Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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 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

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Inducible Tyr/Tet–Ras transgenic mice on INK4a-deficient background developed cutaneous melanomas.
Figure 2: Activated Ras expression is necessary to maintain growth of established cutaneous melanomas in vivo.
Figure 4: VEGF is not sufficient to sustain tumour viability following doxycycline withdrawal.
Figure 3: In vitro and in vivo behaviour of melanoma cells in the presence and absence of doxycycline.

Similar content being viewed by others

References

  1. Bishop, J. M. Molecular themes in oncogenesis. Cell 64, 235–248 (1991).

    Article  CAS  Google Scholar 

  2. Gossen, M.et al. Transcriptional activation by tetracyclines in mammalian cells. Science 268, 1766–1769 (1995).

    Article  ADS  CAS  Google Scholar 

  3. 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).

    CAS  PubMed  Google Scholar 

  4. 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).

    Article  ADS  CAS  Google Scholar 

  5. Chin, L.et al. Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes Dev. 11, 2822– 2834 (1997).

    Article  CAS  Google Scholar 

  6. 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).

    Article  CAS  Google Scholar 

  7. 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).

    Article  CAS  Google Scholar 

  8. 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).

    Article  ADS  CAS  Google Scholar 

  9. 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).

    CAS  PubMed  Google Scholar 

  10. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 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).

    Article  CAS  Google Scholar 

  12. Rak, J.et al. Oncogenes as inducers of tumor angiogenesis. Cancer Metastasis Rev. 14, 263–277 ( 1995).

    Article  CAS  Google Scholar 

  13. Arbiser, J. L.et al . Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways. Proc. Natl Acad. Sci. USA 94, 861–866 (1997).

    Article  ADS  CAS  Google Scholar 

  14. 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).

    Article  ADS  CAS  Google Scholar 

  15. 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).

    Article  ADS  CAS  Google Scholar 

  16. 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).

    CAS  PubMed  Google Scholar 

  17. 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).

    CAS  PubMed  Google Scholar 

  18. Mukhopadhyay, D.et al . Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation. Nature 375, 577–581 (1995).

    Article  ADS  CAS  Google Scholar 

  19. 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).

    CAS  PubMed  Google Scholar 

  20. 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).

    Article  CAS  Google Scholar 

  21. 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).

    CAS  PubMed  Google Scholar 

  22. 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).

    Article  CAS  Google Scholar 

  23. 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).

    Article  CAS  Google Scholar 

  24. 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).

    Article  ADS  CAS  Google Scholar 

  25. 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).

    Article  CAS  Google Scholar 

  26. 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).

    Article  CAS  Google Scholar 

Download references

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

Authors

Corresponding authors

Correspondence to Lynda Chin or Ronald A. DePinho#.

Rights and permissions

Reprints 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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/22788

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing