluorescent protein variants to monitor gene transfer and expression in mammalian cells. Nature Biotech. 14, 606– 609 (1996).
Acknowledgements
We thank G. Schutz for the tyrosinase promoter–enhancer elements; S. Jiao for tissue sample processing and immunohistochemistry; D. Compton for RNA in situ hybridization, and M. Russell for technical assistance. This work was supported by an NIH Mentored Clinician Scientist Award and the Harvard Skin Disease Center Grant (L.C.); by grants from the NIH (C.C.C. and R.A.D.) and from the DFCI Cancer Core (R.A.D. and L.C.). R.A.D. is an American Cancer Society Research Professor; A.T. and J.P. are HHMI Medical Student Fellows.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Chin, L., Tam, A., Pomerantz, J. et al. Essential role for oncogenic Ras in tumour maintenance. Nature 400, 468–472 (1999). https://doi.org/10.1038/22788
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/22788
This article is cited by
-
Peptidomimetics designed to bind to RAS effector domain are promising cancer therapeutic compounds
Scientific Reports (2022)
-
Oncogenic KRAS promotes growth of lung cancer cells expressing SLC3A2-NRG1 fusion via ADAM17-mediated shedding of NRG1
Oncogene (2022)
-
RAS specific protease induces irreversible growth arrest via p27 in several KRAS mutant colorectal cancer cell lines
Scientific Reports (2021)
-
MET targeting: time for a rematch
Oncogene (2020)
-
Current therapy of KRAS-mutant lung cancer
Cancer and Metastasis Reviews (2020)
