Angiogenesis pp 183-191 | Cite as

Tumor Antiangiogenesis: Which Way?

  • Pietro M. Gullino
Part of the NATO ASI Series book series (NSSA, volume 263)


The presence of neoplastic cells in a normal tissue elicits from the host vascular network a large number of microvessels that sustain tumor growth. Angiogenic capacity is peculiar but not restricted to neoplastic cells;1,2 it appears in the course of neoplastic transformation before the cell population can form a tumor upon transplantation;3,4 it suggests an increased risk of neoplastic transformation when acquired by a cell population normally not angiogenic.5,6 Present knowledge of tumor angiogenesis sustains the belief of many investigators that antiangiogenesis treatment of a tumor bearing host might arrest or effectively impair growth of primary as well as metastatic neoplasia. Fig. 1 depicts one observation that supports this belief. In this model a very rapid growth consistently occurs as soon as the vessels colonize the neoplastic cell population, thus, it seems reasonable to expect growth arrest or impairment if angiogenesis is blocked. What guide does present knowledge of angiogenesis offer in searching for an effective antiangiogenesis treatment? An effort to address this question is made here in an environment most suitable for speculation.


Endothelial Cell Proliferation Antiangiogenic Effect Microvascular Endothelium Rabbit Cornea Acidic Fibroblastic Growth Factor 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    P.M. Gullino, Angiogenesis factors, in: “Handbook of Experimental Pharmacology,” R. Baserga, Springer Verlag, New York, 57:427 (1981).Google Scholar
  2. 2.
    J. Folkman, Tumor angiogenesis, Adv. Cancer Res. 19:331(1974) and 32: 1975 (1985).Google Scholar
  3. 3.
    M. Ziehe and P.M. Gullino, Angiogenesis and prediction of sarcoma formation, Cancer Res. 41: 5060 (1981).Google Scholar
  4. 4.
    M. Ziche and P.M. Gullino, Angiogenesis and neoplastic progression in vitro, J. Nat. Cancer Inst. 69: 483 (1982).Google Scholar
  5. 5.
    S.S. Brem, P.M. Gullino, and D. Medina, Angiogenesis: a marker for neoplastic transformation of mammary papillary hyperplasia, Science 195: 880 (1977).Google Scholar
  6. 6.
    S.S. Brem, Jensen H, and P.M. Gullino, Angiogenesis as marker of preneoplastic lesions of the human breast, Cancer 41: 239 (1978).Google Scholar
  7. 7.
    F.Rastinejad, P.J. Polverini, and N.P. Bouck, Regulation of the activity of a new inhibitor of angiogenesis by a cancer suppressor gene, Cell 56: 345 (1989).Google Scholar
  8. 8.
    D.J. Good, P.J. Polverini, F. Rastinejad, M.M. Le-Beau, R.S Lemons, W.A. Frazier, and N.P. Bouck, A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin, Proc. Nat. Acad. Sci. USA 87: 6624 (1990).Google Scholar
  9. 9.
    N.P. Bouck, Tumor angiogenesis: The role of oncogenes and tumor suppressors genes, Cancer Cells 2:179(1990) Cold Spring Harbor Laboratory Press ISSN.Google Scholar
  10. 10.
    M.L. Iruela-Arispa, P. Bornstein, and H. Sage, Thrombospondin exerts an antiangiogenic effect on cord formation by endothelial cells in vitro, Proc. Nat. Acad. Sci. USA 88: 5026 (1991).Google Scholar
  11. 11.
    P. Bagavandoss and J.W. Wilks, Specific inhibition of endothelial cells proliferation by thrombospondin, Biochem. Biophys. Res. Commun. 170: 867 (1990).Google Scholar
  12. 12.
    T. Ichikawa, Y. Ichikawa, and J. Isaacs, Genetic factors andGoogle Scholar
  13. suppression of metastatic ability of prostatic cancer, Cancer Res. 51: 3788 (1991).Google Scholar
  14. 13.
    T.Ichikawa, Y. Ichikawa, J. Dong, A.L. Hawkins, C.A. Griffin, W.B. Isaacs, M. Oshimura, J.C. Barret, and J.T.Isaacs, Localization of metastasis suppressor gene(s) for prostatic cancer to the short arm of human chromosome 11, Cancer Res. 52: 3486 (1992).Google Scholar
  15. 14.
    I. Vlodaysky,J. Folkman, R. Sullivan, R. Fridman, R. Ishai-Michaeli, J. Sasse J, and M. Klagsbrun, Endothelial cell-derived basic fibroblastic growth factor:Synthesis and deposition into subendothelial extracellular matrix, Proc. Nat. Acad. Sci. USA 84: 2292 (1987).Google Scholar
  16. 15.
