Skip to main content
SpringerLink
Log in

Vascular Endothelial Growth Factor Family and Its Receptors

  • Chapter
Antiangiogenic Agents in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

  • 1749 Accesses

Summary

The vascular endothelial growth factors (VEGFs) are key regulators of blood and lymphatic vessel development during embryogenesis and in promoting new vascular growth during physiological and pathological processes in the adult. The VEGF family of ligands in mammals includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placenta growth factor (PlGF). These ligands bind to and activate three receptor tyrosine kinases, designated VEGFR-1, VEGFR-2, and VEGFR-3. VEGF ligands bind to these receptors with overlapping ligand-receptor specificities, and activation may be further modulated through interaction with coreceptors such as the neuropilins (NRP-1 and NRP-2), integrins, or Vascular endothelial-cadherin (VE-cadherin). Ligand activation of VEGFRs triggers a network of distinct downstream-signaling pathways in a cell-type-specific manner that promotes vascular permeability, endothelial cell growth, migration, and survival. VEGF is an important survival factor for hematopoietic stem cells (HSCs) and stimulates the mobilization of endothelial progenitor cells (EPC) from the bone marrow to distant sites of neovascularization. A large body of experimental evidence has established VEGF as an essential molecule in promoting angiogenesis during tumor growth. These findings have led to the development of therapeutic agents that selectively target various VEGF ligands and their receptors. This chapter reviews the biology of VEGF and its receptors, emphasizing their important role for cancerous growth.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Folkman J. What is the evidence that tumors are angiogenesis dependent. J Natl Cancer Inst 1990;82:4–6.

    Article  PubMed  CAS  Google Scholar 

  2. Fidler IJ, Ellis LM. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 1994;79:185–188.

    Article  PubMed  CAS  Google Scholar 

  3. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9:669–676.

    Article  PubMed  CAS  Google Scholar 

  6. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005;23:1011–1027.

    Article  PubMed  CAS  Google Scholar 

  7. Wey JS, Stoeltzing O, Ellis LM. Vascular endothelial growth factor receptors: expression and function in solid tumors. Clin Adv Hematol Oncol 2004;2:37–45.

    PubMed  Google Scholar 

  8. Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med 2003;9:702–712.

    Article  PubMed  CAS  Google Scholar 

  9. Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. Oncologist 2004;9(Suppl 1):2–10.

    Article  PubMed  CAS  Google Scholar 

  10. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005;438:967–974.

    Article  PubMed  CAS  Google Scholar 

  11. Houck K. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol 1991;5:1806–1814.

    PubMed  CAS  Google Scholar 

  12. Tischer E, Mitchell R, Hartman T, et al. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 1991;266:11947–11954.

    PubMed  CAS  Google Scholar 

  13. Ogawa S, Oku A, Sawano A, Yamaguchi S, Yazaki Y, Shibuya M. A novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding domain. J Biol Chem 1998;273:31273–31282.

    Article  PubMed  CAS  Google Scholar 

  14. Suto K, Yamazaki Y, Morita T, Mizuno H. Crystal structures of novel vascular endothelial growth factors (VEGF) from snake venoms: insight into selective VEGF binding to kinase insert domain-containing receptor but not to fms-like tyrosine kinase-1. J Biol Chem 2005;280:2126–2131.

    Article  PubMed  CAS  Google Scholar 

  15. Quinn TP, Peters KG, De Vries C, Ferrara N, Williams LT. Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc Natl Acad Sci USA 1993;90:7533–7537.

    Article  PubMed  CAS  Google Scholar 

  16. Park J, Chen H, Winer J, Houck K, Ferrara N. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 1994;269:25646–25654.

    PubMed  CAS  Google Scholar 

  17. Olofsson B. Vascular endothelial growth factor B (VEGFB) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proc Natl Acad Sci USA 1998;95:10705–10709.

    Article  Google Scholar 

  18. Cao Y, Chen H, Zhou L, et al. Heterodimers of placenta growth factor/vascular endothelial growth factor. J Biol Chem 1996;271:3154–3162.

    Article  PubMed  CAS  Google Scholar 

  19. DiSalvo J, Conn G, Trivedi PG, Palisi TM, Thomas KA. Purification and characterization of a naturally occurring vascular endothelial growth factor bullet placenta growth factor heterodimer. J Biol Chem 1995;270:7717–7723.

    Article  PubMed  CAS  Google Scholar 

  20. Joukov V, Pajusola K, Kaipainen A, et al. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 1996;15:290–298.

    PubMed  CAS  Google Scholar 

  21. 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 USA 1998;95:548–553.

    Article  PubMed  CAS  Google Scholar 

  22. Miao HQ, Klagsbrun M. Neuropilin is a mediator of angiogenesis. Cancer Metastasis Rev 2000;19:29–37.

    Article  PubMed  CAS  Google Scholar 

  23. Eliceiri BP, Cheresh DA. Adhesion events in angiogenesis. Curr Opin Cell Biol 2001;13:563–568.

    Article  PubMed  CAS  Google Scholar 

  24. Dejana E. Endothelial cell-cell junctions: happy together. Nat Rev Mol Cell Biol 2004;5:261–270.

    Article  PubMed  CAS  Google Scholar 

  25. Carmeliet P, Ferreira V, Breier G, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996;380:435–439.

    Article  PubMed  CAS  Google Scholar 

  26. Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 1995;376:66–70.

    Article  PubMed  CAS  Google Scholar 

  27. Shalaby F. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995;376:62–66.

    Article  PubMed  CAS  Google Scholar 

  28. Dumont DJ, Jussila L, Taipale J, et al. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 1998;282:946–949.

    Article  PubMed  CAS  Google Scholar 

  29. Ferrara N. The role of VEGF in the regulation of physiological and pathological angiogenesis. EXS 2005;94:209–231.

    PubMed  Google Scholar 

  30. Mattei MG, Borg JP, Rosnet O, Marme D, Birnbaum D. Assignment of vascular endothelial growth factor (VEGF) and placenta growth factor (PLGF) genes to human chromosome 6p12-p21 and 14q24-q31 regions, respectively. Genomics 1996;32:168–169.

    Article  PubMed  CAS  Google Scholar 

  31. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999;13:9–22.

    PubMed  CAS  Google Scholar 

  32. Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002;20:4368–4380.

    Article  PubMed  CAS  Google Scholar 

  33. Park JE, Keller GA, Ferrara N. The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol Biol Cell 1993;4:1317–1326.

    PubMed  CAS  Google Scholar 

  34. Bergers G, Brekken R, McMahon G, et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2000;2:737–744.

    Article  PubMed  CAS  Google Scholar 

  35. Ferrara N. Molecular and biological properties of vascular endothelial growth factor. J Mol Med 1999;77:527–543.

    Article  PubMed  CAS  Google Scholar 

  36. Ferrara N. Vascular endothelial growth factor. Eur J Cancer 1996;32A:2413–2422.

    Article  PubMed  CAS  Google Scholar 

  37. Bellamy WT, Richter L, Frutiger Y, and Grogan TM. Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res 1999;59:728–733.

    PubMed  CAS  Google Scholar 

  38. Inoue M, Hager JH, Ferrara N, Gerber HP, Hanahan D. VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell 2002;1:193–202.

    Article  PubMed  CAS  Google Scholar 

  39. Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993;362:841–844.

    Article  PubMed  CAS  Google Scholar 

  40. Gerber HP, Kowalski J, Sherman D, Eberhard DA, Ferrara N. Complete inhibition of rhabdomyosarcoma xenograft growth and neovascularization requires blockade of both tumor and host vascular endothelial growth factor. Cancer Res 2000;60:6253–6258.

    PubMed  CAS  Google Scholar 

  41. Holash J, Davis S, Papadopoulos N, et al. VEGF-trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA 2002;99:11393–11398.

    Article  PubMed  CAS  Google Scholar 

  42. Hotz HG, Hines OJ, Masood R, et al. VEGF antisense therapy inhibits tumor growth and improves survival in experimental pancreatic cancer. Surgery 2005;137:192–199.

    Article  PubMed  Google Scholar 

  43. Paavonen K, Horelli-Kuitunen N, Chilov D, et al. Novel human vascular endothelial growth factor genes VEGF-B and VEGF-C localize to chromosomes 11q13 and 4q34, respectively. Circulation 1996;93:1079–1082.

    PubMed  CAS  Google Scholar 

  44. Bellomo D, Headrick JP, Silins GU, et al. Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ Res 2000;86:E29–E35.

    PubMed  CAS  Google Scholar 

  45. Sun Y, Jin K, Childs JT, Xie L, Mao XO, Greenberg DA. Increased severity of cerebral ischemic injury in vascular endothelial growth factor-B-deficient mice. J Cereb Blood Flow Metab 2004;24:1146–1152.

    Article  PubMed  CAS  Google Scholar 

  46. Tjwa M, Luttun A, Autiero M, Carmeliet P. VEGF and PlGF: two pleiotropic growth factors with distinct roles in development and homeostasis. Cell Tissue Res 2003;314:5–14.

    Article  PubMed  CAS  Google Scholar 

  47. Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci USA 1991;88:9267–9271.

    Article  PubMed  CAS  Google Scholar 

  48. Pipp F, Heil M, Issbrucker K, Ziegelhoeffer T, et al. VEGFR-1-selective VEGF homologue PlGF is arteriogenic: evidence for a monocyte-mediated mechanism. Circ Res 2003;92:378–385.

    Article  PubMed  CAS  Google Scholar 

  49. Roy H, Bhardwaj S, Babu M, et al. Adenovirus-mediated gene transfer of placental growth factor to perivascular tissue induces angiogenesis via upregulation of the expression of endogenous vascular endothelial growth factor-A. Hum Gene Ther 2005;16:1422–1428.

    Article  PubMed  CAS  Google Scholar 

  50. Carmeliet P, Moons L, Luttun A, et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 2001;7:575–583.

    Article  PubMed  CAS  Google Scholar 

  51. Luttun A, Tjwa M, Moons L, et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 2002;8:831–840.

    PubMed  CAS  Google Scholar 

  52. Jenkins NA, Woollatt E, Crawford J, et al. Mapping of the gene for vascular endothelial growth factor-D in mouse and man to the X chromosome. Chromosome Res 1997;5:502–505.

    PubMed  CAS  Google Scholar 

  53. McColl BK, Baldwin ME, Roufail S, et al. Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D. J Exp Med 2003;198:863–868.

    Article  PubMed  CAS  Google Scholar 

  54. Jussila L, Alitalo K. Vascular growth factors and lymphangiogenesis. Physiol Rev 2002;82:673–700.

    PubMed  CAS  Google Scholar 

  55. Karkkainen MJ, Haiko P, Sainio K, et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 2004;5:74–80.

    Article  PubMed  CAS  Google Scholar 

  56. Baldwin ME, Halford MM, Roufail S, et al. Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol Cell Biol 2005;25:2441–2449.

    Article  PubMed  CAS  Google Scholar 

  57. Jeltsch M, Kaipainen A, Joukov V, et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 1997;276:1423–1425.

    Article  PubMed  CAS  Google Scholar 

  58. Veikkola T, Jussila L, Makinen T, et al. Signaling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J 2001;20:1223–1231.

    Article  PubMed  CAS  Google Scholar 

  59. Skobe M, Hawighorst T, Jackson DG, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 2001;7:192–198.

    Article  PubMed  CAS  Google Scholar 

  60. Stacker SA, Caesar C, Baldwin ME, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 2001;7:186–191.

    Article  PubMed  CAS  Google Scholar 

  61. Achen MG, Williams RA, Minekus MP, et al. Localization of vascular endothelial growth factor-D in malignant melanoma suggests a role in tumour angiogenesis. J Pathol 2001;193:147–154.

    Article  PubMed  CAS  Google Scholar 

  62. Achen MG, McColl BK, Stacker SA. Focus on lymphangiogenesis in tumor metastasis. Cancer Cell 2005;7:121–127.

    Article  PubMed  CAS  Google Scholar 

  63. Karpanen T, Egeblad M, Karkkainen MJ, et al. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 2001;61:1786–1790.

    PubMed  CAS  Google Scholar 

  64. He Y, Kozaki K, Karpanen T, et al. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst 2002;94:819–825.

    PubMed  CAS  Google Scholar 

  65. He Y, Rajantie I, Pajusola K, et al. Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res 2005;65:4739–4746.

    Article  PubMed  CAS  Google Scholar 

  66. Chen Z, Varney ML, Backora MW, et al. Down-regulation of vascular endothelial cell growth factor-C expression using small interfering RNA vectors in mammary tumors inhibits tumor lymphangiogenesis and spontaneous metastasis and enhances survival. Cancer Res 2005;65:9004–9011.

    Article  PubMed  CAS  Google Scholar 

  67. Shibuya M. Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase (flt) closely related to the fms family. Oncogene 1990;8:519–527.

    Google Scholar 

  68. Terman B. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 1992;187:1579–1586.

    Article  PubMed  CAS  Google Scholar 

  69. Matthews W, Jordan CT, Gavin M, Jenkins NA, Copeland NG, Lemischka IR. A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit. Proc Natl Acad Sci USA 1991;88:9026–9030.

    Article  PubMed  CAS  Google Scholar 

  70. Kaipainen A, Korhonen J, Mustonen T, et al. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci USA 1995;92:3566–3570.

    Article  PubMed  CAS  Google Scholar 

  71. Pajusola K, Aprelikova O, Armstrong E, Morris S, Alitalo K. Two human FLT4 receptor tyrosine kinase isoforms with distinct carboxy terminal tails are produced by alternative processing of primary transcripts. Oncogene 1993;8:2931–2937.

    PubMed  CAS  Google Scholar 

  72. Pajusola K, Aprelikova O, Korhonen J, et al. FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines. Cancer Res 1992;52:5738–5743.

    PubMed  CAS  Google Scholar 

  73. Kowanetz M, Ferrara N. Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin Cancer Res 2006;12:5018–5022.

    Article  PubMed  CAS  Google Scholar 

  74. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signaling – in control of vascular function. Nat Rev Mol Cell Biol 2006;7:359–371.

    Article  PubMed  CAS  Google Scholar 

  75. Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci USA 1998;95:9349–9354.

    Article  PubMed  CAS  Google Scholar 

  76. Dunk C, Ahmed A. Vascular endothelial growth factor receptor-2-mediated mitogenesis is negatively regulated by vascular endothelial growth factor receptor-1 in tumor epithelial cells. Am J Pathol 2001;158:265–273.

    PubMed  CAS  Google Scholar 

  77. Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH. Different signal transduction properties of KDR and Flt-1, two receptors for vascular endothelial growth factor. J Biol Chem 1994;269:26988–26995.

    PubMed  CAS  Google Scholar 

  78. Gille H, Kowalski J, Yu L, et al. A repressor sequence in the juxtamembrane domain of Flt-1 (VEGFR-1) constitutively inhibits vascular endothelial growth factor-dependent phosphatidylinositol 3’-kinase activation and endothelial cell migration. EMBO J 2000;19:4064–4073.

    Article  PubMed  CAS  Google Scholar 

  79. Zeng H, Dvorak HF, Mukhopadhyay D. Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) receptor-1 down-modulates VPF/VEGF receptor-2-mediated endothelial cell proliferation, but not migration, through phosphatidylinositol 3-kinase-dependent pathways. J Biol Chem 2001;276:26969–26979.

    Article  PubMed  CAS  Google Scholar 

  80. Barleon B, Sozzani S, Zhou D, Weich H, Mantovani A, Marme D. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 1996;87:3336–3343.

    PubMed  CAS  Google Scholar 

  81. Clauss M, Weich H, Breier G, et al. The vascular endothelial growth factor receptor flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J Biol Chem 1996;271:17629–17634.

    Article  PubMed  CAS  Google Scholar 

  82. Lyden D, Hattori K, Dias S, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 2001;7:1194–1201.

    Article  PubMed  CAS  Google Scholar 

  83. Chen WS, Kitson RP, Goldfarb RH. Modulation of human NK cell lines by vascular endothelial growth factor and receptor VEGFR-1 (FLT-1). in vivo 2002;16:439–445.

    PubMed  CAS  Google Scholar 

  84. LeCouter J, Moritz DR, Li B, et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 2003;299:890–893.

    Article  PubMed  CAS  Google Scholar 

  85. Autiero M, Waltenberger J, Communi D, et al. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 2003;9:936–943.

    Article  PubMed  CAS  Google Scholar 

  86. Hiratsuka S, Maru Y, Okada A, Seiki M, Noda T, Shibuya M. Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. Cancer Res 2001;61:1207–1213.

    PubMed  CAS  Google Scholar 

  87. Millauer B, Wizigmann-Voos S, Schnurch H, et al. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 1993;72:835–846.

    Article  PubMed  CAS  Google Scholar 

  88. Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res 2000;60:203–212.

    PubMed  CAS  Google Scholar 

  89. Abedi H, Zachary I. Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells. J Biol Chem 1997;272:15442–15451.

    Article  PubMed  CAS  Google Scholar 

  90. Prewett M, Huber J, Li Y, et al. Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. Cancer Res 1999;59:5209–5218.

    PubMed  CAS  Google Scholar 

  91. Bruns CJ, Liu W, Davis DW, et al. Vascular endothelial growth factor is an in vivo survival factor for tumor endothelium in a murine model of colorectal carcinoma liver metastases. Cancer 2000;89:488–499.

    Article  PubMed  CAS  Google Scholar 

  92. McCarty MF, Wey J, Stoeltzing O, et al. ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor with additional activity against epidermal growth factor receptor tyrosine kinase, inhibits orthotopic growth and angiogenesis of gastric cancer. Mol Cancer Ther 2004;3:1041–1048.

    PubMed  CAS  Google Scholar 

  93. Shaheen RM, Tseng WW, Vellagas R, et al. Effects of an antibody to vascular endothelial growth factor receptor-2 on survival, tumor vascularity, and apoptosis in a murine model of colon carcinomatosis. Int J Oncol 2001;18:221–226.

    PubMed  CAS  Google Scholar 

  94. Davis DW, Inoue K, Dinney CP, Hicklin DJ, Abbruzzese JL, McConkey DJ. Regional effects of an antivascular endothelial growth factor receptor monoclonal antibody on receptor phosphorylation and apoptosis in human 253J B-V bladder cancer xenografts. Cancer Res 2004;64:4601–4610.

    Article  PubMed  CAS  Google Scholar 

  95. Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 2004;64:3731–3736.

    Article  PubMed  CAS  Google Scholar 

  96. Inoue K, Slaton JW, Davis DW, et al. Treatment of human metastatic transitional cell carcinoma of the bladder in a murine model with the anti-vascular endothelial growth factor receptor monoclonal antibody DC101 and paclitaxel. Clin Cancer Res 2000;6:2635–2643.

    PubMed  CAS  Google Scholar 

  97. Klement G, Baruchel S, Rak J, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000;105:R15–R24.

    PubMed  CAS  Google Scholar 

  98. Kozin SV, Boucher Y, Hicklin DJ, Bohlen P, Jain RK, Suit HD. Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts. Cancer Res 2001;61:39–44.

    PubMed  CAS  Google Scholar 

  99. Aprelikova O, Pajusola K, Partanen J, et al. FLT4, a novel class III receptor tyrosine kinase in chromosome 5q33-qter. Cancer Res 1992;52:746–748.

    PubMed  CAS  Google Scholar 

  100. Paavonen K, Puolakkainen P, Jussila L, Jahkola T, Alitalo K. Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing. Am J Pathol 2000;156:1499–1504.

    PubMed  CAS  Google Scholar 

  101. Matsumura K, Hirashima M, Ogawa M, et al. Modulation of VEGFR-2-mediated endothelial-cell activity by VEGF-C/VEGFR-3. Blood 2003;101:1367–1374.

    Article  PubMed  CAS  Google Scholar 

  102. Valtola R, Salven P, Heikkila P, et al. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am J Pathol 1999;154:1381–1390.

    PubMed  CAS  Google Scholar 

  103. Tsurusaki T, Kanda S, Sakai H, et al. Vascular endothelial growth factor-C expression in human prostatic carcinoma and its relationship to lymph node metastasis. Br J Cancer 1999;80:309–313.

    Article  PubMed  CAS  Google Scholar 

  104. Clarijs R, Schalkwijk L, Hofmann UB, Ruiter DJ, de Waal RM. Induction of vascular endothelial growth factor receptor-3 expression on tumor microvasculature as a new progression marker in human cutaneous melanoma. Cancer Res 2002;62:7059–7065.

    PubMed  CAS  Google Scholar 

  105. Mandriota SJ, Jussila L, Jeltsch M, et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 2001;20:672–682.

    Article  PubMed  CAS  Google Scholar 

  106. Roberts N, Kloos B, Cassella M, et al. Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res 2006;66:2650–2657.

    Article  PubMed  CAS  Google Scholar 

  107. Hoshida T, Isaka N, Hagendoorn J, et al. Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. Cancer Res 2006;66:8065–8075.

    Article  PubMed  CAS  Google Scholar 

  108. Fujisawa H, Kitsukawa T. Receptors for collapsin/semaphorins. Curr Opin Neurobiol 1998;8:587–592.

    Article  PubMed  CAS  Google Scholar 

  109. Ellis LM. The role of neuropilins in cancer. Mol Cancer Ther 2006;5:1099–1107.

    Article  PubMed  CAS  Google Scholar 

  110. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998;92:735–745.

    Article  PubMed  CAS  Google Scholar 

  111. Migdal M, Huppertz B, Tessler S, et al. Neuropilin-1 is a placenta growth factor-2 receptor. J Biol Chem 1998;273:22272–22278.

    Article  PubMed  CAS  Google Scholar 

  112. Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Yla-Herttuala S, Jaattela M, Alitalo K. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 2001;61:1786–1790.

    PubMed  CAS  Google Scholar 

  113. Favier B, Alam A, Barron P, et al. Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration. Blood 2006;108:1243–1250.

    Article  PubMed  CAS  Google Scholar 

  114. Kawasaki T, Kitsukawa T, Bekku Y, et al. A requirement for neuropilin-1 in embryonic vessel formation. Development 1999;126:4895–4902.

    PubMed  CAS  Google Scholar 

  115. Takashima S, Kitakaze M, Asakura M, et al. Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis. Proc Natl Acad Sci USA 2002;99:3657–3662.

    Article  PubMed  CAS  Google Scholar 

  116. Serini G, Valdembri D, Bussolino F. Integrins and angiogenesis: a sticky business. Exp Cell Res 2006;312:651–658.

    Article  PubMed  CAS  Google Scholar 

  117. Hall H, Hubbell JA. Matrix bound sixth Ig-like domain of cell adhesion molecule L1 acts as an angiogenic factor by ligating alphavbeta3-integrin and activating VEGF-R2. Microvasc Res 2004;68:169–178.

    Article  PubMed  CAS  Google Scholar 

  118. Borges E, Jan Y, Ruoslahti E. Platelet-derived growth factor receptor beta and vascular endothelial growth factor receptor 2 bind to the beta 3 integrin through its extracellular domain. J Biol Chem 2000;275:39867–39873.

    Article  PubMed  CAS  Google Scholar 

  119. Soldi R, Mitola S, Strasly M, Defilippi P, Tarone G, Bussolino F. Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-1. EMBO J 1999;18:882–892.

    Article  PubMed  CAS  Google Scholar 

  120. Reynolds LE, Wyder L, Lively JC, et al. Enhanced pathological angiogenesis in mice lacking beta3 integrin or beta3 and beta5 integrins. Nat Med 2002;8:8643–8650.

    Article  CAS  Google Scholar 

  121. Reynolds AR, Reynolds LE, Nagel TE, et al. Elevated Flk1 (vascular endothelial growth factor receptor-2) signaling mediates enhanced angiogenesis in beta3-integrin-deficient mice. Cancer Res 2004;64:8643–8650.

    Article  PubMed  CAS  Google Scholar 

  122. Hong YK, Lange-Asschenfeldt B, Velasco P, et al. VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins. FASEB J 2004;18:1111–1113.

    PubMed  CAS  Google Scholar 

  123. Carmeliet P, Lampugnani MG, Moons L, et al. Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 1999;98:147–157.

    Article  PubMed  CAS  Google Scholar 

  124. Shay-Salit A, Shushy M, Wofovitz E, et al. VEGF receptor 2 and the adherens junction as a mechanical transducer in vascular endothelial cells. Proc Natl Acad Sci USA 2002;99:9462–9467.

    Article  PubMed  CAS  Google Scholar 

  125. Zanetti A, Lampugnani MG, Balconi G, et al. Vascular endothelial growth factor induces shc association with vascular endothelial cadherin: a potential feedback mechanism to control vascular endothelial growth factor receptor-2 signaling. Arterioscler Thromb Vasc Biol 2002;22:617–622.

    Article  PubMed  CAS  Google Scholar 

  126. Calera MR, Venkatakrishnan A, Kazlauskas A. VE-cadherin increases the half-life of VEGF receptor 2. Exp Cell Res 2004;300:248–256.

    Article  PubMed  CAS  Google Scholar 

  127. Lampugnani MG, Orsenigo F, Gagliani MC, Tacchetti C, Dejana E. Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments. J Cell Biol 2006;174:593–604.

    Article  PubMed  CAS  Google Scholar 

  128. Gavard J, Gutkind JS. VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol 2006;8:1223–1234.

    Article  PubMed  CAS  Google Scholar 

  129. Price DJ, Miralem T, Jiang S, Steinberg R, Avraham H. Role of vascular endothelial growth factor in the stimulation of cellular invasion and signaling of breast cancer cells. Cell Growth Differ 2001;12:129–135.

    PubMed  CAS  Google Scholar 

  130. Wu Y, Hooper AT, Zhong Z, et al. The vascular endothelial growth factor receptor (VEGFR-1) supports growth and survival of human breast carcinoma. Int J Cancer 2006;119:1519–1529.

    Article  PubMed  CAS  Google Scholar 

  131. Wu Y, Zhong Z, Huber J, et al. Anti-vascular endothelial growth factor receptor-1 antagonist antibody as a therapeutic agent for cancer. Clin Cancer Res 2006;21:6573–6584.

    Article  Google Scholar 

  132. Fan F, Wey JS, McCarty MF, et al. Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene 2005;24:2647–2653.

    Article  PubMed  CAS  Google Scholar 

  133. Wey JS, Fan F, Gray MJ, et al. Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer 2005;104:427–438.

    Article  PubMed  CAS  Google Scholar 

  134. Yang AD, Camp ER, Fan F, et al. Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. Cancer Res 2006;66:46–51.

    Article  PubMed  CAS  Google Scholar 

  135. Hahn D, Simak R, Steiner GE, Handisurya A, Susani M, Marberger M. Expression of the VEGF-receptor Flt-1 in benign, premalignant and malignant prostate tissues. J Urol 2000;164:506–510.

    Article  PubMed  CAS  Google Scholar 

  136. Graaeven U, Fiedler W, Karpinski S et al. Melanoma-associated expression of vascular endothelial growth factor and its receptors FLT-1 and KDR. J Cancer Res Clin Oncol. 1999;125:621–629.

    Article  Google Scholar 

  137. Bairey O, Boycov O, Kaganovsky E, Zimra Y, Shaklai M, Rabizadeh E. All three receptors for vascular endothelial growth factor (VEGF) are expressed on B-chronic lymphocytic leukemia (CLL) cells. Leuk Res 2004;28:243–248.

    Article  PubMed  CAS  Google Scholar 

  138. Dias S, Hattori K, Zhu Z, Heissig B, Choy M, Lane W, et al. Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J Clin Invest 2000;106:511–521.

    Article  PubMed  CAS  Google Scholar 

  139. Dias S, Choy M, Alitalo K, Rafii S. Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy. Blood 2002;99:2179–2184.

    Article  PubMed  CAS  Google Scholar 

  140. Su JL, Yang PC, Shih JY, Yang CY, Wei LH, Hsieh CY, Chou CH, Jeng YM, Wang MY, Chang KJ, Hung MC, Kuo ML. The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells. Cancer Cell 2006;9:209–223.

    Article  PubMed  CAS  Google Scholar 

  141. Dias S, Hattori K, Heissig B, et al. Inhibition of both paracrine and autocrine VEGF/VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. Proc Natl Acad Sci USA 2001;98:10857–10862.

    Article  PubMed  CAS  Google Scholar 

  142. Jain RK. Molecular regulation of vessel maturation. Nat Med 2003;9:685–693.

    Article  PubMed  CAS  Google Scholar 

  143. Semenza GL. Regulation of physiological responses to continuous and intermittent hypoxia by hypoxia-inducible factor 1. Exp Physiol 2006;91:803–806.

    Article  PubMed  CAS  Google Scholar 

  144. Enholm B, Paavonen K, Ristimaki A, et al. Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 1997;14:2475–2483.

    Article  PubMed  CAS  Google Scholar 

  145. Nilsson I, Shibuya M, Wennstrom S. Differential activation of vascular genes by hypoxia in primary endothelial cells. Exp Cell Res 2004;299:476–485.

    Article  PubMed  CAS  Google Scholar 

  146. Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, Kerbel RS. 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 1997;151(6):1523–1530.

    PubMed  CAS  Google Scholar 

  147. Yang W, Klos K, Yang Y, Smith TL, Shi D, Yu D. ErbB2 overexpression correlates with increased expression of vascular endothelial growth factors A, C, and D in human breast carcinoma. Cancer 2002;94:2855–2861.

    Article  PubMed  CAS  Google Scholar 

  148. Kumar R, Yarmand-Bagheri R. The role of HER2 in angiogenesis. Semin Oncol 2001;28:27–32.

    Article  PubMed  CAS  Google Scholar 

  149. Ciardiello F, Bianco R, Damiano V, et al. Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res 2000;6:3739–3747.

    PubMed  CAS  Google Scholar 

  150. Bruns CJ, Harbison MT, Davis DW, et al. Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res 2000;6:1936–1948.

    PubMed  CAS  Google Scholar 

  151. Tonra JR, Deevi DS, Corcoran E, et al. Synergistic antitumor effects of combined epidermal growth factor receptor and vascular endothelial growth factor receptor-2 targeted therapy. Clin Cancer Res 2006;12:2197–2207.

    Article  PubMed  CAS  Google Scholar 

  152. Smith LE, Shen W, Perruzzi C, et al. Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nat Med 1999;5:1390–1395.

    Article  PubMed  CAS  Google Scholar 

  153. Miele C, Rochford JJ, Filippa N, Giorgetti-Peraldi S, Van Obberghen E. Insulin and insulin-like growth factor-I induce vascular endothelial growth factor mRNA expression via different signaling pathways. J Biol Chem 2000;275:21695–21702.

    Article  PubMed  CAS  Google Scholar 

  154. Reinmuth N, Fan F, Liu W, et al. Impact of insulin-like growth factor receptor-I function on angiogenesis, growth, and metastasis of colon cancer. Lab Invest 2002;82:1377–1389.

