Skip to main content
SpringerLink
Log in

Oncogenes as inducers of tumor angiogenesis

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Summary

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Barbacid M: ras genes. Ann Rev Biochem 56: 779–827, 1987

    Google Scholar 

  2. Pronk GJ, Bos JL: The role of p21ras in receptor tyrosine signalling. Biochim Biophys Acta 1198: 131–147, 1994

    Google Scholar 

  3. Khosravi-Far R, Der CJ: The Ras signal transduction pathway. Cancer Metastasis Rev in press: 1995

  4. Buick RN, Filmus J, Quaroni A: Activated H-ras transforms rat intestinal epithelial cells with expression of α-TGF. Exp Cell Res 170: 300–309, 1987

    Google Scholar 

  5. Filmus J, Robles AL, Shi W, Wong MJ, Colombo LL, Conti CJ: Induction of cyclin D1 overexpression by activatedras. Oncogene 9: 3726–3633, 1994

    Google Scholar 

  6. Bischop M: Molecular themes in oncogenesis. Cell 64: 235–248, 1991

    Google Scholar 

  7. Folkman J: What is the evidence that tumors are angiogenesis-dependent? J Natl Cancer Inst 82: 4–6, 1990

    Google Scholar 

  8. Holmgren L, O'Reilly MS, Folkman J: Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Medicine 1: 149–153, 1995

    Google Scholar 

  9. Rak JN, St. Croix B, Kerbel RS: Consequences of angiogenesis for tumor progression, metastasis and cancer therapy. Anti-Cancer Drugs 6: 3–18, 1995

    Google Scholar 

  10. Thompson TC, Southgate J, Kitchener G, Land H: Multistage carcinogenesis induced byras andmyc oncogenes in a reconstituted organ. Cell 56: 917–930, 1989

    Google Scholar 

  11. Sugihara T, Kaul SC, Mitsui Y, Wadhwa R: Enhanced expression of multiple forms of VEGF is associated with spontaneous immortalization of murine fibroblasts. Biochim Biophys Acta 1224: 365–370, 1994

    Google Scholar 

  12. Folkman J, Watson K, Ingber D, Hanahan D: Induction of angiogenesis during transition from hyperplasia to neoplasia. Nature 339: 58–61, 1989

    Google Scholar 

  13. Kandel J, Bossy-Wetzel E, Radvanyi F, Klagsbrun M, Folkman J, Hanahan D: Neovascularization is associated with a switch to the export of bFGF in the multistep development of fibrosarcoma. Cell 66: 1095–1104, 1991

    Google Scholar 

  14. Rak J, Mitsuhashi Y, Bayko L, Filmus J, Sasazuki T, Kerbel RS: Mutantras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 55: 4575–4580, 1995

    Google Scholar 

  15. Grugel S, Finkenzeller G, Weindel K, Barleon B, Marmé 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

    Google Scholar 

  16. Koch AE, Polverini PJ, Kunkel SL, Harlow LA, DiPietro LA, Elner VM, Elner SG, Strieter RM: Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258: 1798–1801, 1992

    Google Scholar 

  17. Hu DE, Hory Y, Fan TP: Interleukin-8 stimulates angiogenesis in rats. Inflammation 17: 135–143, 1993

    Google Scholar 

  18. Petzelbauer P, Watson CA, Pfau SE, Pober JS: IL-8 and angiogenesis: evidence that human endothelial cells lack receptors and do not respond to IL-8in vitro. Cytokine 7: 267–272, 1995

    Google Scholar 

  19. Baird A, Durkin T: Inhibition of endothelial cell proliferation by type-beta transforming growth factor: interactions with acidic and basic fibroblast growth factors. Biochem Biophys Res Commun 138: 476–482, 1986

    Google Scholar 

  20. Frater-Schroder M, Muller G, Birchmeier W, Bohlen P: Transforming growth factor beta inhibits endothelial cell proliferation. Biochem Biophys Res Commun 137: 295–302, 1986

