Cancer and Metastasis Reviews

, Volume 14, Issue 4, pp 263–277 | Cite as

Oncogenes as inducers of tumor angiogenesis

  • J. Rak
  • J. Filmus
  • G. Finkenzeller
  • S. Grugel
  • D. Marmé
  • R. S. Kerbel


Dominantly acting transforming oncogenes are generally considered to contribute to tumor development and progression by their direct effects on tumor cell proliferation and differentiation. However, the growth of solid tumors beyond 1–2 mm in diameter requires the induction and maintenance of a tumor blood vessel supply, which is attributed in large part to the production of angiogenesis promoting growth factors by tumor cells. The mechanisms which govern the expression of angiogenesis growth factors in tumor cells are largely unknown, but dominantly acting oncogenes may have a much greater impact than hitherto realized. An example of this is the induction of expression of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) by mutant H- or K-ras oncogenes, as well as v-src and v-raf, in transformed fibroblasts or epithelial cells. Besides VEGF/VPF, mutantras genes are known to upregulate the expression of a variety of other growth factors thought to have direct or indirect stimulating effects on angiogenesis, e.g. TGF-β and TGF-α. This effect may be mediated through the ras-raf-MAP kinase signal transduction pathway, resulting in activation of transcription factors such as AP1, which can then bind to relevant sites in the promoter regions of genes encoding angiogenesis growth factors. In principle, similar events could take place after activation or overexpression of many other oncogenes, especially those which can mediate their function through rasdependent signal transduction pathways. The regulatory effect of oncogenes on mediators of angiogenesis has some potentially important therapeutic consequences. For example, it strengthens the rationale of pharmacologically targeting oncogene products, such as mutant RAS proteins, as an anti-tumor therapeutic strategy. Such drugs may attack the source of one or more angiogenic growth factors and by doing so, function, at least in part, as anti-angiogenic agents in vivo.

Key words

VEGF/VPF ras/raf/src oncogenes angiogenesis progression 


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Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • J. Rak
    • 1
    • 3
  • J. Filmus
    • 1
    • 3
  • G. Finkenzeller
    • 2
  • S. Grugel
    • 2
  • D. Marmé
    • 2
  • R. S. Kerbel
    • 1
    • 3
  1. 1.Division of Cancer Biology ResearchSunnybrook Health Science CentreToronto, OntarioCanada
  2. 2.Institute of Molecular MedicineTumor Biology CentreFreiburgGermany
  3. 3.Department of Medical BiophysicsUniversity of TorontoCanada

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