    PubMed  CAS  Google Scholar 

  155. Stoeltzing O, Liu W, Reinmuth N, Fan F, et al. Regulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and angiogenesis by an insulin-like growth factor-I receptor autocrine loop in human pancreatic cancer. Am J Pathol 2003;163:1001–1011.

    PubMed  CAS  Google Scholar 

  156. Tang Y, Zhang D, Fallavollita L, Brodt P. Vascular endothelial growth factor C expression and lymph node metastasis are regulated by the type I insulin-like growth factor receptor. Cancer Res 2003;63:1166–1171.

    PubMed  CAS  Google Scholar 

  157. Zeng H, Datta K, Neid M, Li J, Parangi S, Mukhopadhyay D. Requirement of different signaling pathways mediated by insulin-like growth factor-I receptor for proliferation, invasion, and VPF/VEGF expression in a pancreatic carcinoma cell line. Biochem Biophys Res Commun 2003;302:46–55.

    Article  PubMed  CAS  Google Scholar 

  158. Poulaki V, Mitsiades CS, McMullan C, et al. Regulation of vascular endothelial growth factor expression by insulin-like growth factor I in thyroid carcinomas. J Clin Endocrinol Metab 2003;88:5392–5398.

    Article  PubMed  CAS  Google Scholar 

  159. Slomiany MG, Black LA, Kibbey MM, Day TA, Rosenzweig SA. IGF-1 induced vascular endothelial growth factor secretion in head and neck squamous cell carcinoma. Biochem Biophys Res Commun 2006;342:851–858.

    Article  PubMed  CAS  Google Scholar 

  160. Van Belle E, Witzenbichler B, Chen D, et al. Potentiated angiogenic effect of scatter factor/hepatocyte growth factor via induction of vascular endothelial growth factor: the case for paracrine amplification of angiogenesis. Circulation 1998;97:381–390.

    PubMed  Google Scholar 

  161. Kotsuji-Maruyama T, Imakado S, Kawachi Y, Otsuka F. PDGF-BB induces MAP kinase phosphorylation and VEGF expression in neurofibroma-derived cultured cells from patients with neurofibromatosis 1. J Dermatol 2002;29:713–717.

    PubMed  CAS  Google Scholar 

  162. Cao R, Brakenhielm E, Li X, et al. Angiogenesis stimulated by PDGF-CC, a novel member in the PDGF family, involves activation of PDGFR-alphaalpha and -alphabeta receptors. FASEB J 2002;16:1575–1583.

    Article  PubMed  CAS  Google Scholar 

  163. Reinmuth N, Liu W, Jung YD, et al. Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB J 2001;15:1239–1241.

    PubMed  CAS  Google Scholar 

  164. Dong J, Grunstein J, Tajada M, et al. VEGF-null cells require PDGFR a signaling-mediated stromal fibroblast recruitment for tumorigenesis. EMBO 2004;23:2800–2810.

    Article  CAS  Google Scholar 

  165. Rak J, Mitsuhashi Y, Sheehan C, et al. Oncogenes and tumor angiogenesis: differential modes of vascular endothelial growth factor up-regulation in ras-transformed epithelial cells and fibroblasts. Cancer Res 2000;60:490–498.

    PubMed  CAS  Google Scholar 

  166. Rak J, Yu JL, Kerbel RS, Coomber BL. What do oncogenic mutations have to do with angiogenesis/vascular dependence of tumors. Cancer Res 2002;62:1931–1934.

    PubMed  CAS  Google Scholar 

  167. Konishi T, Huang CL, Adachi M, et al. The K-ras gene regulates vascular endothelial growth factor gene expression in non-small cell lung cancers. Int J Oncol 2000;16:501–511.

    PubMed  CAS  Google Scholar 

  168. Ikeda N, Nakajima Y, Sho M, et al. The association of K-ras gene mutation and vascular endothelial growth factor gene expression in pancreatic carcinoma. Cancer 2001;92:488–499.

    Article  PubMed  CAS  Google Scholar 

  169. Rak J, Kerbel RS. Ras regulation of vascular endothelial growth factor and angiogenesis. Methods Enzymol 2001;333:267–283.

    PubMed  CAS  Google Scholar 

  170. Okada F, Rak JW, Croix BS, et al. Impact of oncogenes in tumor angiogenesis: mutant K-ras up-regulation 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 1998;95:3609–3614.

    Article  PubMed  CAS  Google Scholar 

  171. Rak J, Mitsuhashi Y, Bayko L, et al. Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 1995;55:4575–4580.

    PubMed  CAS  Google Scholar 

  172. Ellis LM, Staley CA, Liu W, et al. 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 1998;273:1052–1057.

    Article  PubMed  CAS  Google Scholar 

  173. Fleming RY, Ellis LM, Parikh NU, Liu W, Staley CA, Gallick GE. Regulation of vascular endothelial growth factor expression in human colon carcinoma cells by activity of src kinase. Surgery 1997;122:501–507.

    Article  PubMed  CAS  Google Scholar 

  174. Ebos JM, Tran J, Master Z, et al. Imatinib mesylate (STI-571) reduces Bcr-Abl-mediated vascular endothelial growth factor secretion in chronic myelogenous leukemia. Mol Cancer Res 2002;1:89–95.