    Google Scholar 

  21. Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH, Fauci AS: Transforming growth factor type beta: rapid induction of fibrosis and angiogenesisin vivo and stimulation of collagen formationin vitro. Proc Natl Acad Sci (USA) 83: 4167–4171, 1986

    Google Scholar 

  22. Risau W: Differentiation of endothelium. FASEB J 9: 926, 1995

    Google Scholar 

  23. Senger DR, Perruzzi CA, Feder J, Dvorak HG: A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res 46: 5629–5632, 1986

    Google Scholar 

  24. Senger DR, Connolly D, Perruzzi CA, Alsup D, Nelson R, Leimgruber R, Feder J, Dvorak HF: Purification of a vascular permeability factor (VPF) from tumor cell conditioned medium. Fed Proc 46: 2102, 1987

    Google Scholar 

  25. Dvorak HF, Brown LF, Detmar M, Dvorak AM: Review: Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146: 1029–1039, 1995

    Google Scholar 

  26. Kolch W, Martiny-Baron G, Kieser A, Marmé D: Regulation of the expression of VEGF/VPF and its receptors: role in tumor angiogenesis. Breast Cancer Res Treat 36: 139–155, 1995

    Google Scholar 

  27. Klagsbrun M, Soker S: VEGF/VPF: the angiogenesis factor found? Curr Biol 3: 699–702, 1993

    Google Scholar 

  28. Ferrara N: The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res Treat 36: 127–137, 1995

    Google Scholar 

  29. Mustonen T, Alitalo K: Endothelial receptor tyrosine kinases involved in angiogenesis. J Cell Biol 129: 895–898, 1995

    Google Scholar 

  30. Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N: Inhibition of vascular endothelial growth factorinduced angiogenesis suppresses tumour growthin vivo. Nature 362: 841–844, 1993

    Google Scholar 

  31. Warren RS, Yuan H, Mati MR, Gillett NA, Ferrara N: Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest 95: 1789–1797, 1995

    Google Scholar 

  32. Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A: Glioblastoma growth inhibitedin vivo by a dominant-negative Flk-1 mutant. Nature 367: 576–579, 1994

    Google Scholar 

  33. Toi M, Inada K, Suzuki H, Tominage T: Tumor angiogenesis in breast cancer: its importance as a prognostic indicator and the association with vascular endothelial growth factor expression. Breast Cancer Res Treat 36: 193–204, 1995

    Google Scholar 

  34. 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

    Google Scholar 

  35. Mukhopadhyay D, Tsiokas L, Zhou X-M, Foster D, Brugge JS, Sukhatme VP: Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation. Nature 375: 577–581, 1995

    Google Scholar 

  36. Stein I, Neeman M, Shweiki D, Itin A, Keshet E: Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemiainduced genes. Mol Cell Biol 15: 5363–5368, 1995

    Google Scholar 

  37. Kieser A, Weich HA, Brandner G, Marmé D, Kolch W: Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 9: 363–369, 1994

    Google Scholar 

  38. Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA: The human gene for vascular endothelial growth factor. J Biol Chem 266: 11947–11954, 1991

    Google Scholar 

  39. Finkenzeller G, Technau A, Marmé D: Hypoxia-induced transcription of the vascular endothelial growth factor gene is independent of functional AP-1 transcription factor. Biochem Biophys Res Commun 208: 432–439, 1995

    Google Scholar 

  40. Jamal H, Cano-gauci DF, Buick RN, Filmus J: Activatedras andsrc induce CD44 overexpression in rat intestinal epithelial cells. Oncogene 9: 417–423, 1994

    Google Scholar 

  41. 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

    Google Scholar 

  42. Vukicevic S, Kleinman HK, Luyten FP, Roberts AB, Roche NS, Reddi AH: Identification of multiple active growth factors in basement membrane matrigel suggests caution in interpretation of cellular activity related to extracellular matrix components. Exp Cell Res 202: 1–8, 1992

