International Journal of Hematology

, Volume 75, Issue 3, pp 246–256 | Cite as

Angiogenesis in Hematologic Malignancies and Its Clinical Implications

  • Renchi Yang
  • Zhong Chao Han
Review Article


Angiogenesis is defined as a neoformation of blood vessels of capillary origin. Hematopoiesis is closely linked with angiogenesis, for they share a common ancestor, the hemangioblast. Although it is well established that growth in solid tumors is dependent on angiogenesis, its role in hematologic malignancies has not yet been clarified. In this review, the direct evidence, ie, increased microvessel density, and the indirect evidence, ie, elevated level of angiogenic factors or overexpression of messenger RNA or protein of angiogenic factors, for and against the role of angiogenesis in the development and progression of hematologic malignancies are presented.

Key words

Angiogenesis Hematopoiesis Prognosis Angiogenic factor Treatment 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Risau W. Mechanisms of angiogenesis.Nature. 1997;386:671–674.PubMedCrossRefGoogle Scholar
  2. 2.
    Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation.Nature. 2000;407:242–248.PubMedCrossRefGoogle Scholar
  3. 3.
    Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases.Nature. 2000;407:249–257.PubMedCrossRefGoogle Scholar
  4. 4.
    Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.Cell. 1996;86:353–364.PubMedCrossRefGoogle Scholar
  5. 5.
    Han ZC, Liu Y. Angiogenesis: state of the art.Int J Hematol. 1999;70:68–82.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Browder T, Folkman J, Pirie-Shepherd S. The hemostatic system as a regulator of angiogenesis.J Biol Chem. 2000;275:1521–1524.PubMedCrossRefGoogle Scholar
  7. 7.
    Gastl G, Hermann T, Steurer M, et al. Angiogenesis as a target for tumor treatment.Oncology. 1997;54:177–184.PubMedCrossRefGoogle Scholar
  8. 8.
    Folkman J. Clinical applications of research on angiogenesis.N Engl J Med. 1995;333:1757–1763.PubMedCrossRefGoogle Scholar
  9. 9.
    Bussolino F, Di Renzo MF, Ziche M, et al. Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth.J Cell Biol. 1992;119:629–641.PubMedCrossRefGoogle Scholar
  10. 10.
    Grant DS, Kleinman HK, Goldberg ID, et al. Scatter factor induces blood vessel formation in vivo.Proc Natl Acad Sci U S A. 1993;90:1937–1941.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen.Science. 1989;246:1306–1309.PubMedCrossRefGoogle Scholar
  12. 12.
    Olofsson B, Korpelainen E, Pepper MS, et al. Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells.Proc Natl Acad Sci U S A. 1998;95:11709–11714.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Cao Y, Linden P, Farnebo J, et al. Vascular endothelial growth factor C induces angiogenesis in vivo.Proc Natl Acad Sci U S A. 1998;95:14389–14394.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Achen MG, Jeltsch M, Kukk E, et al. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4).Proc Natl Acad Sci U S A. 1998;95:548–553.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Cameliet P. Mechanisms of angiogenesis and arteriogenesis.Nat Med. 2000;6:389–395.CrossRefGoogle Scholar
  16. 16.
    Nelson NJ. Inhibitors of angiogenesis enter phase III testing.J Natl Cancer Inst. 1998;90:960–963.PubMedCrossRefGoogle Scholar
  17. 17.
    Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis.Science. 1997;275:964–967.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G. A common precursor for hematopoietic and endothelial cells.Development. 1998;125:725–732.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Choi K. Hemangioblast development and regulation.Biochem Cell Biol. 1998;76:947–956.PubMedCrossRefGoogle Scholar
  20. 20.
    Asahara T, Masuda H, Takahashi T, et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogene-sis in physiological and pathological neovascularization.Circ Res. 1999;85:221–228.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Asahara T, Takahashi T, Masuda H, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells.EMBO J. 1999;18:3964–3972.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Peichev M, Naiyer AJ, Pereira D, et al. Expression of VEGF-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors.Blood. 2000;95:952–958.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Lin Y, Weisdorf DJ, Solovey A, Hebbel RP. Origins of circulating endothelial cells outgrowth from blood.J Clin Invest. 2000;105:71–77.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Shi Q, Rafii S, Wu MH, et al. Evidence for circulating bone marrow-derived endothelial cells.Blood. 1998;92:362–367.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Schuh AC, Faloon P, Hu QL, Bhimani M, Choi K. In vitro hemato-poietic and endothelial potential of flk-1 (-/-) embryonic stem cells and embryos.Proc Natl Acad Sci U S A. 1999;96:2159–2164.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Fina L, Molgaard HV, Robertson D, et al. Expression of the CD34 gene in vascular endothelial cells.Blood. 1990;75:2417–2426.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Ziegler BL, Valtieri M, Almeida Porada G, et al. KDR receptor: a key marker defining hematopoietic stem cells.Science. 1999;285:1553–1558.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Ito A, Nomura S, Hirota S, Suda J, Suda T, Kitamura Y. Enhanced expression of CD34 messenger RNA by developing endothelial cells of mice.Lab Invest. 1995;72:532–538.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Young PE, Baumhueter S, Lasky LA. The sialomucin CD34 is expressed on hematopoietic cells and blood vessels during murine development.Blood. 1995;85:96–105.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Shalaby F, Rossant J, Yamaguchi TP, et al. Failure of blood island formation and vasculogenesis in FLK-1 deficient mice.Nature. 1995;376:62–66.PubMedCrossRefGoogle Scholar
  31. 31.
    Shalaby F, Ho J, Stanford WL, et al. A requirement for Flk-1 in primitive and definitive hematopoiesis and vasculogenesis.Cell. 1997;89:981–990.PubMedCrossRefGoogle Scholar
  32. 32.
    Fong GH, Rossant J, Gertsenstein M, Brietman ML. Role of the FLT-1 receptor kinase in regulating the assembly of vascular endothelium.Nature. 1995;376:66–70.PubMedCrossRefGoogle Scholar
  33. 33.
    Sato TN, Tozawa Y, Deutsch U, et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation.Nature. 1995;376:70–74.PubMedCrossRefGoogle Scholar
  34. 34.
    Rafii S, Mohle R, Shapiro F, Frey BM, Moore MAS. Regulation of hematopoiesis by microvascular endothelium.Leuk Lymphoma. 1997;27:375–386.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Imai K, Kobayashi M, Wang J, et al. Selective transendothelial migration of hematopoietic progenitor cells: a role in homing of progenitor cells.Blood. 1999;93:149–156.PubMedGoogle Scholar
  36. 36.
    Solanilla A, Grosset C, Lemercier C, et al. Expression of Flt-ligand by the endothelial cell.Leukemia. 2000;14:153–162.PubMedCrossRefGoogle Scholar
  37. 37.
    Bikfalvi A, Han ZC. Angiogenic factors are hematopoietic growth factors and vice versa.Leukemia. 1994;8:523–529.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Ribatti D, Presta M, Vacca A, et al. Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo.Blood. 1999;93:2627–2636.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Tordjman R, Delaire S, Plouet J, et al. Erythroblasts are a source of angiogenic factors.Blood. 2001;97:1968–1974.PubMedCrossRefGoogle Scholar
  40. 40.
    Pelletier L, Regnard J, Fellmann D, Charbord P. An in vitro model for the study of human bone marrow angiogenesis: role of hemato-poietic cytokines.Lab Invest. 2000;80:501–511.PubMedCrossRefGoogle Scholar
  41. 41.
    Broxmeyer HE, Cooper S, Li ZH, et al. Myeloid progenitor cell regulatory effects of vascular endothelial cell growth factor.Int J Hematol. 1995;62:203–215.PubMedCrossRefGoogle Scholar
  42. 42.
    Bautz F, Rafii S, Kanz L, Möhle R. Expression and secretion of vascular endothelial growth factor-A by cytokine-stimulated hemato-poietic progenitor cells: Possible role in the hematopoietic microenvironment.Exp Hematol. 2000;28:700–706.PubMedCrossRefGoogle Scholar
  43. 43.
    Takakura N, Watanabe T, Suenobu S, et al. A role for hematopoietic stem cells in promoting angiogenesis.Cell. 2000;102:199–209.PubMedCrossRefGoogle Scholar
  44. 44.
    Hamada K, Oike Y, Takakura N, et al. VEGF-C signaling pathways through VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis.Blood. 2000;96:3793–3800.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Zhang W, Stoica G, Tasca SI, Kelly KA, Meininger CJ. Modulation of tumor angiogenesis by stem cell factor.Cancer Res. 2000;60:6757–6762.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Brizzi MF, Battaglia E, Montrucchio G, et al. Thrombopoietin stimulates endothelial cell motility and neoangiogenesis by a platelet-activating factor-dependent mechanism.Circ Res. 1999;84:785–796.PubMedCrossRefGoogle Scholar
  47. 47.
    Crisa L, Cirulli V, Smith KA, Ellisman MH, Torbett BE, Salomon DR. Human cord blood progenitors sustain thymic T-cell development and a novel form of angiogenesis.Blood. 2000;94:3928–3940.Google Scholar
  48. 48.
    Katoh O, Tauchi H, Kawaishi K, Kimura A, Satow Y. Expression of the vascular endothelial growth factor (VEGF) receptor gene, KDR, in hematopoietic cells and inhibitory effect of VEGF on apoptotic cell death caused by ionizing radiation.Cancer Res. 1995;55:5687–5692.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Ratajczak MZ, Ratajczak J, Machalinski B, et al. Role of vascular endothelial growth factor (VEGF) and placenta-derived growth factor (PIGF) in regulating human haemopoietic cell growth.Br J Haematol. 1998;103:969–979.PubMedCrossRefGoogle Scholar
  50. 50.
    Hattori K, Dias S, Heissig B, et al. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells.J Exp Med. 2001;193:1005–1014.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Wartiovaara U, Salven P, Mikkola H, et al. Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation.Thromb Haemost. 1998;80:171–175.PubMedCrossRefGoogle Scholar
  52. 52.
    Mohle R, Green D, Moore MAS, Nachman RL, Rafii S. Constitutive production and thrombin-induced release of vascular endothe-lial growth factor by human megakaryocytes and platelets.Proc Natl Acad Sci U S A. 1997;94:663–668.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Villars F, Bordenave L, Bareille R, Amedee J. Effect of human endothelial cells on human bone marrow stromal cell phenotype: role of VEGF?J Cell Biochem. 2000;79:672–685.PubMedCrossRefGoogle Scholar
  54. 54.
    Ikehara S. Role of hepatocyte growth factor in hemopoiesis.Leuk Lymphoma. 1996;23:297–303.PubMedCrossRefGoogle Scholar
  55. 55.
    Nishino T, Hisha H, Nishino N, Adachi M, Ikehara S. Hepatocyte growth factor as a hematopoietic regulator.Blood. 1995;85:3093–3100.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Takai K, Hara J, Matsumoto K, et al. Hepatocyte growth factor is constitutively produced by human bone marrow stromal cells and indirectly promotes hematopoiesis.Blood. 1997;89:1560–1565.PubMedPubMedCentralGoogle Scholar
  57. 57.
    DeCarvalho S. In vitro angiogenic activity of RNA from leukemic lymphocytes.Angiology. 1978;29:497–505.PubMedCrossRefGoogle Scholar
  58. 58.
    Nguyen M, Watanabe H, Budson AE, Richie JP, Hayes DF, Folk-man J. Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers.J Natl Cancer Inst. 1994;86:356–361.PubMedCrossRefGoogle Scholar
  59. 59.
    Perez-Atayde AR, Sallan SE, Tedrow U, Connors S, Allred E, Folkman J. Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia.Am J Pathol. 1997;150:815–821.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Schneider P, Jerome MV, Soria PC, Vannier JP. The role of angio-genesis in leukemia proliferation.Am J Pathol. 1999;155:1007–1009.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Vacca A, Ribatti D, Iurlaro M, et al. Human lymphoblastoid cells produce extracellular matrix-degrading enzymes and induce endothelial cell proliferation, migration, morphogenesis, and angiogenesis.Int J Clin Lab Res. 1998;28:55–68.PubMedCrossRefGoogle Scholar
  62. 62.
    Bellamy WT, Richter L, Frutiger Y, Grogan TM. Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies.Cancer Res. 1999;59:728–733.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Fiedler W, Graeven U, Ergun S, et al. Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia.Blood. 1997;89:1870–1875.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Fiedler W, Graeven U, Ergun S, et al. Expression of FLT4 and its ligand VEGF-C in acute myeloid leukemia.Leukemia. 1997;11:1234–1237.CrossRefGoogle Scholar
  65. 65.
    Hayashibara T, Fujimoto T, Miyanishi T, et al. Vascular endothelial growth factor at high plasma levels is associated with extranodal involvement in adult T cell leukemia patients.Leukemia. 1999;13:1634–1635.PubMedCrossRefGoogle Scholar
  66. 66.
    Aguayo A, Estev E, Kantarjian H, et al. Cellular vascular endothe-lial growth factor is a predictor of outcome in patients with acute myeloid leukemia.Blood. 1999;94:3717–3721.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Hussong JW, Rodgers GM, Shami PJ. Evidence of increased angio-genesis in patients with acute myeloid leukemia.Blood. 2000;95:309–313.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Padro T, Ruiz S, Bieker R, et al. Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia.Blood. 2000;95:2637–2644.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Aguayo A, Kantarjian H, Manshouri T, et al. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes.Blood. 2000;96:2240–2245.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Dias S, Hattori K, Zhu Z, et al. Autocrine stimulation of VEGF-2 activates human leukemic cell growth and migration.J Clin Invest. 2000;106:511–521.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Fusetti L, Pruneri G, Gobbi A, et al. Human myeloid and lymphoid malignancies in the non-obese diabetic/severe combined immunodeficiency mouse model: frequency of apoptotic cells in solid tumors and efficiency and speed of engraftment correlate with vascular endothelial growth factor production.Cancer Res. 2000;60:2527–2534.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Foss B, Mentzoni L, Bruserud O. Effects of vascular endothelial growth factor on acute myelogenous leukemia blasts.J Hematother Stem Cell Res. 2001;10:81–93.PubMedCrossRefGoogle Scholar
  73. 73.
    Molica S, Vitelli G, Levato D, Gandolfo GM, Liso V. Increased serum levels of vascular endothelial growth factor predict risk of progression in early B-cell chronic lymphocytic leukaemia.Br J Haematol. 1999;107:605–610.PubMedCrossRefGoogle Scholar
  74. 74.
    Chen H, Treweeke AT, West DC, et al. In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells.Blood. 2000;96:3181–3187.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Kini AR, Kay NE, Peterson LC. Increased bone marrow angiogen-esis in B cell chronic lymphocytic leukemia.Leukemia. 2000;14:1414–1418.PubMedCrossRefGoogle Scholar
  76. 76.
    Aguayo A, O’Brien S, Keating M, et al. Clinical relevance of intra-cellular vascular endothelial growth factor levels in B-cell chronic lymphocytic leukemia.Blood. 2000;96:768–770.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Ferrajoli A, Manshouri T, Estrov Z, et al. High levels of vascular endothelial growth factor receptor-2 correlate with shortened survival in chronic lymphocytic leukemia.Clin Cancer Res. 2001;7:795–799.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Aguayo A, Manshouri T, O’Brien S, et al. Clinical relevance of Flt1 and Tie1 angiogenesis receptors expression in B-cell chronic lym-phocytic leukemia (CLL).Leuk Res. 2001;25:279–285.PubMedCrossRefGoogle Scholar
  79. 79.
    Krejci P, Dvorak D, Krahulcova E, et al. FGF-2 abnormalities in B cell chronic lymphocytic and chronic myeloid leukemias.Leukemia. 2001;15:228–237.PubMedCrossRefGoogle Scholar
  80. 80.
    Nakamura S, Gohda E, Matsuo Y, Yamamoto I, Minowada J. Significant amount of hepatocyte growth factor detected in blood and bone marrow plasma of leukemia patients.Br J Haematol. 1994;87:640–642.PubMedCrossRefGoogle Scholar
  81. 81.
    Hino M, Inaba M, Goto H, et al. Hepatocyte growth factor levels in bone marrow plasma of patients with leukaemia and its gene expression in leukaemic blast cells.Br J Cancer. 1996;73:119–123.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Hjorth-Hansen H, Seidel C, Lamvik J, Borset M, Sundan A, Waage A. Elevated serum concentrations of hepatocyte growth factor in acute myelocytic leukemia.Eur J Haematol. 1999;62:129–134.PubMedCrossRefGoogle Scholar
  83. 83.
    Pons E, Uphoff CC, Drexler HG. Expression of hepatocyte growth factor and its receptor c-met in human leukemia-lymphoma cell lines.Leuk Res. 1998;22:797–804.PubMedCrossRefGoogle Scholar
  84. 84.
    Weimar IS, Voermans C, Bourhis JH, et al. Hepatocyte growth factor/scatter factor (HGF/SF) affects proliferation and migration of myeloid leukemic cells.Leukemia. 1998;12:1195–1203.PubMedCrossRefGoogle Scholar
  85. 85.
    Jucker M, Gunther A, Gradl G, et al. The Met/hepatocyte growth factor receptor (HGFR) gene is overexpressed in some cases of human leukemia and lymphoma.Leuk Res. 1994;18:7–16.PubMedCrossRefGoogle Scholar
  86. 86.
    Katoh O, Takahashi T, Oguri T, Kuramoto K, Watanabe H. Vascular endothelial growth factor inhibits apoptotic death in hemato-poietic cells after exposure to chemotherapeutic drugs by inducing MCL1 acting as an antiapoptotic factor.Cancer Res. 1998;58:5565–5569.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Massova I, Khotra LP, Fridman R, Mahashery S. Matrix metallo-proteinases: structures, evolution, and diversification.FASEB J. 1998;12:1075–1095.PubMedCrossRefGoogle Scholar
  88. 88.
    Morgunova E, Tuuttila A, Bergmann U, et al. Structure of human pro-matrix metalloproteinase-2: activation mechanism revealed.Science. 1999;284:1667–1670.PubMedCrossRefGoogle Scholar
  89. 89.
    Stetler-Stevenson WG, Hewitt R, Corcoran M. Matrix metallopro-teinases and tumor invasion: from correlation and causality to the clinic.Semin Cancer Biol. 1996;7:47–154.CrossRefGoogle Scholar
  90. 90.
    Janowska-Wieczorek A, Marquez LA, Matsuzaki A, et al. Expression of matrix metalloproteinases (MMP-2 and MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1 and -2) in acute myel-ogenous leukemia blasts: comparison with normal bone marrow cells.Br J Haematol. 1999;105:402–411.PubMedCrossRefGoogle Scholar
  91. 91.
    Lundberg LG, Lerner R, Sundelin P, Rogers R, Folman J, Palmblad J. Bone marrow in polycythemia vera, chronic myelocytic leukemia and myelofibrosis has an increased vascularity.Am J Pathol. 2000;157:15–19.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Mesa RA, Hanson CA, Rajkumar SV, Schroeder G, Tefferi A. Evaluation and clinical correlations of bone marrow angiogenesis in myelofibrosis with myeloid metaplasia.Blood. 2000;96:3374–3380.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Yoon SY, Teffer A, Li CY. Bone marrow stromal cell distribution of basic fibroblast growth factor in chronic myeloid disorders.Haema-tologica. 2001;86:52–57.Google Scholar
  94. 94.
    Pruneri G, Bertolini F, Soligo D, et al. Angiogenesis in myelodys-plastic syndromes.Br J Cancer. 1999;81:1398–1401.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Bellamy WT, Richter L, Sirjani D, et al. Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes.Blood. 2001;97:1427–1434.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Gunsilius E, Duba HC, Petzer AL, et al. Evidence from a leukemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells.Lancet. 2000;355:1688–1691.PubMedCrossRefGoogle Scholar
  97. 97.
    Ribatti D, Vacca A, Nico B, et al. Bone marrow angiogenesis and mast cell density increase simultaneously with progression of human multiple myeloma.Br J Cancer. 1999;79:451–455.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Vacca A, Ribatti D, Roncall L, et al. Bone marrow angiogenesis and progression in multiple myeloma.Br J Haematol. 1994;87:503–508.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Vacca A, Ribatti D, Roncall L, Dammacco F. Angiogenesis in B cell lymphoproliferative diseases. Biological and clinical studies.Leuk Lymphoma. 1995;20:27–38.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Rajkumar SV, Fonseca R, Witzig TE, Gertz MA, Greipp PR. Bone marrow angiogenesis in patients achieving complete response after stem cell transplantation for multiple myeloma.Leukemia. 1999;13:469–472.PubMedCrossRefGoogle Scholar
  101. 101.
    Laroche M, Brousset P, Ludot I, et al. Increased vascularization in myeloma.Eur J Haematol. 2001;66:89–93.PubMedCrossRefGoogle Scholar
  102. 102.
    Rajkumar SV, Leong T, Roche PC, et al. Prognostic value of bone marrow angiogenesis in multiple myeloma.Clin Cancer Res. 2000;6:3111–3116.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Sezer O, Niemoller K, Eucker J, et al. Bone marrow microvessel density is a prognostic factor for survival in patients with multiple myeloma.Ann Hematol. 2000;79:574–577.PubMedCrossRefGoogle Scholar
  104. 104.
    Ahn MJ, Park CK, Choi JH, et al. Clinical significance of microves-sel density in multiple myeloma patients.J Korean Med Sci. 2001;16:45–50.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Schreiber S, Ackermann J, Obermair A, et al. Multiple myeloma with deletion of chromosome 13q is characterized by increased bone marrow neovascularization.Br J Haematol. 2000;110:605–609.PubMedCrossRefGoogle Scholar
  106. 106.
    Vacca A, Di Loreto M, Ribatti D, et al. Bone marrow of patients with active multiple myeloma: angiogenesis and plasma cell adhesion molecules LFA-1, VLA-4, LAM-1, and CD44.Am J Hematol. 1995;50:9–14.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Sezer O, Jakob C, Eucker J, et al. Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothe-lial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma.Eur J Haematol. 2001;66:83–88.PubMedCrossRefGoogle Scholar
  108. 108.
    Di Raimondo F, Azzaro MP, Palumbo GA, et al. Angiogenic factors in multiple myeloma: higher levels in bone marrow than in peripheral blood.Haematologica. 2000;85:800–805.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Seidel C, Borset M, Hjertner O, et al. High level of soluble synde-can-1 in myeloma-derived bone marrow: modulation of hepatocyte growth factor activity.Blood. 2000;96:3139–3146.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Dankbar B, Padro T, Leo R, et al. Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma.Blood. 2000;95:2630–2636.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Seidel C, Borset M, Turesson I, Abildgaard N, Sundan A, Waage A for the Nordic Myeloma Study Group. Elevated serum concentrations of hepatocyte growth factor in patients with multiple myeloma.Blood. 1998;91:806–812.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Borset M, Hjorth-Hansen H, Seidel C, Sundan A, Waage A. Hepa-tocyte growth factor and its receptor c-Met in multiple myeloma.Blood. 1996;88:3998–4004.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Borset M, Seidel C, Hjorth-Hansen H, Waage A, Sundan A. The role of hepatocyte growth factor and its receptor c-met in multiple myeloma and other blood malignancies.Leuk Lymphoma. 1999;32:249–256.PubMedCrossRefGoogle Scholar
  114. 114.
    Vacca A, Ribatti D, Presta M, et al. Bone marrow neovasculariza-tion, plasma cell angiogenic potential, and matrix metallopro-teinase-2 secretion parallel progression of human multiple myeloma.Blood. 1999;93:3064–3073.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Yaccoby S, Barlogie B, Epstein J. Primary myeloma cells growing in SCID-hu mice: a model for studying the biology and treatment of myeloma and its manifestations.Blood. 1998;92:2908–2913.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Dominici M, Campioni D, Lanza F, et al. Angiogenesis in multiple myeloma: correlation between in vitro endothelial colonies growth (CFU-En) and clinical-biological features.Leukemia. 2001;15:171–176.PubMedCrossRefGoogle Scholar
  117. 117.
    Foss HD, Araujo I, Demel G, Klotzbach H, Hummel M, Stein H. Expression of vascular endothelial growth factor in lymphomas and Castleman’s disease.J Pathol. 1997;183:44–50.PubMedCrossRefGoogle Scholar
  118. 118.
    Salven P, Teerenhovi L, Joensuu H. A high pretreatment serum vascular endothelial growth factor concentration is associated with poor outcome in non-Hodgkin’s lymphoma.Blood. 1997;90:3167–3172.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Salven P, Teerenhovi L, Joensuu H. A high pretreatment serum basic fibroblast growth factor concentration is an independent predictor of poor prognosis in non-Hodgkin’s lymphoma.Blood. 1999;94:3334–3339.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Salven P, Orpana A, Teerenhovi L, Joensuu H. Simultaneous elevation in the serum concentrations of the angiogenic growth factors VEGF and bFGF is an independent predictor of poor prognosis in non-Hodgkin lymphoma: a single-institution study of 200 patients.Blood. 2000;96:3712–3718.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Bertolini F, Paolucci M, Peccatori F, et al. Angiogenic growth factors and endostatin in non-Hodgkin’s lymphoma.Br J Haematol. 1999;106:504–509.PubMedCrossRefGoogle Scholar
  122. 122.
    Ribatti D, Vacca RD, Nico B, Fanelli M, Roncali L, Dammacco F. Angiogenesis spectrum in the stroma of B-cell non-Hodgkin’s lymphomas. An immunohistochemical and ultrastructural study.Eur J Haematol. 1996;56:45–53.PubMedCrossRefGoogle Scholar
  123. 123.
    Weimar IS, de Jong D, Muller EJ, et al. Hepatocyte growth factor/ scatter factor promotes adhesion of lymphoma cells to extracellular matrix molecules via α4β1 and α5β1 integrins.Blood. 1997;89:990–1000.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Teofili L, Di Febo AL, Pierconti F, et al. Expression of the c-met proto-oncogene and its ligand, hepatocyte growth factor, in Hodg-kin disease.Blood. 2001;97:1063–1069.PubMedCrossRefGoogle Scholar
  125. 125.
    Schaerer L, Schmid MH, Mueller B, Dummer RG, Burg G, Kempf W. Angiogenesis in cutaneous lymphoproliferative disorders: microvessel density discriminates between cutaneous B-cell lymphomas and B-cell pseudolymphomas.Am J Dermatopathol. 2000;22:140–143.PubMedCrossRefGoogle Scholar
  126. 126.
    Ribatti D, Vacca A, Marzullo A, et al. Angiogenesis and mast cell density with tryptase activity increase simultaneously with pathological progression in B-cell non-Hodgkin’s lymphomas.Int J Cancer. 2000;85:171–175.PubMedCrossRefGoogle Scholar
  127. 127.
    Vacca A, Ribatti D, Ruco L, et al. Angiogenesis extent and macrophage density increase simultaneously with pathological progression in B-cell non-Hodgkin’s lymphomas.Br J Cancer. 1999;79:965–970.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Bairey O, Zimra Y, Kaganovsky E, Shaklai M, Okon E, Rabizadeh E. Microvessel density in chemosensitive and chemoresistant diffuse large B-cell lymphomas.Med Oncol. 2000;17:314–318.PubMedCrossRefGoogle Scholar
  129. 129.
    Vacca A, Morretti S, Ribatti D, et al. Progression of mycosis fun-goides is associated with changes in angiogenesis and expression of matrix metalloproteinases 2 and 9.Eur J Cancer. 1997;33:1685–1692.PubMedCrossRefGoogle Scholar
  130. 130.
    Croix BS, Rago C, Victor V, et al. Genes expressed in human tumor endothelium.Science. 2000;289:1197–1202.CrossRefGoogle Scholar
  131. 131.
    Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma.N Engl J Med. 1999;341:1565–1571.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Neben K, Hawighorst H, Moehler TM, et al. Clinical response to thalidomide monotherapy correlates with improvement in dynamic magnetic resonance (d-MRI) angiogenesis parameters [abstract].Blood. 1999;94:124a.Google Scholar
  133. 133.
    Juliusson G, Celsing F, Turesson I, Adriansson M, Malm C. Thalidomide frequently induces good partial remission and best response ever in patients with advanced myeloma and prior high dose mel-phalan and autotransplant [abstract].Blood. 1999;94:124a.Google Scholar
  134. 134.
    Raza S, Veksler Y, Sabir T, Li Z, Anderson L, Jagannath S. Durable response to thalidomide in relapse/refractory multiple myeloma (MM)[abstract].Blood. 2000;96:168a.Google Scholar
  135. 135.
    Moehler TM, Neben K, Hawighorst H, et al. Thalidomide plus CED chemotherapy as salvage therapy in poor prognosis multiple myeloma [abstract].Blood. 2000;96:290b.Google Scholar
  136. 136.
    Durie BGM, Stepan DE. Efficacy of low dose thalidomide (T) in multiple myeloma [abstract].Blood. 1999;94:316a.Google Scholar
  137. 137.
    Rajkumar SV, Fonseca R, Dispenzieri A, et al. Thalidomide in the treatment of relapsed and refractory myeloma.Mayo Clin Proc. 2000;75:897–901.PubMedCrossRefGoogle Scholar
  138. 138.
    Schiller G, Vescio R, Berenson J. Thalidomide for the treatment of multiple myeloma relapsing after autologous peripheral blood progenitor cell transplant [abstract].Blood. 1999;94:317a.Google Scholar
  139. 139.
    Desikan R, Munshi N, Zeldis J, et al. Activity of thalidomide (THAL) in multiple myeloma (MM) confirmed in 180 patients with advanced disease [abstract].Blood. 1999;94:603a.Google Scholar
  140. 140.
    Weber DM, Gavino M, Delasalle K, Rankin K, Giralt S, Alexanian R. Thalidomide alone or with dexamethasone for multiple myeloma [abstract].Blood. 1999;94:604a.Google Scholar
  141. 141.
    Chen CI, Adesanya A, Sutton DM, Brandwein J, Stewart AK. Low-dose thalidomide in patients with advanced refractory multiple myeloma [abstract].Blood. 1999;94:308b.Google Scholar
  142. 142.
    Wu K, Schaafsma MR, Smit WM, Neef C, Richel DJ. Thalidomide as anti-angiogenesis treatment in patients with chemotherapy resistant multiple myeloma (MM) [abstract].Blood. 1999;94:316b.Google Scholar
  143. 143.
    Kneller A, Raanani P, Hardan I, et al. Therapy with thalidomide in refractory multiple myeloma patients-the revival of an old drug.Br J Haematol. 2000;108:391–393.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Coleman M, Gelfand RM, Leonard JP. Combination non-myelo-suppressive therapy (thalidomide, clarithromycin, dexamethasone) for plasma cell myeloma: a preliminary report [abstract].Blood. 1999;94:308b.Google Scholar
  145. 145.
    Srkalovic G, Karam MA, Mclain DA, Hussein MA. Melphalan, thalidomide and decadron (MTD) for refractory/relapsed multiple myeloma (MM) [abstract].Blood. 1999;94:314b.Google Scholar
  146. 146.
    Zomas A, Anagnostopoulos N, Dimopoulos MA. Successful treatment of multiple myeloma relapsing after high-dose therapy and autologous transplantation with thalidomide as a single agent.Bone Marrow Transplant. 2000;25:1319–1320.PubMedCrossRefGoogle Scholar
  147. 147.
    Weber DM, Rankin K, Gavino M, Delasalle K, Alexanian R. Thal-idomide with dexamethasone for resistant multiple myeloma.Blood. 2000;96:167a.Google Scholar
  148. 148.
    Palumbo A, Giaccone L, Bertola A, et al. Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma.Haematologica. 2001;86:399–403.PubMedPubMedCentralGoogle Scholar
  149. 149.
    Yakoub-Agha I, Attal M, Dumontet C, et al. Thalidomide in patients with advanced myeloma: survival prognostic factors.Blood. 2000;96:167a.Google Scholar
  150. 150.
    Rajkumar SV, Hayman S, Fonseca R, et al. Thalidomide plus dex-amethasone (Thal/Dex) and thalidomide alone (Thal) as first line therapy for newly diagnosed myeloma [abstract].Blood. 2000;96:168a.Google Scholar
  151. 151.
    Barlogie B, Spencer T, Tricot G, et al. Long term follow up of 169 patients receiving a phase II trial of single agent thalidomide for advanced and refractory multiple myeloma (MM).Blood. 2000;96:514a.Google Scholar
  152. 152.
    D’Amato RJ, Loughnan MS, Flynn E, et al. Thalidomide is an inhibitor of angiogenesis.Proc Natl Acad Sci U S A. 1994;91:4082–4085.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Shima Y, Treon SP, Yoshizaki K, et al. Clinical and biological activity of thalidomide (THAL) in multiple myeloma (MM) [abstract].Blood. 1999;94:125a.Google Scholar
  154. 154.
    Cheng D, Kini AR, Rodriguez J, Burt RK, Peterson LC, Traynor AE. Microvascular density and cytotoxic T cell activation correlate with response to thalidomide therapy in myeloma patients [abstract].Blood. 1999;94:315a.Google Scholar
  155. 155.
    Haslett PAJ, Corral LG, Albert M, Kaplan G. Thalidomide costim-ulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset.J Exp Med. 1998;187:1885–1892.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Geitz H, Handt S, Zwingenberger K. Thalidomide selectively modulates the density of cell surface molecules involved in the adhesion cascade.Immunopharmacol. 1996;31:213–221.CrossRefGoogle Scholar
  157. 157.
    Or R, Feferman R, Shoshan S. Thalidomide reduces vascular density in granulation tissue of subcutaneously implanted polyvinyl alcohol sponges in guinea pigs.Exp Hematol. 1998;26:217–221.PubMedPubMedCentralGoogle Scholar
  158. 158.
    Sauer H, Gunther J, Hescheler J, Wartenberg M. Thalidomide inhibits angiogenesis in embryoid bodies by the generation of hydroxyl radicals.Am J Pathol. 2000;156:151–158.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Bauer KS, Dixon SC, Figg WD. Inhibition of angiogenesis by thalidomide requires metabolic activation, which is species-dependent.Biochem Pharmacol. 1998;55:1827–1834.PubMedCrossRefGoogle Scholar
  160. 160.
    Petrucci MT, Ricciardi MR, Gregorj C, et al. Thalidomide effects on apoptosis in multiple myeloma: ex-vivo and in vitro study.Blood. 2000;96:366a.Google Scholar
  161. 161.
    Hideshima T, Chauhan D, Shima Y, et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy.Blood. 2000;2943–2950.Google Scholar
  162. 162.
    Rajkumar SV, Timm M, Mesa RA, et al. Effect of thalidomide on myeloma cell apoptosis and VEGF secretion.Blood. 2000;96:364a.Google Scholar
  163. 163.
    Thomas DA, Aguayo A, Estey E, et al. Thalidomide as anti-angio-genesis therapy (RX) in refractory or relapsed leukemias [abstract].Blood. 1999;94:507a.Google Scholar
  164. 164.
    Raza A, Lisak L, Andrews C, et al. Thalidomide produces transfusion independence in patients with long-standing refractory anemias and myelodysplastic syndromes (MDS) [abstract].Blood. 1999;94:661a.Google Scholar
  165. 165.
    Thoma DA, Aguayo A, Giles FJ, et al. Thalidomide anti-angiogen-esis therapy (RX) in Philadelphia (Ph)-negative myeloproliferative disorders (MPD) and myelofibrosis (MF) [abstract].Blood. 1999;94:702a.Google Scholar
  166. 166.
    Estey E, Albitar M, Cortes J, et al. Addition of thalidomide(T) to chemotherapy did not increase remission rate in poor prognosis AML/MDS.Blood. 2000;96:323a.Google Scholar
  167. 167.
    Boehm T, Folkman J, Browder T, O’Reilly MS. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance.Nature. 1997;390:404–407.PubMedCrossRefGoogle Scholar
  168. 168.
    Mantell DJ, Owens PE, Bundred NJ, Mawer EB, Canfield AE. 1 α,25-dihydroxyvitamin D3 inhibits angiogenesis in vitro and in vivo.Circ Res. 2000;87:214–220.PubMedCrossRefGoogle Scholar
  169. 169.
    Roboz GJ, Dias S, Lam G, et al. Arsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis.Blood. 2000;96:1525–1530.PubMedPubMedCentralGoogle Scholar
  170. 170.
    Vacca A, Iurlaro M, Ribatti D, et al. Antiangiogenesis is produced by nontoxic doses of vinblastine.Blood. 1999;94:4143–4155.PubMedPubMedCentralGoogle Scholar
  171. 171.
    Yao L, Pike SE, Setsuda J, et al. Effective targeting of tumor vasculature by the angiogenesis inhibitors vasostatin and interleukin-12.Blood. 2000;96:1900–1905.PubMedPubMedCentralGoogle Scholar
  172. 172.
    Cervenak L, Morbidell L, Donati D, et al. Abolished angiogenicity and tumorigenicity of Burkitt lymphoma by interleukin-10.Blood. 2000;96:2568–2573.PubMedPubMedCentralGoogle Scholar
  173. 173.
    Bertolini F, Fusetti L, Rabascio C, Cinieri S, Martinelli G, Pruneri G. Inhibition of angiogenesis and induction of endothelial and tumor cell apoptosis by green tea in animal models of human high-grade non-Hodgkin’s lymphoma.Leukemia. 2000;14:1477–1482.PubMedCrossRefGoogle Scholar
  174. 174.
    Bertolini F, Fusetti L, Mancuso P, et al. Endostatin, an antiangiogenic drug, induces tumor stabilization after chemotherapy or anti-CD20 therapy in a NOD/SCID mouse model of human high-grade non-Hodgkin lymphoma.Blood. 2000;96:282–287.PubMedPubMedCentralGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2002

Authors and Affiliations

  1. 1.State Key Laboratory of Experimental HematologyInstitute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeTianjinPeople’s Republic of China

Personalised recommendations