    I. Vlodaysky, R. Fridman, R. Sullivan, J. Sasse, and M. Klagsbrun, Aortic endothelial cells synthesize basic fibroblastic growth factor which remains cell associated and platelet-derived growth factor-like protein which is secreted, J. Cell. Physiol. 131: 402 (1987).Google Scholar
  17. 10.
    I. Vlodaysky, Z.Fues, R. Ishai-Michaeli, P. Bashkin, E.Levi, G. Korner, R. Bar-Shavit, and M. Klagsbrun, Extracellular matrix-resident basic fibroblastic growth factor: Implication, for the control of angiogenesis, J. Cell. Biochem. 45: 167 (1991).Google Scholar
  18. 17.
    I. Vlodaysky, L.K. Johnson, G. Greenburg, and D. Gospodarowicz, Vascular endothelial cells maintained in the absence of fibroblastic growth factor undergo structural alterations that are incompatible with their in vivo differentiated properties, J. Cell. Biol. 83: 468 (1979).Google Scholar
  19. 18.
    S. Araki, Y. Shimada, K. Kaji, and H. Hayashi, Apoptosis of vascular endothelial cells by fibroblast growth factor deprivation, Biochem. Biophys. Res. Comm. 168: 1194 (1990).Google Scholar
  20. 19.
    R. Ishai-Michaeli, A. Eldor, and I. Vlodaysky I, Heparanase activity expressed by platelets, neutrophils and lymphoma cells releases active fibroblastic growth factor from extracellular matrix, Cell Regulation 1: 833 (1990).Google Scholar
  21. 20.
    M. Ziche, G. Alessandri, and P.M. Cullino, Gangliosides promote the angiogenic response, Lab. Invest. 61: 629 (1989).Google Scholar
  22. 21.
    G. Alessandri, G. De Cristan, M. Ziche, A.P.M. Cappa, and P.M. Gullino, Growth and motility of microvascular endothelium are modulated by the relative concentration of gangliosides in the medium, J. Cell. Physiol. 151: 23 (1992).Google Scholar
  23. 22.
    M.Ziche, L. Morbidelli, G. Alessandri, and P.M. Gullino, Angiogenesis can be stimulated or repressed in vivo by a change in the GM3:GD3 ganglioside ratio, Lab. Invest. 67: 711 (1992).Google Scholar
  24. 23.
    J.R. Merwin, M.J. Lynch, J.A. Madri, I. Pastan, and C.B. Siegall, Acidic fibroblastic growth factor - Pseudomonas exotoxin chimeric protein elicits antiangiogenic effects on endothelial cells, Cancer Res. 52: 4995 (1992).Google Scholar
  25. 24.
    K. Norioka, M. Hara, A. Kitani, T. Hirose, W. Hirose, M. Harigai, K. Suzuki, M. Kawakam, H. Tabata, M. Kawagoe, and H. Nakamura, Inhibitory effect of human recombinant interleukin loeand r on growth of human vascular endothelial cells, Biochem. Biophys. Res. Comm. 145: 969 (1987).Google Scholar
  26. 25.
    T.E. Maione, G.S. Gray, S. Petro, A.J. Hunt, A.L. Donner, S.I. Bauer, H.F. Carson, and R.J. Sharpe, Inhibition of angiogenesis by recombinant human platelet factor 4 and related peptides, Science 247(1990).Google Scholar
  27. 26.
    T.E. Maione, G.S. Gray, A.J. Hunt, and R.J. Sharpe, Inhibition of tumor growth in mice by an analogue of platelet factor 4 that lacks affinity for heparin and retains potent angiostatic activity, Cancer Res. 51: 2077 (1991).Google Scholar
  28. 27.
    T. Matsubara, and M. Ziff, Inhibition of human endothelial cell proliferation by gold compounds, J. Clin. Invest. 79: 1440 (1987).Google Scholar
  29. 28.
    A.E. Koch, M. Cho, J. Burrows, S.J. Leibovich, and P.J. Polverini, Inhibition of production of macrophage-derived angiogenic activity by the anti-rheumatic agents gold-sodium thiomalate and auranofin, Biochem. Biophys. Res. Comm. 154: 205 (1988).Google Scholar
  30. 29.
    M.M. Grant, H.C. Koo, W. Rosenfeld, Oxygen affects human endothelial cell proliferation by inactivation of fibroblast growth factors, Am. J. Physiol. 263: L370 (1987).Google Scholar
  31. 30.
    G. Muller, J. Beherens, U. Nussbaumer, P. Bohlen, and W. Bircmeier, Inhibitory action of transforming growth factor f3 on endothelial cells, Proc. Nat. Acad. Sci. USA 84: 5600 (1987).Google Scholar
  32. 31.
    N. Ferrara, L. Clapp, and R. Weiner, The 16K fragment of prolactin specifically inhibits basal or fibroblastic growth factor stimulated growth of capillary endothelial cells, Endocrinology 129: 986 (1991).Google Scholar
  33. 32.
    B.N. Yamaja-Setty, K.L. Dubowy, and M.J. Stuart, Endothelial cell proliferation may be mediated via the production of endogenous lipo-oxygenase metabolites, Biochem. Biophys. Res. Comm. 144: 345 (1987).Google Scholar
  34. 33.