    PubMed  CAS  Google Scholar 

  175. Yuan A, Yu CJ, Luh KT, Kuo SH, Lee YC, Yang PC. Aberrant p53 expression correlates with expression of vascular endothelial growth factor mRNA and interleukin-8 mRNA and neoangiogenesis in non-small-cell lung cancer. J Clin Oncol 2002;20:900–910.

    Article  PubMed  CAS  Google Scholar 

  176. Fujisawa T, Watanabe J, Kamata Y, Hamano M, Hata H, Kuramoto H. Effect of p53 gene transfection on vascular endothelial growth factor expression in endometrial cancer cells. Exp Mol Pathol 2003;74:276–281.

    Article  PubMed  CAS  Google Scholar 

  177. Hassan I, Wunderlich A, Slater E, Hoffmann S, Celik I, Zielke A. Antisense p53 decreases production of VEGF in follicular thyroid cancer cells. Endocrine 2006;29:409–412.

    Article  PubMed  CAS  Google Scholar 

  178. Pal S, Datta K, Mukhopadhyay D. Central role of p53 on regulation of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) expression in mammary carcinoma. Cancer Res 2001;61:6952–6957.

    PubMed  CAS  Google Scholar 

  179. Bouvet M, Ellis LM, Nishizaki M, et al. Adenovirus-mediated wild-type p53 gene transfer down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human colon cancer. Cancer Res 1998;58:2288–2292.

    PubMed  CAS  Google Scholar 

  180. Zundel W, Schindler C, Haas-Kogan D, et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 2000;14:391–396.

    PubMed  CAS  Google Scholar 

  181. Maxwell PH, Wiesener MS, Chang GW, et al. The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999;399:271–275.

    Article  PubMed  CAS  Google Scholar 

  182. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983;219:983–985.

    Article  PubMed  CAS  Google Scholar 

  183. Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Path 1995;146:1029–1039.

    PubMed  CAS  Google Scholar 

  184. Yoshiji H, Kuriyama S, Hicklin DJ, et al. The vascular endothelial growth factor receptor KDR/Flk-1 is a major regulator of malignant ascites formation in the mouse hepatocellular carcinoma model. Hepatology 2001;33:841–847.

    Article  PubMed  CAS  Google Scholar 

  185. Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK. Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc Natl Acad Sci USA 1996;93:14765–14770.

    Article  PubMed  CAS  Google Scholar 

  186. Shaheen RM, Ahmad SA, Liu W, et al. Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer 2001;85:584–589.

    Article  PubMed  CAS  Google Scholar 

  187. Bates DO, Harper SJ. Regulation of vascular permeability by vascular endothelial growth factors. Vascul Pharmacol 2002;39:225–237.

    Article  PubMed  CAS  Google Scholar 

  188. Feng D, Nagy JA, Hipp J, Dvorak HF, Dvorak AM. Vesiculo-vacuolar organelles and the regulation of venule permeability to macromolecules by vascular permeability factor, histamine, and serotonin. J Exp Med 1996;183:1981–1986.

    Article  PubMed  CAS  Google Scholar 

  189. Roberts WG, Palade GE. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 1995;108:2369–2379.

    PubMed  CAS  Google Scholar 

  190. Esser S, Lampugnani MG, Corada M, Dejana E, Risau W. Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells. J Cell Sci 1998;111:1853–1865.

    PubMed  CAS  Google Scholar 

  191. Fukumura D, Gohongi T, Kadambi A, Izumi Y, Ang J, Yun CO, Buerk DG, Huang PL, Jain RK. Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc Natl Acad Sci USA 2001;98:2604–2609.

    Article  PubMed  CAS  Google Scholar 

  192. Eliceiri BP, Paul R, Schwartzberg PL, Hood JD, Leng J, Cheresh DA. Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell 1999;4:915–924.

    Article  PubMed  CAS  Google Scholar 

  193. Zachary I. Signaling mechanisms mediating vascular protective actions of vascular endothelial growth factor. Am J Physiol Cell Physiol 2001;280:C1375–C1386.

    PubMed  CAS  Google Scholar 

  194. Gerber H, McMurtrey A, Kowalski J, et al. Vascular endothelial growth factor regulates endothelial cell survival by the PI3-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem 1998;273:30366–30343.

    Article  Google Scholar 

  195. Gerber HP, Dixit V, Ferrara N. Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J Biol Chem 1998;273:13313–13316.

    Article  PubMed  CAS  Google Scholar 

  196. Gerber HP, Malik AK, Solar GP, et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 2002;417:954–958.

    Article  PubMed  CAS  Google Scholar 

  197. Kopp HG, Ramos CA, Rafii S. Contribution of endothelial progenitors and proangiogenic hematopoietic cells to vascularization of tumor and ischemic tissue. Curr Opin Hematol 2006;13:175–181.

    Article  PubMed  CAS  Google Scholar 

  198. Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR-1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005;438:820–827.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Daniel J. Hicklin PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Genzyme Corporation, Framingham, MA

    Beverly A. Teicher PhD

  2. M. D. Anderson Cancer Center, The University of Texas, Houston, TX

    Lee M. Ellis MD

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Humana Press

About this chapter

Cite this chapter

Hicklin, D.J. (2008). Vascular Endothelial Growth Factor Family and Its Receptors. In: Teicher, B.A., Ellis, L.M. (eds) Antiangiogenic Agents in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-184-0_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-184-0_1

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-870-6

  • Online ISBN: 978-1-59745-184-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation