Cancer and Metastasis Reviews

, Volume 15, Issue 2, pp 231–236 | Cite as

Treating cancer by inhibiting angiogenesis: new hopes and potential pitfall

  • J. Rak
  • R. S. Kerbel
Tumor Angiogenesis


Angiogenesis is essential for progressive solid tumor growth and thus constitutes a very promising therapeutic target. Recent developments in understanding of the molecular mechanisms involved in tumor blood vessel formation provides a rational basis for anti-angiogenic drug development, especially of more selective and effective agents. However, for the very same reason, it is time to think more critically about some of the potential pitfalls and difficulties associated with this treatment strategy and of research needed to define realistic expectations in this area.

Key words

angiogenesis dependence oncogenes VEGF 


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  1. 1.
    Folkman J: What is the evidence that tumors are angiogenesis-dependent? J. Natl. Canc. Inst. 82: 4–6, 1989Google Scholar
  2. 2.
    Folkman J: Angiogenesis and breast cancer. J. Clin. Oncol. 12: 441–443, 1994Google Scholar
  3. 3.
    Fidler IJ, Ellis LM: The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 79: 185–188, 1994Google Scholar
  4. 4.
    Rak JN, St. Croix B, Kerbel RS: Consequences of angiogenesis for tumor progression, metastasis and cancer therapy. Anti-Cancer Drugs 6: 3–18, 1995Google Scholar
  5. 5.
    Rak JW, Hegmann EJ, Kerbel RS: The role of angiogenesis in tumor progression and metastasis, Advances in molecular and cell biology. Edited by Heppner GH. JAI Press. Inc., 1993, pp 205–251Google Scholar
  6. 6.
    Rak JW, Hegmann EJ, Lu C, Kerbel RS: Progressive loss of sensitivity to endothelium-derived growth inhibitors expressed by human melanoma cells during disease progression. J Cell Physiol 159: 245–255, 1994Google Scholar
  7. 7.
    Hamada J, Cavanaugh PG, Miki K, Nicholson GL: A paracrine migration-stimulating factor for metastatic tumor cells secreted by mouse hepatic sinusoidal endothelial cells: identification as complement component C3b. Cancer Res 53: 4418–4423, 1993Google Scholar
  8. 8.
    Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other diseases. Nature Medicine 1: 2, 1995Google Scholar
  9. 9.
    Brooks PC, Stromblad S, Klemke R, Visscher D, Sarkar FH, Cheresh DA: Antiintegrin αvβ3 blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest 96: 1815–1822, 1995Google Scholar
  10. 10.
    Folkman J, Ingher D: Inhibition of angiogenesis. Sem Cancer Biol 3: 89–96, 1993Google Scholar
  11. 11.
    Denekamp J. Angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy. Br J Radiol 66: 181–196, 1993Google Scholar
  12. 12.
    Kerbel RS: Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. BioEssays 13: 31–36, 1991Google Scholar
  13. 13.
    Jain RK: Barriers to drug delivery in solid tumors. Scientific Am 58–65, 1994Google Scholar
  14. 14.
    Teicher BA, Holden SA, Dupuis NP, Kakeji Y, Ikebe M, Emi Y, Goff D: Potentiation of cytotoxic therapies by TNP-470 and minocycline in mice bearing EMT-6 mammary carcinoma. Breast Cancer Res Treat 36: 227–236, 1995Google Scholar
  15. 15.
    Friedlander M, Brooks PC, Shaffer RW, Kincaid CM, Varner JA, Cheresh DA: Definition of two angiogenic pathways by distinct α integrins. Science 270: 1500, 1995Google Scholar
  16. 16.
    Plate KH, Breier G, Weich HA, Risau W: Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359: 845–848, 1992Google Scholar
  17. 17.
    Mustonen T, Alitalo K: Endothelial receptor tyrosine kinases involved in angiogenesis. J Cell Biol 129: 895–898, 1995Google Scholar
  18. 18.
    Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A: Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367: 576–579, 1994Google Scholar
  19. 19.
    Ferrara N: The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res Treat 36: 127–137, 1995Google Scholar
  20. 20.
    Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrera N: Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362: 841–844, 1993Google Scholar
  21. 21.
    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, 1995Google Scholar
  22. 22.
    Hori A, Sasada R, Matsutani E, Naito K, Sakura Y, Fujita T Kozai Y: Suppression of solid tumor growth by immuneutralizing monoclonal antibody against human basic fibroblast growth factor. Cancer Res 51: 6180–6184, 1991Google Scholar
  23. 23.
    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, 1995Google Scholar
  24. 24.
    Bouck N: Tumor angiogenesis: the role of oncogenes and tumor suppressor genes. Cancer Cells 2: 179–185, 1990Google Scholar
  25. 25.
    Rak J, Filmus J, Finkenzeller G, Grugel S, Marme D, Kerbel RS: Oncogenes as inducers of tumor angiogenesis. Cancer Metastasis Rev 14: 263–277, 1995Google Scholar
  26. 26.
    Dameron KM, Volpert OV, Tainsky MA, Bouck N: Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265: 1582–1584, 1994Google Scholar
  27. 27.
    Van Meir EG, Polverini PJ, Chazin VR, Huang SH-J, Tribolet N, Cavanee WK: Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells. Nature Genetics 8: 171–182, 1994Google Scholar
  28. 28.
    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: 26915–25919, 1995Google Scholar
  29. 29.
    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, 1995Google Scholar
  30. 30.
    Rak J, Mitsuhashi Y, Bayko L, Filmus J, Sasazuki T, Kerbel RS: Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 55: 4575–4580, 1995Google Scholar
  31. 31.
    Kieser A, Weich HA, Brandner G, Marme D, Kolch W: Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 9: 963–969, 1994Google Scholar
  32. 32.
    Wizigmann-Voos S, Breier G, Risau W, Plate KH: Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau diseas-associated and sporadic hemangioblastoma. Cancer Res 55: 1358–1364, 1995Google Scholar
  33. 33.
    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 in ras transgenic mice. Nature Medicine 1: 792–797, 1995Google Scholar
  34. 34.
    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, 1995Google Scholar
  35. 35.
    Gibbs JB, Oliff Aà: Pharmaceutical research in molecular oncology. Cell 79: 193–198, 1994Google Scholar
  36. 36.
    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 expression of a mutant c-H-ras oncogene. J Cell Biol 131: 1587–1598, 1995Google Scholar
  37. 37.
    Fox SB, Gatter KC, Bicknell R, Going JJ, Stanton P, Cooke TG, Harris AL: Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer. Cancer Res 53: 4161–4163, 1993Google Scholar
  38. 38.
    Christofori G, Naik P, Hanahan D: Vascular endothelial growth factor and its receptors, flt-1 and flk-1, are expressed in normal pancreatic islets and throughout islet cell tumorigenesis. Mol Endocrinol 9: 1760–1770, 1995Google Scholar
  39. 39.
    Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ: Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379: 88–91, 1996Google Scholar

Copyright information

© Kluwer Academic Publishers 1996

Authors and Affiliations

  • J. Rak
    • 1
  • R. S. Kerbel
    • 1
  1. 1.Reichmann Research Building, Division of Cancer Biology ResearchSunnybrook Health Science CentreTorontoCanada

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