Skip to main content
SpringerLink
Log in

Molecular Mechanisms of Tumor Angiogenesis and Tumor Progression

  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

The formation of new blood vessels (angiogenesis) is crucial for the growth and persistence of primary solid tumors and their metastases. Furthermore, angiogenesis is also required for metastatic dissemination, since an increase in vascular density will allow easier access of tumor cells to the circulation. Induction of angiogenesis precedes the formation of malignant tumors, and increased vascularization seems to correlate with the invasive properties of tumors and thus with the malignant tumor phenotype. In the last few years, the discovery and characterization of tumor-derived angiogenesis modulators greatly contributed to our understanding of how tumors regulate angiogenesis. However, although angiogenesis appears to be a rate-limiting event in tumor growth and metastatic dissemination, a direct connection between the induction of angiogenesis and the progression to tumor malignancy is less well understood. In this review, we discuss the most recent observations concerning the modulation of angiogenesis and their implications in tumor progression, as well as their potential impact on cancer therapy.

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.

Similar content being viewed by others

References

  1. Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1: 27-31, 1995

    Google Scholar 

  2. Hanahan D, Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353-64, 1996

    Google Scholar 

  3. Bouck N, Stellmach V, Hsu SC: How tumors become angiogenic. Adv Cancer Res 69: 135-74, 1996

    Google Scholar 

  4. Risau W: Mechanisms of angiogenesis. Nature 386: 671-4, 1997

    Google Scholar 

  5. Fox SB, Harris AL: Markers of tumor angiogenesis: clinical applications in prognosis and anti-angiogenic therapy. Invest New Drugs 15: 15-28, 1997

    Google Scholar 

  6. Iruela-Arispe ML, Dvorak HF: Angiogenesis: a dynamic balance of stimulators and inhibitors. Thromb Haemost 78: 672-7, 1997

    Google Scholar 

  7. Korpelainen EI, Alitalo K: Signaling angiogenesis and lymphangiogenesis. Curr Opin Cell Biol 10: 159-64, 1998

    Google Scholar 

  8. Gale NW, Yancopoulos GD: Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev 13: 1055-66, 1999

    Google Scholar 

  9. Ferrara N, Davis-Smyth T: The biology of vascular endothelial growth factor. Endocr Rev 18: 4-25, 1997

    Google Scholar 

  10. Christofori G: The role of fibroblast growth factors in tumor progression and angiogenesis. In: Bicknell R, Lewis CE, Ferrara N (eds): Tumor Angiogenesis. Oxford University Press, 1997, pp 201-37

  11. Vlodavsky I, Christofori G: Fibroblast growth facors in tumor progression and angiogenesis. In: Teicher BA (ed): Antiangiogenic Agents in Cancer Therapy. Totowa, NJ, Humana Press, Inc., 1998, pp 93-118

    Google Scholar 

  12. Ortega S, Ittmann M, Tsang SH, Ehrlich M, Basilico C: Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. Proc Natl Acad Sci USA 95: 5672-7, 1998

    Google Scholar 

  13. Ozaki H, Okamoto N, Ortega S, Chang M, Ozaki K, Sadda S, Vinores MA, Derevjanik N, Zack DJ, Basilico C, Campochiaro PA: Basic fibroblast growth factor is neither necessary nor sufficient for the development of retinal neovascularization. Am J Pathol 153: 757-65, 1998

    Google Scholar 

  14. Seghezzi G, Patel S, Ren CJ, Gualandris A, Pintucci G, Robbins ES, Shapiro RL, Galloway AC, Rifkin DB, Mignatti P: Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries.Anautocrine mechanism contributing to angiogenesis. J Cell Biol 141: 1659-73, 1998

    Google Scholar 

  15. Pepper MS, Mandriota SJ: Regulation of vascular endothelial growth factor receptor-2 (Flk-1) expression in vascular endothelial cells. Exp Cell Res 241: 414-25, 1998

    Google Scholar 

  16. Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD: Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87: 1171-80, 1996

    Google Scholar 

  17. Sato TN, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gendron-Maguire M, Gridley T, Wolburg H, Risau W, Qin Y: Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376: 70-4, 1995

    Google Scholar 

  18. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD: Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277: 55-60, 1997

    Google Scholar 

  19. Lin P, Buxton JA, Acheson A, Radziejewski C, Maisonpierre PC, Yancopoulos GD, Channon KM, Hale LP, Dewhirst MW, George SE, Peters KG: Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2. Proc Natl Acad Sci USA 95: 8829-34, 1998

    Google Scholar 

  20. Folkman J, Shing Y: Angiogenesis. J Biol Chem 267: 10931-4, 1992

    Google Scholar 

  21. Zetter BR: Angiogenesis and tumor metastasis. Annu Rev Med 49: 407-24, 1998

    Google Scholar 

  22. Sidky YA, Borden EC: Inhibition of angiogenesis by interferons: effects on tumor-and lymphocyte-induced vascular responses. Cancer Res 47: 5155-61, 1987

    Google Scholar 

  23. Voest EE, Kenyon BM, O'Reilly MS, Truitt G, D'Amato RJ, Folkman J: Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst 87: 581-6, 1995

    Google Scholar 

  24. Cao Y, Chen C, Weatherbee JA, Tsang M, Folkman J: grobeta, a-C-X-C-chemokine, is an angiogenesis inhibitor that suppresses the growth of Lewis lung carcinoma in mice. J Exp Med 182: 2069-77, 1995

    Google Scholar 

  25. Angiolillo AL, Sgadari C, Taub DD, Liao F, Farber JM, Maheshwari S, Kleinman HK, Reaman GH, Tosato G: Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med 182: 155-62, 1995

    Google Scholar 

  26. Varner JA, Cheresh DA: Integrins and cancer. Curr Opin Cell Biol 8: 724-30, 1996

    Google Scholar 

  27. Eliceiri BP, Cheresh DA: The role of alphav integrins during angiogenesis. Mol Med 4: 741-50, 1998

    Google Scholar 

  28. Ferrara N, Alitalo K: Clinical applications of angiogenic growth factors and their inhibitors. Nat Med 5: 1359-64, 1999

    Google Scholar 

  29. Anand-Apte B, Pepper MS, Voest E, Montesano R, Olsen B, Murphy G, Apte SS, Zetter B: Inhibition of angiogenesis by tissue inhibitor of metalloproteinase-3. Invest Ophthalmol Vis Sci 38: 817-23, 1997

    Google Scholar 

  30. Johnson MD, Kim HR, Chesler L, Tsao-Wu G, Bouck N, Polverini PJ: Inhibition of angiogenesis by tissue inhibitor of metalloproteinase. J Cell Physiol 160: 194-202, 1994

    Google Scholar 

  31. Murphy AN, Unsworth EJ, Stetler-Stevenson WG: Tissue inhibitor of metalloproteinases-2 inhibits bFGF-induced human microvascular endothelial cell proliferation. J Cell Physiol 157: 351-8, 1993

    Google Scholar 

  32. Homandberg GA, Williams JE, Grant D, Schumacher B, Eisenstein R: Heparin-binding fragments of fibronectin are potent inhibitors of endothelial cell growth. Am J Pathol 120: 327-32, 1985

    Google Scholar 

  33. Grant DS, Kleinman HK, Martin GR: The role of basement membranes in vascular development. Ann NY Acad Sci 588: 61-72, 1990

    Google Scholar 

  34. Dawson DW, Bouck NP: Thrombospondin as an inhibitor of angiogenesis. In: Teicher BA (ed): Antiangiogenic Agents In Cancer Therapy, Vol. 3. Totowa, NJ, Humana Press Inc., 1999, pp 185-203

    Google Scholar 

  35. Dawson DW, Pearce SF, Zhong R, Silverstein RL, Frazier WA, Bouck NP: CD36 mediates the in vitro inhibitory effects of thrombospondin-1 on endothelial cells. J Cell Biol 138:707-17, 1997

    Google Scholar 

  36. O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J: Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88: 277-85, 1997

    Google Scholar 

  37. O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J: Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79: 315-28, 1994

    Google Scholar 

  38. Moser TL, Stack MS, Asplin I, Enghild JJ, Hojrup P, Everitt L, Hubchak S, Schnaper HW, Pizzo SV: Angiostatin binds ATP synthase on the surface of human endothelial cells. Proc Natl Acad Sci USA 96: 2811-6, 1999

    Google Scholar 

  39. Stack MS, Gately S, Bafetti LM, Enghild JJ, Soff GA: Angiostatin inhibits endothelial and melanoma cellular invasion by blocking matrix-enhanced plasminogen activation. Biochem J 340: 77-84, 1999

    Google Scholar 

  40. Redlitz A, Daum G, Sage EH: Angiostatin diminishes activation of the mitogen-activated protein kinases ERK-1 and ERK-2 in human dermal microvascular endothelial cells. J Vasc Res 36: 28-34, 1999

    Google Scholar 

  41. Claesson-Welsh L, Welsh M, Ito N, Anand-Apte B, Soker S, Zetter B, O'Reilly M, Folkman J: Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin-binding motif RGD. Proc Natl Acad Sci USA 95: 5579-83, 1998

