Anti-angiogenesis Therapy and Strategies for Integrating It with Adjuvant Therapy

  • A. L. Harris
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 152)

Abstract

The growth of tumors above about 1 mm in diameter requires angiogenesis, the development of a new blood supply, from pre-existing vasculature (Folkman 1990). This applies to both the primary and secondary lesions. Angiogenesis is also essential for systemic metastasis, and it has recently been shown that it is essential for local invasion (Skobe et al. 1997). Normal vasculature is quiescent and each endothelial cell divides only once in 10 years, apart from the endometrial and ovarian angiogenesis during the menstrual cycle and during wound healing. In human tumors the number of dividing endothelial cells may be 50 times greater than in normal tissue. These vessels are leaky, have upregulated vascular growth factor receptors and cell adhesion molecules and are in a procoagulant state. Thus they provide a new therapeutic target with many factors differently expressed between tumor and normal endothelium. This review describes some of the angiogenic pathways and discusses how emerging anti-angiogenic drugs can be integrated into adjuvant trials.

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References

  1. Asahara T, Bauters C, Zheng LP, Takeshita S, Bunting S, Ferrara N, Symes JF, Isner JM (1995) Synergistic effect of vascular endothelial growth-factor and basic fibroblast growth-factor on angiogenesis in vivo. Circulation 92:365–371Google Scholar
  2. Boehm T, Folkman J, Browder T, O’Reilly MS (1997) Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390:404–407PubMedCrossRefGoogle Scholar
  3. Brooks PC (1996) Cell-adhesion molecules in angiogenesis. Cancer Metastasis Rev 15:187–194PubMedCrossRefGoogle Scholar
  4. Brooks PC, Stromblad S, Klemke R, Visscher D, Sarkar FH, Cheresh DA (1995) Antiintegrin alpha-v-beta-3 blocks in human breast-cancer growth and angiogenesis in human skin. J Clin Invest 96:1815–1822PubMedCrossRefGoogle Scholar
  5. Brown PD, Giavazzi R (1995) Matrix metalloproteinase inhibition — a review of antitumor activity. Ann Oncol 6:967–974PubMedGoogle Scholar
  6. Bunn HF, Poyton RO (1996) Oxygen sensing and molecular adaptation to hypoxia. Physiol Rev 76:839–885PubMedGoogle Scholar
  7. Cao YH, Chen A, An SSA, Ji RWD, Davidson D, Cao YM, Llinas M (1997) Kringle-5 of plasminogen is a novel inhibitor of endothelial-cell growth. J Biol Chem 272:22924–22928PubMedCrossRefGoogle Scholar
  8. Carmeliet P, MacKman N, Moons L, Luther T, Gressens P, Vanvlaenderen I, Demunck H, Kasper M, Breier G, Evrard P, Muller M, Risau W, Edgington T, Collen D (1996) Role of tissue factor in embryonic blood-vessel development. Nature 383:73–75PubMedCrossRefGoogle Scholar
  9. Castellani P, Viale G, Dorcaratto A, Nicolo G, Kaczmarek J, Querze G, Zardi L (1994) The fibronectin isoform containing the ed-b oncofetal domain — a marker of angiogenesis. Int J Cancer 59:612–618PubMedCrossRefGoogle Scholar
  10. Chan HY, Harris AL (1996) Gene therapy targeting to tumor endothelium. In: Sobol RE, Scanlon KJ (eds) The internet book of gene therapy — cancer therapeutics. Appleton and Lange, Stamford, pp 211–227Google Scholar
  11. Claffey KP, Robinson GS (1996) Regulation of vegf/vpf expression in tumor-cells — consequences for tumor-growth and metastasis. Cancer Metastasis Rev 15:165–176PubMedCrossRefGoogle Scholar
  12. Clapp C, Delaescalera GM (1997) Prolactins — novel regulators of angiogenesis. News Physiol Sci 12:231–237Google Scholar