    Google Scholar 

  43. Fridman R, Giaccone G, Kanemoto T, Martin GR, Gazdar AF, Mulshine JL: Reconstituted basement membrane (matrigel) and laminin can enhance the tumorigenicity and the drug resistance of small cell lung cancer cell lines. Proc Natl Acad Sci (USA) 87: 6698–6702, 1990

    Google Scholar 

  44. Kibbey MC, Grant DS, Kleinman HK: Role of the SIKVAV site of laminin in promotion of angiogenesis and tumor growth: anin vivo matrigel model. J Natl Canc Inst 84: 1633–1638, 1992

    Google Scholar 

  45. Kobayashi H, Man S, MacDougall JR, Graham CH, Lu C, Kerbel RS: Variant sublines of early-stage human melanomas selected for tumorigenicity in nude mice express a multicytokine resistant phenotype. Am J Pathol 144: 776–786, 1994

    Google Scholar 

  46. Bonfil RD, Vinyals A, Bustuoabad OD, Llorens A, Benavides FJ, Gonzales-Garrigues M, Fabra A: Stimulation of angiogenesis as an explanation of Matrigel-enhanced tumorigenicity. Int J Cancer 58: 233–239, 1994

    Google Scholar 

  47. Klein G: Multistep emancipation of tumors from growth control: can it be cured in a single step? BioEssays 12: 347–351, 1990

    Google Scholar 

  48. Dameron KM, Volpert OV, Tainsky MA, Bouck N: Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265: 1582–1584, 1994

    Google Scholar 

  49. Van Meir EG, Polverini PJ, Chazin VR, Huang SH-J, Tribolet N, Cavanee WK: Release of an inhibitor of angiogenesis upon induction of wild typep53 expression in glioblastoma cells. Nature Genetics 8: 171–182, 1994

    Google Scholar 

  50. Huang H-JS, Yee J-K, Shew J-Y, Chen P-L, Bookstein R, Friedmann T, Lee EY-HP, Lee W-H: Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells. Science 242: 1563–1566, 1988

    Google Scholar 

  51. Bookstein R, Shew J-Y, Chen P-L, Scully P, Lee W-H: Suppression of tumorigenicity of human prostate carcinoma cells by replacing a mutatedRB gene. Science 247: 712, 1995

    Google Scholar 

  52. Iliopoulos O, Kibel A, Gray S, Kaelin Jr WG: Tumour suppression by the human von Hippel-Lindau gene product. Nature Medicine 1: 822, 1995

    Google Scholar 

  53. Wizigmann-Voos S, Breier G, Risau W, Plate KH: Up-regulation of vascular endothelial growth factor andits receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res 55: 1358–1364, 1995

    Google Scholar 

  54. Alon T, Hemo I, Itin A, Pe'er J, Stone J, Keshet E: Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nature Medicine 1: 1024–1028, 1995

    Google Scholar 

  55. Strawhecker JM, Pelling JC: Inhibition of mouse skin tumorigenesis by dexamethasone occurs through a Ha-ras-independent mechanism. Carcinogenesis 13: 2075–2080, 1992

    Google Scholar 

  56. Lee K, Iwamura M, Crockett ATK: Cortisone inhibition of tumor angiogenesis measured by a quantitative colorimetric assay in mice. Cancer Chemoth Pharm 26: 461–463, 1990

    Google Scholar 

  57. Lee K, Erturk E, Mayer R, Cockett ATK: Efficacy of antitumor chemotherapy in C3H mice enhanced by the antiangiogenesis steroid, cortisone acetate. Cancer Res 47: 5021–5024, 1987

    Google Scholar 

  58. Kerppola TK, Luk D, Curran T: Fos is a preferential target of glucocorticoid receptor inhibition of AP-1 activity in vitro. Mol Cell Biol 13: 3782–3791, 1993