    Google Scholar 

  42. Lucas R, Holmgren L, Garcia I, Jimenez B, Mandriota SJ, Borlat F, Sim BK, Wu Z, Grau GE, Shing Y, Soff GA, Bouck N, Pepper MS: Multiple forms of angiostatin induce apoptosis in endothelial cells. Blood 92: 4730-41, 1998

    Google Scholar 

  43. Taddei L, Chiarugi P, Brogelli L, Cirri P, Magnelli L, Raugei G, Ziche M, Granger HJ, Chiarugi V, Ramponi G: Inhibitory effect of full-length human endostatin on in vitro angiogenesis. Biochem Biophys Res Commun 263: 340-5, 1999

    Google Scholar 

  44. Dhanabal M, Ramchandran R, Waterman MJ, Lu H, Knebelmann B, Segal M, Sukhatme VP: Endostatin induces endothelial cell apoptosis. J Biol Chem 274: 11721-6, 1999

    Google Scholar 

  45. Sasaki T, Larsson H, Kreuger J, Salmivirta M, Claesson-Welsh L, Lindahl U, Hohenester E, Timpl R: Structural basis and potential role of heparin/heparan sulfate binding to the angiogenesis inhibitor endostatin. Embo J 18: 6240-8, 1999

    Google Scholar 

  46. Miosge N, Sasaki T, Timpl R: Angiogenesis inhibitor endostatin is a distinct component of elastic fibers in vesselwalls. FASEB J 13: 1743-50, 1999

    Google Scholar 

  47. Chang Z, Choon A, Friedl A: Endostatin binds to blood vessels in situ independent of heparan sulfate and does not compete for fibroblast growth factor-2 binding. Am J Pathol 155: 71-6, 1999

    Google Scholar 

  48. Yamaguchi N, Anand-Apte B, Lee M, Sasaki T, Fukai N, Shapiro R, Que I, Lowik C, Timpl R, Olsen BR: Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding. EMBO J 18: 4414-23, 1999

    Google Scholar 

  49. Boehm T, O'Reilly MS, Keough K, Shiloach J, Shapiro R, Folkman J: Zinc-binding of endostatin is essential for its antiangiogenic activity. Biochem Biophys Res Commun 252: 190-4, 1998

    Google Scholar 

  50. Bergers G, Hanahan D, Coussens LM: Angiogenesis and apoptosis are cellular parameters of neoplastic progression in transgenic mouse models of tumorigenesis. Int J Dev Biol 42: 995-1002, 1998

    Google Scholar 

  51. Shweiki D, Itin A, Soffer D, Keshet E: Vascular endothelial growth factor induced by hypoxia may mediate hypoxiainitiated angiogenesis. Nature 359: 843-5, 1992

    Google Scholar 

  52. Plate KH, Breier G, Millauer B, Ullrich A, Risau W: Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Res 53: 5822-7, 1993

    Google Scholar 

  53. Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ, Hankinson O, Pugh CW, Ratcliffe PJ: Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA 94: 8104-9, 1997

    Google Scholar 

  54. Grunstein J, Roberts WG, Mathieu-Costello O, Hanahan D, Johnson RS: Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function. Cancer Res 59: 1592-8, 1999

    Google Scholar 

  55. Ellis LM, Staley CA, Liu W, Fleming RY, Parikh NU, Bucana CD, Gallick GE: Down-regulation of vascular endothelial growth factor in a human colon carcinoma cell line transfected with an antisense expression vector specific for c-src. J Biol Chem 273: 1052-7, 1998

    Google Scholar 

  56. Rofstad EK, Danielsen T: Hypoxia-induced angiogenesis and vascular endothelial growth factor secretion in human melanoma. Br J Cancer 77: 897-902, 1998

    Google Scholar 

  57. Kuwabara K, Ogawa S, Matsumoto M, Koga S, Clauss M, Pinsky DJ, Lyn P, Leavy J, Witte L, Joseph-Silverstein J et al.: Hypoxia-mediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclsear phagocytes stimulates growth of hypoxic endothelial cells. Proc Natl Acad Sci USA 92: 4606-10, 1995

    Google Scholar 

  58. Fukumura D, Xavier R, Sugiura T, Chen Y, Park EC, Lu N, Selig M, Nielsen G, Taksir T, Jain RK, Seed B: Tumor induction of VEGF promoter activity in stromal cells. Cell 94: 715-25, 1998

    Google Scholar 

  59. Christofori G: The implication of angiogenesis on tumor invasiveness. Angiogenesis 2: 21-3, 1998

    Google Scholar 

  60. Christofori G, Luef S: Novel forms of acidic fibroblast growth factor-1 are constitutively exported by β tumor cell lines independent from conventional secretion and apoptosis. Angiogenesis 1: 55-70, 1997

    Google Scholar 

  61. 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: 1095-104, 1991

    Google Scholar 

  62. Kerbel RS, Viloria-Petit A, Okada F, Rak J: Establishing a link between oncogenes and tumor angiogenesis. Mol Med 4: 286-95, 1998

    Google Scholar 

  63. Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T, Kerbel RS: Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 55: 4575-80, 1995

    Google Scholar 

  64. Shi YP, Ferrara N: Oncogenic ras fails to restore an in vivo tumorigenic phenotype in embryonic stem cells lacking vascular endothelial growth factor (VEGF). Biochem Biophys Res Commun 254: 480-3, 1999

    Google Scholar 

  65. Okada F, Rak JW, Croix BS, Lieubeau B, Kaya M, Roncari L, Shirasawa S, Sasazuki T, Kerbel RS: Impact of oncogenes in tumor angiogenesis: mutant K-ras upregulation 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: 3609-14, 1998

    Google Scholar 

  66. Theurillat JP, Hainfellner J, Maddalena A, Weissenberger J, Aguzzi A: Early induction of angiogenetic signals in gliomas of GFAP-v-src transgenic mice. Am J Pathol 154: 581-90, 1999

    Google Scholar 

  67. Arbiser JL, Moses MA, Fernandez CA, Ghiso N, Cao Y, Klauber N, Frank D, Brownlee M, Flynn E, Parangi S, Byers HR, Folkman J: Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways. Proc Natl Acad Sci USA 94: 861-6, 1997

    Google Scholar 

  68. Skobe M, Rockwell P, Goldstein N, Vosseler S, Fusenig NE: Halting angiogenesis suppresses carcinoma cell invasion. Nat Med 3: 1222-7, 1997

    Google Scholar 

  69. Dameron KM, Volpert OV, Tainsky MA, Bouck N: The p53 tumor suppressor gene inhibits angiogenesis by stimulating the production of thrombospondin. Cold Spring Harb Symp Quant Biol 59: 483-9, 1994

    Google Scholar 

  70. Giri D, Ittmann M: Inactivation of the PTEN tumor suppressor gene is associated with increased angiogenesis in clinically localized prostate carcinoma. Hum Pathol 30: 419-24, 1999

    Google Scholar 

  71. Pal S, Claffey KP, Dvorak HF, Mukhopadhyay D: The von Hippel-Lindau gene product inhibits vascular permeability factor/vascular endothelial growth factor expression in renal cell carcinoma by blocking protein kinaseCpathways. J Biol Chem 272: 27509-12, 1997

    Google Scholar 

  72. Parangi S, Dietrich W, Christofori G, Lander ES, Hanahan D: Tumor suppressor loci on mouse chromosomes 9 and 16 are lost at distinct stages of tumorigenesis in a transgenic model of islet cell carcinoma. Cancer Res 55: 6071-6, 1995

    Google Scholar 

  73. O'Reilly MS, Holmgren L, Chen C, Folkman J: Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 2: 689-92, 1996

    Google Scholar 

  74. Boehm T, Folkman J, Browder T, O'Reilly MS: Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390: 404-7, 1997

    Google Scholar 

  75. Bergers G, Javaherian K, Lo KM, Folkman J, Hanahan D: Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284: 808-12, 1999

    Google Scholar 

  76. Parangi S, O'Reilly M, Christofori G, Holmgren L, Grosfeld J, Folkman J, Hanahan D: Antiangiogenic therapy of transgenic mice impairs de novo tumor growth. Proc Natl Acad Sci USA 93: 2002-7, 1996

    Google Scholar 

  77. Teicher BA, Sotomayor EA, Huang ZD: Antiangiogenic agents potentiate cytotoxic cancer therapies against primary and metastatic disease. Cancer Res 52: 6702-4, 1992

    Google Scholar 

  78. Kakeji Y, Teicher BA: Preclinical studies of the combination of angiogenic inhibitors with cytotoxic agents. Invest New Drugs 15: 39-48, 1997

    Google Scholar 

  79. Kerbel RS: A cancer therapy resistant to resistance. Nature 390: 335-6, 1997

    Google Scholar 

  80. Cao Y: Endogenous angiogenesis inhibitors: angiostatin, endostatin, and other proteolytic fragments. Prog Mol Subcell Biol 20: 161-76, 1998

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research Institute of Molecular Pathology, Vienna, Austria

    Ugo Cavallaro & Gerhard Christofori

Authors
  1. Ugo Cavallaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gerhard Christofori
    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

Cavallaro, U., Christofori, G. Molecular Mechanisms of Tumor Angiogenesis and Tumor Progression. J Neurooncol 50, 63–70 (2000). https://doi.org/10.1023/A:1006414621286

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006414621286

Search

Navigation