  13. Czubayko F, Liaudetcoopman EDE, Aigner A, Tuveson AT, Berchem GJ, Wellstein A (1997) A secreted FGF-binding protein can serve as the angiogenic switch in human cancer. Nat Med 3:1137–1140PubMedCrossRefGoogle Scholar
  14. Dach GU, Patterson AV, Firth JD, Ratcliffe PJ, Townsend KMS, Stratford IJ, Harris AL (1997) Targeting gene expression to hypoxic tumor cells. Nat Med 3:515–520CrossRefGoogle Scholar
  15. Damert A, Ikeda E, Risau W (1997) Activator-protein-1 binding potentiates the hypoxia-in-ducible factor-1-mediated hypoxia-induced transcriptional activation of vascular-en-dothelial growth-factor expression in c 6 glioma-cells. Biochem J 327:419–423PubMedGoogle Scholar
  16. Dirix LY, Vermeulen PB, Pawinski A, Prove A, Benoy I, Depooter C, Martin M, Vanoosterom AT (1997) Elevated levels of the angiogenic cytokines basic fibroblast growth-factor and vascular endothelial growth-factor in sera of cancer patients. Br J Cancer 76:238–243PubMedCrossRefGoogle Scholar
  17. Engels K, Fox SB, Whitehouse RM, Gatter KC, Harris AL (1997) Up-regulation of thymidine phosphorylase expression is associated with a discrete pattern of angiogenesis in ductal carcinomas in-situ of the breast. J Pathol 182:414–420PubMedCrossRefGoogle Scholar
  18. Folkman J (1990) What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82:4–6PubMedCrossRefGoogle Scholar
  19. Fox SB, Harris AL (1997) Markers of tumor angiogenesis — clinical applications in prognosis and anti-angiogenic therapy. Invest New Drugs 15:15–28PubMedCrossRefGoogle Scholar
  20. Fox SB, Leek RD, Weekes MP, Whitehouse RM, Gatter KC, Harris AL (1995) Quantitation and prognostic value of breast cancer angiogenesis: comparison of microvessel density, Chalkley count and computer image analysis. J Pathol 177:275–283PubMedCrossRefGoogle Scholar
  21. Fox SB, Engels K, Comley M, Whitehouse RM, Turley H, Gatter KC, Harris AL (1997 a) Relationship of elevated tumor thymidine phosphorylase in node-positive breast carcinomas to the effects of adjuvant CMF. Ann Oncol 8:271–275PubMedCrossRefGoogle Scholar
  22. Fox SB, Leek RD, Bliss J, Mansi JL, Gusterson B, Gatter KC, Harris AL (1997b) Association of tumor angiognesis with bone-marrow micrometastases in breast-cancer patients. J Natl Cancer Inst 89:1044–1049PubMedCrossRefGoogle Scholar
  23. Friedlander M, Brooks PC, Shaffer RW, Kincaid CM, Varner JA, Cheresh DA (1995) Definition of 2 angiogenic pathways by distinct alpha(v) integrins. Science 270:1500–1502PubMedCrossRefGoogle Scholar
  24. Gasparini G, Harris AL (1997) p53 and angiogenesis in neoplasia. In: Klijn JGM (ed) Prognostic and predictive value of p53. Elsevier, Rotterdam, pp 115–130Google Scholar
  25. Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumors. Nature 379:88–91PubMedCrossRefGoogle Scholar
  26. Griffiths L, Dachs G, Bicknell R, Harris AL, Stratford IJ (1997) The influence of oxygen tension and pH on the expression of platelet-derived endothelial cell growth factor/thymi-dine phosphorylase in human breast tumor cells grown in vitro and in vivo. Cancer Res 57:570–572PubMedGoogle Scholar
  27. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364PubMedCrossRefGoogle Scholar
  28. Hildenbrand R, Dilger I, Horlin A, Stutte HJ (1995) Urokinase plasminogen-activator induces angiogenesis and tumor vessel invasion in breast cancer. Pathol Res Pract 191:403–409PubMedCrossRefGoogle Scholar
  29. Holmgren L, O’Reilly MS, Folkman J (1995) Dormancy of micrometastases — balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1:149–153PubMedCrossRefGoogle Scholar
  30. Horak ER, Leek R, Klenk N (1992) Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastasis and survival in breast cancer. Lancet 340:1120–1124PubMedCrossRefGoogle Scholar
  31. Huang XM, Molema G, King S, Watkins L, Edgington TS, Thorpe PE (1997) Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Science 275:547–550PubMedCrossRefGoogle Scholar
  32. Iliopoulos O, Levy AP, Jiang C, Kaelin WG, Goldberg MA (1996) Negative regulation of hypoxia-inducible genes by the von-Hippel-Lindau protein. Proc Natl Acad Sci USA 93:10595–10599PubMedCrossRefGoogle Scholar
  33. Jagger RT, Chan HY, Harris AL (1997) Endothelial cell-specific expression of tumor necrosis factor-alpha from the KDR or E-selectin promotors following retroviral delivery. Hum Gen Ther 8:2239–2247CrossRefGoogle Scholar
  34. Jain RK, Koenig GC, Dellian M, Fukumura D, Munn LL, Melder RJ (1996) Leukocyte-en-dothelial adhesion and angiogenesis in tumors. Cancer Metastasis Rev 15:195–204PubMedCrossRefGoogle Scholar
  35. Kakeji Y, Teicher BA (1997) Preclinical studies of the combination of angiogenic inhibitors with cytotoxic agents. Invest New Drugs 15:39–48PubMedCrossRefGoogle Scholar
  36. Kevil CG, Debenedetti A, Payne DK, Coe LL, Laroux FS, Alexander JS (1996) Translational regulation of vascular-permeability factor by eukaryotic initiation-factor 4 e — implications for tumor angiogenesis. Int J Cancer 65:785–790PubMedCrossRefGoogle Scholar
  37. Konno H, Tanaka T, Kanai T, Maruyama K, Nakamura S, Baba S (1996) Efficacy of an angiogenesis inhibitor, tnp-470, in xenotransplanted human colorectal cancer with high metastatic potential. Cancer 77:1736–1740PubMedGoogle Scholar
  38. Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56:4625–4629PubMedGoogle Scholar
  39. Lindner DJ, Borden EC (1997) Effects of tamoxifen and interferon-beta or the combination on tumor-induced angiogenesis. Int J Cancer 71:456–461PubMedCrossRefGoogle Scholar
  40. Maltepe E, Schmidt JV, Baunoch D, Bradfield CA, Simon MC (1997) Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein arnt. Nature 386:403–407PubMedCrossRefGoogle Scholar
  41. Mariani G, Lasku A, Balza E, Gaggero B, Motta C, Diluca L, Dorcaratto A, Viale GA, Neri D, Zardi L (1997) Tumor targeting potential of the monoclonal-antibody bc-1 against oncofetal fibronectin in nude mice bearing human tumor implants. Cancer 80:2378–2384PubMedCrossRefGoogle Scholar
  42. Martin L, Green B, Renshaw C, Lowe D, Rudland P, Leinster SJ, Winstanley J (1997 a) Examining the technique of angiogenesis assessment in invasive brreast cancer. Br J Cancer 76:1046–1054PubMedCrossRefGoogle Scholar
  43. Martin L, Holcombe C, Green B, Leinster SJ, Winstanley J (1997b) Is a histological section representative of whole tumor vascularity in breast cancer? Br J Cancer 76:40–43PubMedCrossRefGoogle Scholar
  44. Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ, Hankinson O, Pugh CW, Ratcliffe PJ (1997) Hypoxia-inducible factor-I modulates gene expression in solid tumor and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA 94:8104–8109PubMedCrossRefGoogle Scholar
  45. Mazure NM, Chen EY, Yeh P, Laderoute KR, Giaccia AJ (1996) Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth-factor expression. Cancer Res 56:3436–3440PubMedGoogle Scholar
  46. McCulloch P, Choy A, Martin L (1995) Association between tumor angiogenesis and tumorcell shedding into effluent venous blood during breast cancer surgery. Lancet 346:1334–1335PubMedCrossRefGoogle Scholar
  47. Millauer B, Longhi MP, Plate KH, Shawver LK, Risau W, Ullrich A, Strawn LM (1996) Dominant-negative inhibition of flk-1 suppresses the growth of many tumor types in vivo. Cancer Res 56:1615–1620PubMedGoogle Scholar
  48. Min HY, Doyle LV, Vitt CR, Zandonella CL, Strattonthomas JR, Shuman MA, Rosenberg S (1996) Urokinase receptor antagonists inhibit angiogenesis and primary tumor growth in syngeneic mice. Cancer Res 56:2428–2433PubMedGoogle Scholar
  49. Moghaddam A, Zhang H-T, Fan T-PD, Hu D-E, Lees VC, Turley H, Fox SB, Gatter KC, Harris AL, Bicknell R (1995) Thymidine phosphorylase is angiogenic and promotes tumor growth. Proc Natl Acad Sci USA 92:998–1002PubMedCrossRefGoogle Scholar
  50. Montrucchio G, Lupia E, Demartino A, Battaglia E, Arese M, Tizzani A, Bussolino F, Camussi G (1997) Nitric oxide mediates angiogenesis induced in vivo by platelet-activating-factor and tumor-necrosis-factor-alpha. Am J Pathol 151:557–563PubMedGoogle Scholar
  51. Nathan CA, Carter P, Liu L, Li BD, Abreo F, Tudor A, Zimmer SG, Debenedetti A (1997) Elevated expression of eif4e and FGF-2 isoforms during vascularization of breast carcinomas. Oncogene 15:1087–1094PubMedCrossRefGoogle Scholar
  52. O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao YH, Sage EH, Folkman J (1994) Angiostatin — a novel angiogenesis inhibitior that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79:315–328PubMedCrossRefGoogle Scholar
  53. O’Reilly MS, Boehm T, Shing T, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277–285PubMedCrossRefGoogle Scholar
  54. Olofsson B, Pajusola K, Kaipainen A, Voneuler G, Joukov V, Saksela O, Orpana A, Petersson RF, Alitalo K, Eriksson U (1996) Vascular endothelial growth-factor-b, a novel growth factor for endothelial cells. Proc Natl Acad Sci USA 93:2576–2581PubMedCrossRefGoogle Scholar
  55. Petit AMV, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, Kerbel RS (1997) Neutralizing antibodies against epidermal growth-factor and erbb-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo — angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 151:1523–1530PubMedGoogle Scholar
  56. Pezzella F, Dibacco A, Andreola S, Nicholson AG, Pastorino U, Harris AL (1996) Angiogenesis in primary lung cancer and lung secondaries. Eur J Cancer 32 A:2494–2500CrossRefGoogle Scholar
  57. Pluda JM (1997) Tumor-associated angiogenesis — mechanisms, clinical implications, and therapeutic strategies. Semin Oncol 24:203–218PubMedGoogle Scholar
  58. Rak J, Kerbel RS (1996) Treating cancer by inhibiting angiogenesis — new hopes and potential pitfalls. Cancer Metastasis Rev 15:231–236PubMedCrossRefGoogle Scholar
  59. Relf M, Lejeune S, Scott PAE, Fox S, Smith K, Leek R, Moghaddam A, Whitehouse R, Bicknell R, Harris AL (1997) Expression of the angiogenic factors vascular endothelial-cell growth-factor, acidic and basic fibroblast growth-factor, tumor-growth factor-beta-1, platelet derived endothelial-cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 57:963–969PubMedGoogle Scholar
  60. Saleh M, Vasilopoulos K, Stylli SS, Kaye AH, Wilks AF (1996) The expression of antisense vascular endothelial growth-factor (vegf) sequences inhibits intracranial c6 glioma growth in vivo by suppressing tumor angiogenesis. J Clin Neurosci 3:366–372PubMedCrossRefGoogle Scholar
  61. Skobe M, Rockwell P, Goldstein N, Vosseler S, Fusenig NE (1997) Halting angiogenesis suppresses carcinoma cell invasion. Nat Med 3:1222–1227PubMedCrossRefGoogle Scholar
  62. Strawn LM, McMahon G, App H, Schreck R, Kuchler WR, Longhi MP, Hui TH, Tang C, Levitzki A, Gazit A, Chen I, Keri G, Orfi L, Risau W, Flamme I, Ullrich A, Hirth KP, Shawver LK (1996) Flk-1 as a target for tumor-growth inhibition. Cancer Res 56:3540–3545PubMedGoogle Scholar
  63. Taraboletti G, Belotti D, Borsotti P, Vergani V, Rusnati M, Presta M, Giavazzi R (1997) The 140-kilodalton antiangiogenic fragment of thrombospondin-1 binds to basic fibroblast growth factor. Cell Growth Differ 8:471–479PubMedGoogle Scholar
  64. Teicher BA (1995) Angiogenesis and cancer metastases — therapeutic approaches. Crit Rev Oncol Hematol 20:9–39PubMedCrossRefGoogle Scholar
  65. Toi M, Kondo S, Suzuki H, Yamamoto Y, Inada K, Imazawa T, Taniguchi T, Tominaga T (1996) Quantitative analysis of vascular endothelial growth factor in primary breast cancer. Cancer 77:1101–1106PubMedCrossRefGoogle Scholar
  66. Vermeiden PB, Gasparini G, Fox SB, Toi M, Martin L, McCulloch P, Pezella F, Viale G, Weidner N, Harris AL, Dirix LY (1996) Qunatification of angiogenesis in solid human tumors — an international consensus on the methodology and criteria of evaluation. Eur J Cancer 32A:2474–2484Google Scholar
  67. Waltenberger J, Mayr U, Frank H, Hombach V (1996) Suramin is a potent inhibitor of vascular endothelial growth-factor — a contribution to the molecular basis of its antiangiogenic action. J Mol Cell Cardiol 28:1523–1529PubMedCrossRefGoogle Scholar
  68. Wamil BD, Thurman GB, Sundell HW, Devore RF, Wakefield G, Johnson DH, Wang YF, Helleqvist CG (1997) Soluble e-selection in cancer patients as a marker of the therapeutic efficacy of cm 101, a tumor-inhibiting anti-neovascularization agent, evaluated in phase I clinical trial. J Cancer Res Clin Oncol 123:173–179PubMedCrossRefGoogle Scholar
  69. Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, Meli S, Gasparini G (1992) Tumor angiogenesis. A new significant and independent prognostic indictor in early-stage breast carcinoma. J Natl Cancer Inst 84:1875–1887PubMedCrossRefGoogle Scholar
  70. Wenger RH, Gassmann M (1997) Oxygen(es) and the hypoxia-inducible factor-i. Biol Chem 378:609–616PubMedGoogle Scholar
  71. White FC, Carroll SM, Kamps MP (1995) Vegf messenger-RNA is reversibly stabilized by hypoxia and persistently stabilized in vegf-overexpressing human tumor-cell lines. Growth Factors 12:289–301PubMedCrossRefGoogle Scholar
  72. Wilson WR, Pruijn FB (1995) Hypoxia-activated prodrugs as antitumor agents — strategies for maximizing tumor-cell killing. Clin Exp Pharmacol Physiol 22:881–885PubMedCrossRefGoogle Scholar
  73. Wong AL, Haroon ZA, Werner S, Dewhirst MW, Greenberg CS, Peters KG (1997) Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues. Circ Res 81:567–574PubMedGoogle Scholar
  74. Yue TL, Wang XK, Louden CS, Gupta S, Pillarisetti K, Gu JL, Hart TK, Lysko PG, Feuerstein GZ (1997) 2-methoxyestradiol, an endogenous estrogen metabolite, induces apoptosis in endothelial cells and inhibits angiogenesis — possible role for stress-activated protein-kinase signaling pathway and fas expression. Mol Pharmacol 51:951–962PubMedGoogle Scholar
  75. Zabel DD, Feng JJ, Scheuenstuhl H, Hunt TK, Hussain MZ (1996) Lactate stimulation of macrophage-derived angiogenic acitivity is associated with inhibition of poly(adp-ribose) synthesis. Lab Invest 74:644–649PubMedGoogle Scholar
  76. Zhang H-T, Craft P, Scott PAE, Ziche M, Weich HA, Harris AL, Bicknell R (1995) Enhancement of tumor growth and vascular density by transfection of vascular endothelial cell growth factor into MCF-7 human breast carcinoma cells. J Natl Cancer Inst 87:213–219PubMedCrossRefGoogle Scholar
  77. Zhang N, Zhong R, Wang ZY, Deuel TF (1997) Human breast-cancer growth inhibited in vivo by a dominant-negative pleiotrophin mutant. J Biol Chem 272:16733–16736PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin · Heidelberg 1998

Authors and Affiliations

  • A. L. Harris
    • 1
  1. 1.ICRF Molecular Oncology LaboratoryJohn Radcliffe HospitalOxfordUK

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