    T. Matsubara, R. Saura, K. Hirohata, and M. Ziff, Inhibition of human endothelial cell proliferation in vitro and neovascularization in vivo by D-penicillamine, J. Clin. Invest. 83: 158 (1989).Google Scholar
  35. 34.
    M. Takigawa, M. Enomoto, Y. Nishida, H.O. Pan, A. Kinoshita, and F. Suzuki, Tumor angiogenesis and polyamines: of difluoromethylornithine, an irreversible inhibitor of ornithine dicarboxylase, inhibits B16 melanoma-induced angiogenesis in ovo and the proliferation of vascular endothelial cells in vitro, Cancer Res. 50: 4131 (1990).Google Scholar
  36. 35.
    G.E. Besner, and M. Klagsbrun, Macrophages secrete a heparin-binding inhibitor of endothelial cell growth, Microvascular Res. 42: 187 (1991).Google Scholar
  37. 36.
    I. Saiki, J. Murata, T. Makabe, N. Nishi, S. Tokura, and I. Azuma, Inhibition of tumor angiogenesis by a synthetic cell-adhesive polypeptide containing the Arg-Gly-Asp (RGD) sequence of fibronectin poly (RGD) Jpn. J. Cancer Res. 81: 668 (1990).Google Scholar
  38. 37.
    S. Taylor, and J. Folkman, Protamine is an inhibitor of angiogenesis, Nature 297: 307 (1982).Google Scholar
  39. 38.
    J. Folkman, R. Langer, Linhardt, C. Haudenschild, and S. Taylor, Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone, Science 221: 719 (1983).Google Scholar
  40. 39.
    R. Crum, S. Szabo, and J. Folkman, A new class of steroids inhibits angiogenesis in the presence of heparin or a heparin fragment, Science 230: 1375 (1985).Google Scholar
  41. 40.
    J. Folkman J, and D. E. Ingberg, Angiostatic steroids, Amer. Surg. 206: 374 (1987).Google Scholar
  42. 41.
    D.E. Ingberg, and J. Folkman, Inhibition of angiogenesis through modulation of collagen metabolism, Lab. Invest. 59: 44 (1988).Google Scholar
  43. 42.
    N.G. Tanaka, N. Sakamoto, K. Inoue, H. Korenaga, S. Kadoya, H. Ogawa, and Y. Osada, Antitumor effect of an antiangiogenic polysaccharide from an arthrobacter species with and without a steroid, Cancer Res. 49: 6727 (1989).Google Scholar
  44. 43.
    Y. Tokida, Aratani, A. Morita, and Y. Kitagawa, Production of two variant laminin forms by endothelial cells and shift in their relative levels by angiostatic steroids, J. Biol. Chem. 265: 18123 (1990).Google Scholar
  45. 44.
    N. Sakamoto, M. Iwahana, N.G. Tanaka, and Y. Osada, Inhibition of angiogenesis and tumor growth by a synthetic laminin peptide CDPGYIGSR-NH2, Cancer Res. 51: 903 (1991).Google Scholar
  46. 45.
    M.E. Maragoudakis, M. Sarmonika, and M. Panoutsacopoulou, Inhibition of basement membrane biosynthesis prevents angiogenesis, J. Pharmacol. Exp. Therapeutics 244: 729 (1988).Google Scholar
  47. 46.
    W.M. Leuko, L. Liotta, M.S. Wicha, Vonderhaar, and W.R. Kidwell, Sensitivity of N-Nitrosomethyl urea-induced rat mammary tumors to cis-hydroxypraline, an inhibitor of collagen production, Cancer Res. 41: 2855 (1981).Google Scholar
  48. 47.
    L.M. Hiebert, and L.B. Jaques, Heparin concentration in endothelium, Thrombosis Res 8: 195 (1976).Google Scholar
  49. 48.
    P.A. D’Amore, Heparin-endothelial cell interaction, Haemostasis 20 suppl. 1: 159 (1990).Google Scholar
  50. 49.
    S. Ungari, K.S. Raju, G. Alessandri, and P.M. Gullino, Cooperation between fibronectin and heparin in the mobilization of capillary endothelium, Invasion and metastasis 5: 193 (1985).Google Scholar
  51. 50.
    D. Ingberg, T. Fujita, S. Kishimoto, K. Sudo, T.Kanamaru, H. Brem, and J. Folkman, Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumor growth, Nature 348: 555 (1990).Google Scholar
  52. 51.
    E.A. Woltering, R. Barrie, T.M. O’Dorisio, D. Arce, T. Ure, A. Cramer, D. Holmes, J. Robertson, and J. Fassler, Somatostatin analogues inhibit angiogenesis in the chick chorioallantoic membrane, J. Surg. Res. 50: 245 (1991).Google Scholar
  53. 52.
    Y.A. Sidky, and E.C. Borden, Inhibition of angiogenesis by interferons: effects on tumor and lymphocyte-induced vascular responses, Cancer Res. 47: 5155 (1987).Google Scholar
  54. 53.
    F.J. Burrows, Y. Watanabe, and P.E. Thorpe, A murine model for antibody-directed targeting of vascular endothelial cells in solid tumors, Cancer Res. 52: 5954 (1992).Google Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Pietro M. Gullino
    • 1
  1. 1.Department of Biomedical SciencesUniversity of TorinoTorinoItaly

Personalised recommendations