    Google Scholar 

  59. Saez E, Rutberg SE, Mueller E, Oppenheim H, Smoluk J, Yuspa SH, Spiegelman BM: c-fos is required for malignant progression for skin tumors. Cell 82: 721–732, 1995

    Google Scholar 

  60. Anzano M, Roberts A, Delarco J, Wakefield L, Assoian R, Roche N, Smith J, Lazarus J, Sporn M: Increased secretion of type beta transforming growth factor accompanies viral transformation of cells. Mol Cell Biol 5: 242–247, 1985

    Google Scholar 

  61. Pertovaara L, Kaipanen A, Mustonen T, Orpana A, Ferrara N, Saksela O, Alitalo K: Vascular endothelial growth factor is induced in response to transforming growth factor-β in fibroblastic and epithelial cells. J Biol Chem 269: 6271–6274, 1994

    Google Scholar 

  62. Detmar M, Brown LF, Claffey KP, Kiang-Teck Y, Kocher O, Jackman RW, Berse B, Dvorak HFL Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med 180: 1141–1146, 1994

    Google Scholar 

  63. Pepper MS, Ferrara N, Orci L, Montesano R: Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesisin vitro. Biochem Biophys Res Commun 189: 824–831, 1992

    Google Scholar 

  64. Goto F, Goto K, Weindel K, Folkman J: Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels. Lab Invest 69: 508, 1993

    Google Scholar 

  65. Toi M, Inada K, Hoshima S, Suzuki H, Kondo S, Tominaga T: Vascular endothelial growth factor and platelet-derived endothelial cell growth factor are frequently coexpressed in highly vascularized human breast cancer. Clin Cancer Res 1: 961–964, 1995

    Google Scholar 

  66. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61: 759–767, 1990

    Google Scholar 

  67. Galand P, Jacobovitz D, Alexandre K: Immunohistochemical detection of c-Ha-ras oncogene p21 product in pre-neoplastic and neoplastic lesions during hepatocarcinogenesis in rats. Int J Cancer 41: 155–161, 1995

    Google Scholar 

  68. Hasegawa H, Ueda M, Watanabe M, Teramoto T, Mukai M, Kitajima M: K-ras gene mutations in early colorectal cancer... flat elevated vs polyp-forming cancer... Oncogene 10: 1413–1416, 1995

    Google Scholar 

  69. Minamoto T, Sawaguchi K, Mai M, Yamashita N, Sugimura T, Esumi H: Infrequent K-ras activation in superficial-type (flat) colorectal adenomas and adenocarcinomas. Cancer Res 54: 2841–2844, 1994

    Google Scholar 

  70. Rak J, Mituhashi Y, Erdos V, Huang S-N, Filmus J, Kerbel RS: Massive programmed cell death in intestinal epithelial cells induced by three-dimensional growth conditions: suppression by mutant c-H-ras oncogenes. J Cell Biol in press: 1995

  71. Berse B, Brown LF, Van De Water L, Dvorak HF, Senger DR: Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell 3: 211–220, 1992

    Google Scholar 

  72. Ohta Y, Tone T, Shitara T, Funato T, Jiao L, Kashfian BI, Yoshida E, Horng M, Tsai P, Lauterbach K, Kashani-Sabet M, Florenes VA, Fodstad O: H-ras ribozyme-mediated alteration of the human melanoma phenotype. Gene Therapy Neopl Dis 716: 242, 1994

    Google Scholar 

  73. Kashani-Sabet M, Funato T, Tone T, Jiao L, Wang W, Yoshida E, Kashfinn BI, Shitara T, Wu AM, Moreno JG, Traweek ST, Ahlering TE, Scanlon KJ: Reversal of the malignant phenotype by an anti-ras ribozyme. Antisense Res Dev 2: 3–15, 1992

    Google Scholar 

  74. Ferrari G, Greene LA: Proliferative inhibition by dominant-negative Ras rescues naive and neuronally differentiated PC12 cells from apoptotic death. EMBO J 13: 5922–5928, 1994

    Google Scholar 

  75. Sakai N, Ogiso Y, Fujita H, Watari H, Koike T, Kuzumaki N: Induction of apoptosis by a dominant negative H-RAS mutant (116Y) in K562 cells. Exp Cell Res 215: 131–136, 1994

    Google Scholar 

  76. James GL, Goldstein JL, Brown MS: Polylysine and DVIM sequences of K-rasB dictate specificity of prenylation and confer resistance to benzodiazepine peptidomimeticin vitro. J Biol Chem 270: 6221–6226, 1995

    Google Scholar 

  77. Kohl NE, Mosser SD, deSolms SJ, Giuliani EA, Pompliano DL, Graham SL, Smith RL, Scolnick EM, Oliff A, Gibbs JB: Selective inhibition ofras-dependent transformation by a farnesyltransferase inhibitor. Science 260: 1934–1942, 1993

    Google Scholar 

  78. Gibbs JB, Oliff A, Kohl NE: Farnesyltransferase inhibitors: ras research yields a potential cancer therapeutic. Cell 77: 175–178, 1994

    Google Scholar 

  79. Lowry DR, Willumsen BM: Rational cancer therapy. Nature Medicine 1: 747–748, 1995

    Google Scholar 

  80. Kiaris H, Spandidos DA: Mutations ofras genes in human tumours. Int J Oncol 7: 413–421, 1995

    Google Scholar 

  81. Kohl NE, Wilson FR, Mossier SD, Giuliani E, deSolms SJ, Conner MW, Anthony NJ, Holtz WJ, Gomez RP, Lee T-J, Smith RL, Graham SL, Hartman GD, Gibbs JB, Oliff A: Protein farnesyltransferase inhibitors block the growth ofras-independent tumors in nude mice. Proc Natl Acad Sci (USA) 91: 9141–9145, 1994

    Google Scholar 

  82. Kohl NE, Omer CA, Conner MW, Anthony NJ, Davide JP, deSolms SJ, Giuliani EA, Gomez RP, Graham SL, Hamilton K, Handt LK, Hartman GD, Koblan KS, Kral AM, Miller PJ, Mosser SD, O'Neill TJ, Rands E, Schaber MD, Gibbs JB, Oliff A: Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas inras transgenic mice. Nature Medicine 1: 792–797, 1995

    Google Scholar 

  83. Singh RK, Gutman M, Bucana CD, Sanchez R, Llansa N, Fidler IJ: Interferons α and β down-regulate the expression of basic fibroblast growth factor in human carcinomas. Proc Natl Acad Sci (USA) 92: 4562–4566, 1995

    Google Scholar 

  84. Burrows FJ, Thorpe PE: Eradication of large solid tumors in mice with an immunotoxin directed against tumor vasculature. Proc Natl Acad Sci (USA) 90: 8996–9000, 1993

    Google Scholar 

  85. Bouck N: Tumor angiogenesis: the role of oncogenes and tumor suppressor genes. Cancer Cells 2: 179–185, 1990

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cancer Biology Research, Sunnybrook Health Science Centre, M4N 3M5, Toronto, Ontario, Canada

    J. Rak, J. Filmus & R. S. Kerbel

  2. Institute of Molecular Medicine, Tumor Biology Centre, D-79106, Freiburg, Germany

    G. Finkenzeller, S. Grugel & D. Marmé

  3. Department of Medical Biophysics, University of Toronto, Canada

    J. Rak, J. Filmus & R. S. Kerbel

Authors
  1. J. Rak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Filmus
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. Finkenzeller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Grugel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. Marmé
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R. S. Kerbel
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rak, J., Filmus, J., Finkenzeller, G. et al. Oncogenes as inducers of tumor angiogenesis. Cancer Metast Rev 14, 263–277 (1995). https://doi.org/10.1007/BF00690598

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00690598

Key words

Search

Navigation