Skip to main content
SpringerLink
Log in
Book cover

Regulation of Gene Expression in the Tumor Environment pp 79–124Cite as

Molecular Basis for Vascular Endothelial Growth Factor Expression in Tumor

  • Chapter

  • 413 Accesses

Part of the book series: TTME ((TTME,volume 2))

Abstract

Vascular endothelial growth factor (VEGF) critically regulates tumor angiogenesis through its potent functions as a stimulator of endothelial cell survival, mitogenesis, migration, and differentiation, as well as vascular permeability, immunosuppression and mobilization of endothelial progenitor cells from the bone marrow into the peripheral circulation. Genetic alterations and a chaotic tumor microenvironment are clearly attributed to numerous abnormalities in the expression and signaling of VEGF and confer a tremendous survival and growth advantage to vascular endothelial cells as manifested by exuberant tumor angiogenesis and a consequent malignant phenotype. Designing effective therapeutic strategies targeting VEGF to control tumor growth and metastasis requires understanding the molecular mechanisms of both inducible and constitutive VEGF expression.

This is a preview of subscription content, 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   129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
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

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 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(4587):983–85.

    Article  CAS  PubMed  Google Scholar 

  2. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246:1306–09.

    Article  CAS  PubMed  Google Scholar 

  3. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989;246:1309–12.

    Article  CAS  PubMed  Google Scholar 

  4. Baldwin ME, Stacker SA, Achen MG. Molecular control of lymphangiogenesis. Bioessays. 2002;24:1030–40.

    Article  CAS  PubMed  Google Scholar 

  5. Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Detmar MJ, Lawitts JA, Benjamin L, Tan X, Manseau EJ, Dvorak AM, Dvorak HF. Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med. 2002;196:1497–506.

    Article  CAS  PubMed  Google Scholar 

  6. Ohm JE, Gabrilovich DI, Sempowski GD, Kisseleva E, Parman KS, Nadaf S, Carbone DP. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood.2003;101:4878–86.

    Article  CAS  PubMed  Google Scholar 

  7. Ohm JE, Carbone DP. VEGF as a mediator of tumor-associated immunodeficiency. Immunol Res. 2001; 23: 263–72.

    Article  CAS  PubMed  Google Scholar 

  8. Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L, Wu Y, Hicklin D, Zhu Z, Hackett NR, Crystal RG, Moore MA, Hajjar KA, Manova K, Benezra R, Rafii S. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med. 2001; 7:1194–201.

    Article  CAS  PubMed  Google Scholar 

  9. Rafii S, Lyden D, Benezra R, Hattori K, Heissig B. Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat Rev Cancer. 2002; 2:826–35.

    Article  CAS  PubMed  Google Scholar 

  10. Mann DR, Plant TM. Leptin and pubertal development. Semin Reprod Med. 2002; 20: 93–102.

    Article  CAS  PubMed  Google Scholar 

  11. 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: 168–69.

    Article  CAS  PubMed  Google Scholar 

  12. Paavonen K, Horelli-Kuitunen N, Chilov D, Kukk E, Pennanen S, Kallioniemi OP, Pajusola K, Olofsson B, Eriksson U, Joukov V, Palotie A, Alitalo K. Novel human vascular endothelial growth factor genes VEGF-B and VEGF-C localize to chromosomes 11q13 and 4q34, respectively. Circulation. 1996; 93: 1079–82.

    CAS  PubMed  Google Scholar 

  13. Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K. 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 Jan 15;15(2):290–98. Erratum in: EMBO J. 1996; 15: 1751.

    Google Scholar 

  14. Yamada Y, Nezu J, Shimane M, Hirata Y. Molecular cloning of a novel vascular endothelial growth factor, VEGF-D. Genomics. 1997; 42: 483–88.

    Article  CAS  PubMed  Google Scholar 

  15. Lyttle DJ, Fraser KM, Fleming SB, Mercer AA, Robinson AJ. Homologs of vascular endothelial growth factor are encoded by the poxvirus orf virus. J Virol. 1994; 68: 84–92.

    CAS  PubMed  Google Scholar 

  16. 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: 9267–71.

    Article  CAS  PubMed  Google Scholar 

  17. Olofsson B, Korpelainen E, Pepper MS, Mandriota SJ, Aase K, Kumar V, Gunji Y, Jeltsch MM, Shibuya M, Alitalo K, Eriksson U. Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proc Natl Acad Sci USA. 1998; 95: 11709–14.

    Article  CAS  PubMed  Google Scholar 

  18. Makinen T, Olofsson B, Karpanen T, Hellman U, Soker S, Klagsbrun M, Eriksson U, Alitalo K. Differential binding of vascular endothelial growth factor B splice and proteolytic isoforms to neuropilin-1. J Biol Chem. 1999; 274: 21217–22.

    Article  CAS  PubMed  Google Scholar 

  19. Achen MG, Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA. 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: 548–53.

    Article  CAS  PubMed  Google Scholar 

  20. Stacker SA, Stenvers K, Caesar C, Vitali A, Domagala T, Nice E, Roufail S, Simpson RJ, Moritz R, Karpanen T, Alitalo K, Achen MG. Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers. J Biol Chem. 1999; 274: 32127–36.

    Article  CAS  PubMed  Google Scholar 

  21. Wise LM, Veikkola T, Mercer AA, Savory LJ, Fleming SB, Caesar C, Vitali A, Makinen T, Alitalo K, Stacker SA. Vascular endothelial growth factor (VEGF)-like protein from orf virus NZ2 binds to VEGFR2 and neuropilin-1. Proc Natl Acad Sci USA. 1999; 96: 3071–76.

    Article  CAS  PubMed  Google Scholar 

  22. Cao Y, Ji WR, Qi P, Rosin A, Cao Y. Placenta growth factor: identification and characterization of a novel isoform generated by RNA alternative splicing. Biochem Biophys Res Commun. 1997; 235: 493–98.

    Article  CAS  PubMed  Google Scholar 

  23. Park JE, Chen HH, Winer J, Houck KA, 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: 25646–54.

    CAS  PubMed  Google Scholar 

  24. DiSalvo J, Bayne ML, Conn G, Kwok PW, Trivedi PG, Soderman DD, Palisi TM, Sullivan KA, Thomas KA. Purification and characterization of a naturally occurring vascular endothelial growth factor: placenta growth factor heterodimer. J Biol Chem. 1995; 270: 7717–23.

    Article  CAS  PubMed  Google Scholar 

  25. Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Biochem Soc Trans. 2003; 31(Pt 1): 20–24.

    CAS  PubMed  Google Scholar 

  26. 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: 735–45.

    Article  CAS  PubMed  Google Scholar 

  27. Stacker SA, Baldwin ME, Achen MG. The role of tumor lymphangiogenesis in metastatic spread. FASEB J. 2002; 16: 922–34.

    Article  CAS  PubMed  Google Scholar 

  28. Zachary I, Gliki G. Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovasc Res. 2001; 49: 568–81.

    Article  CAS  PubMed  Google Scholar 

  29. Karkkainen MJ, Saaristo A, Jussila L, Karila KA, Lawrence EC, Pajusola K, Bueler H, Eichmann A, Kauppinen R, Kettunen MI, Yla-Herttuala S, Finegold DN, Ferrell RE, Alitalo K. A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci USA. 2001; 98: 12677–82.

    Article  CAS  PubMed  Google Scholar 

  30. Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989; 161: 851–58.

    Article  CAS  PubMed  Google Scholar 

  31. Olofsson B, Pajusola K, Kaipainen A, von Euler G, Joukov V, Saksela O, Orpana A, Pettersson RF, Alitalo K, Eriksson U. Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci USA. 1996; 93: 2576–81.

    Google Scholar 

  32. Matsumoto T, Claesson-Welsh L. VEGF receptor signal transduction. Sci STKE. 2001; 2001(112): RE21.

    Google Scholar 

  33. Zachary I. Signaling mechanisms mediating vascular protective actions of vascular endothelial growth factor. Am J Physiol Cell Physiol. 2001; 280: C1375–86.

    Google Scholar 

  34. Cross MJ, Claesson-Welsh L. FGF and VEGF function in angiogenesis: signalling pathways, biological responses and therapeutic inhibition. Trends Pharmacol Sci. 2001; 22: 201–7.

    Article  CAS  PubMed  Google Scholar 

  35. Almand B, Resser JR, Lindman B, Nadaf S, Clark JI, Kwon ED, Carbone DP, Gabrilovich DI. Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res. 2000; 6(5): 1755–66.

    CAS  PubMed  Google Scholar 

  36. Saito H, Tsujitani S, Ikeguchi M, Maeta M, Kaibara N. Relationship between the expression of vascular endothelial growth factor and the density of dendritic cells in gastric adenocarcinoma tissue. Br J Cancer. 1998; 78: 1573–7.

    CAS  PubMed  Google Scholar 

  37. Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, Carbone DP. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood. 1998; 92: 4150–66.

    CAS  PubMed  Google Scholar 

  38. Oyama T, Ran S, Ishida T, Nadaf S, Kerr L, Carbone DP, Gabrilovich DI. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol. 1998; 160: 1224–32.

    CAS  PubMed  Google Scholar 

  39. Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med. 1996; 2: 1096–103.

    Article  CAS  PubMed  Google Scholar 

  40. Gabrilovich DI, Ishida T, Nadaf S, Ohm JE, Carbone DP. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res. 1999; 5: 2963–70.

    CAS  PubMed  Google Scholar 

  41. Bouloumie A, Schini-Kerth VB, Busse R. Vascular endothelial growth factor up-regulates nitric oxide synthase expression in endothelial cells. Cardiovasc Res. 1999; 41: 773–80.

    Article  CAS  PubMed  Google Scholar 

  42. Shen BQ, Lee DY, Zioncheck TF. Vascular endothelial growth factor governs endothelial nitric-oxide synthase expression via a KDR/Flk-1 receptor and a protein kinase C signaling pathway. J Biol Chem. 1999; 274: 33057–63.

    Article  CAS  PubMed  Google Scholar 

  43. Pepper MS, Ferrara N, Orci L, Montesano R. Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. Biochem Biophys Res Commun. 1991; 181: 902–06.

    Article  CAS  PubMed  Google Scholar 

  44. Landgren E, Schiller P, Cao Y, Claesson-Welsh L. Placenta growth factor stimulates MAP kinase and mitogenicity but not phospholipase C-gamma and migration of endothelial cells expressing Flt 1. Oncogene. 1998; 16: 359–67.

    Article  CAS  PubMed  Google Scholar 

  45. Mason JC, Lidington EA, Yarwood H, Lublin DM, Haskard DO. Induction of endothelial cell decay-accelerating factor by vascular endothelial growth factor: a mechanism for cytoprotection against complement-mediated injury during inflammatory angiogenesis. Arthritis Rheum. 2001; 44: 138–50.

    Article  CAS  PubMed  Google Scholar 

  46. Zebrowski BK, Yano S, Liu W, Shaheen RM, Hicklin DJ, Putnam JB Jr, Ellis LM. Vascular endothelial growth factor levels and induction of permeability in malignant pleural effusions. Clin Cancer Res. 1999; 5: 3364–68.

    CAS  PubMed  Google Scholar 

  47. Zebrowski BK, Liu W, Ramirez K, Akagi Y, Mills GB, Ellis LM. Markedly elevated levels of vascular endothelial growth factor in malignant ascites. Ann Surg Oncol. 1999; 6: 373–78.

    Google Scholar 

  48. Hazelton D, Nicosia RF, Nicosia SV. Vascular endothelial growth factor levels in ovarian cyst fluid correlate with malignancy. Clin Cancer Res. 1999; 5: 823–29.

    CAS  PubMed  Google Scholar 

  49. Minagawa N, Nakayama Y, Hirata K, Onitsuka K, Inoue Y, Nagata N, Itoh H. Correlation of plasma level and immunohistochemical expression of vascular endothelial growth factor in patients with advanced colorectal cancer. Anticancer Res. 2002; 22: 2957–63.

    CAS  PubMed  Google Scholar 

  50. Chao C, Al-Saleem T, Brooks JJ, Rogatko A, Kraybill WG, Eisenberg B. Vascular endothelial growth factor and soft tissue sarcomas: tumor expression correlates with grade. Ann Surg Oncol. 2001; 8: 260–67.

    Article  CAS  PubMed  Google Scholar 

  51. Lamszus K, Lengler U, Schmidt NO, Stavrou D, Ergun S, Westphal M. Vascular endothelial growth factor, hepatocyte growth factor/scatter factor, basic fibroblast growth factor, and placenta growth factor in human meningiomas and their relation to angiogenesis and malignancy. Neurosurgery. 2000; 46: 938–47.

    Article  CAS  PubMed  Google Scholar 

  52. 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: 4368–80.

    Article  CAS  PubMed  Google Scholar 

  53. Toi M, Matsumoto T, Bando H. Vascular endothelial growth factor: its prognostic, predictive, and therapeutic implications. Lancet Oncol. 2001; 2: 667–73.

    Article  CAS  PubMed  Google Scholar 

  54. Gasparini G, Toi M, Gion M, Verderio P, Dittadi R, Hanatani M, Matsubara I, Vinante O, Bonoldi E, Boracchi P, Gatti C, Suzuki H, Tominaga T. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst. 1997 Jan 15; 89(2): 139–47.

    Google Scholar 

  55. Yamamoto S, Konishi I, Mandai M, Kuroda H, Komatsu T, Nanbu K, Sakahara H, Mori T. Expression of vascular endothelial growth factor (VEGF) in epithelial ovarian neoplasms: correlation with clinicopathology and patient survival, and analysis of serum VEGF levels. Br J Cancer. 1997; 76: 1221–27.

    CAS  PubMed  Google Scholar 

  56. Abdulrauf SI, Edvardsen K, Ho KL, Yang XY, Rock JP, Rosenblum ML. Vascular endothelial growth factor expression and vascular density as prognostic markers of survival in patients with low-grade astrocytoma. J Neurosurg. 1998; 88: 513–20.

    Article  CAS  PubMed  Google Scholar 

  57. Ishigami SI, Arii S, Furutani M, Niwano M, Harada T, Mizumoto M, Mori A, Onodera H, Imamura M. Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer. Br J Cancer. 1998; 78: 1379–84.

    CAS  PubMed  Google Scholar 

  58. Yuan A, Yu CJ, Chen WJ, Lin FY, Kuo SH, Luh KT, Yang PC. Correlation of total VEGF mRNA and protein expression with histologic type, tumor angiogenesis, patient survival and timing of relapse in non-small-cell lung cancer. Int J Cancer. 2000; 89: 475–83.

    Article  CAS  PubMed  Google Scholar 

  59. Seo Y, Baba H, Fukuda T, Takashima M, Sugimachi K. High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer. 2000; 88: 2239–45.

    Article  CAS  PubMed  Google Scholar 

  60. Tempfer C, Obermair A, Hefler L, Haeusler G, Gitsch G, Kainz C. Vascular endothelial growth factor serum concentrations in ovarian cancer. Obstet Gynecol. 1998; 92: 360–63.

    Article  CAS  PubMed  Google Scholar 

  61. Hyodo I, Doi T, Endo H, Hosokawa Y, Nishikawa Y, Tanimizu M, Jinno K, Kotani Y. Clinical significance of plasma vascular endothelial growth factor in gastrointestinal cancer. Eur J Cancer. 1998; 34: 2041–45.

    Article  CAS  PubMed  Google Scholar 

  62. Karayiannakis AJ, Syrigos KN, Polychronidis A, Zbar A, Kouraklis G, Simopoulos C, Karatzas G. Circulating VEGF levels in the serum of gastric cancer patients: correlation with pathological variables, patient survival, and tumor surgery. Ann Surg. 2002; 236: 37–42.

    Article  PubMed  Google Scholar 

  63. Aguayo A, Kantarjian HM, Estey EH, Giles FJ, Verstovsek S, Manshouri T, Gidel C, O’Brien S, Keating MJ, Albitar M. Plasma vascular endothelial growth factor levels have prognostic significance in patients with acute myeloid leukemia but not in patients with myelodysplastic syndromes. Cancer. 2002; 95: 1923–30.

    Article  PubMed  Google Scholar 

  64. de Bont ES, Fidler V, Meeuwsen T, Scherpen F, Hahlen K, Kamps WA. Vascular endothelial growth factor secretion is an independent prognostic factor for relapse-free survival in pediatric acute myeloid leukemia patients. Clin Cancer Res. 2002; 8: 2856–61.

    PubMed  Google Scholar 

  65. Rosen LS. Clinical experience with angiogenesis signaling inhibitors: focus on vascular endothelial growth factor (VEGF) blockers. Cancer Control. 2002; 9(2 Suppl): 36–44.

    PubMed  Google Scholar 

  66. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002; 29(6 Suppl 16): 15–18.

    CAS  PubMed  Google Scholar 

  67. Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA. The human gene for vascular endothelial growth factor: multiple protein forms are encoded through alternative exon splicing. J Biol Chem. 1991; 266: 11947–54.

    CAS  PubMed  Google Scholar 

  68. Lander HM, Jacovina AT, Davis RJ, Tauras JM. Differential activation of mitogen-activated protein kinases by nitric oxide-related species. J Biol Chem. 1996; 271: 19705–09.

    Article  CAS  PubMed  Google Scholar 

  69. Benckert C, Jonas S, Cramer T, Von Marschall Z, Schafer G, Peters M, Wagner K, Radke C, Wiedenmann B, Neuhaus P, Hocker M, Rosewicz S. Transforming growth factor beta 1 stimulates vascular endothelial growth factor gene transcription in human cholangiocellular carcinoma cells. Cancer Res. 2003; 63: 1083–92.

    CAS  PubMed  Google Scholar 

  70. Shi Q, Le X, Abbruzzese JL, Peng Z, Qian CN, Tang H, Xiong Q, Wang B, Li XC, Xie K. Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma. Cancer Res. 2001; 61: 4143–54.

    CAS  PubMed  Google Scholar 

  71. Sanchez-Elsner T, Botella LM, Velasco B, Corbi A, Attisano L, Bernabeu C. Synergistic cooperation between hypoxia and transforming growth factor-beta pathways on human vascular endothelial growth factor gene expression. J Biol Chem. 2001; 276: 38527–35.

    Article  CAS  PubMed  Google Scholar 

  72. Kimura H, Weisz A, Kurashima Y, Hashimoto K, Ogura T, D’Acquisto F, Addeo R, Makuuchi M, Esumi H. Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide. Blood. 2000; 95: 189–97.

    CAS  PubMed  Google Scholar 

  73. Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL, Xie K. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene. 2003; 22: 319–29.

    Article  CAS  PubMed  Google Scholar 

  74. Mueller MD, Vigne JL, Minchenko A, Lebovic DI, Leitman DC, Taylor RN. Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta. Proc Natl Acad Sci USA. 2000; 97: 10972–77.

    Article  CAS  PubMed  Google Scholar 

  75. Kadonaga JT, Carner KR, Masiarz FR, Tjian R. Isolation of cDNA encoding transcription factor Sp1 and functional analysis of the DNA binding domain. Cell. 1987; 51: 1079–90.

    Article  CAS  PubMed  Google Scholar 

  76. Reisinger K, Kaufmann R, Gille J. Increased Sp1 phosphorylation as a mechanism of hepatocyte growth factor (HGF/SF)-induced vascular endothelial growth factor (VEGF/VPF) transcription. J Cell Sci. 2003; 116(Pt 2): 225–38.

    Article  CAS  PubMed  Google Scholar 

  77. Ryuto M, Ono M, Izumi H, Yoshida S, Weich HA, Kohno K, Kuwano M. Induction of vascular endothelial growth factor by tumor necrosis factor alpha in human glioma cells. Possible roles of SP-1. J Biol Chem. 1996; 271: 28220–28.

    Article  CAS  PubMed  Google Scholar 

  78. Siemeister G, Weindel K, Mohrs K, Barleon B, Martiny-Baron G, Marme D. Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein. Cancer Res. 1996; 56: 2299–301.

    CAS  PubMed  Google Scholar 

  79. Mukhopadhyay D, Knebelmann B, Cohen HT, Ananth S, Sukhatme VP. The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. Mol Cell Biol. 1997; 17: 5629–39.

    CAS  PubMed  Google Scholar 

  80. Cohen HT, Zhou M, Welsh AM, Zarghamee S, Scholz H, Mukhopadhyay D, Kishida T, Zbar B, Knebelmann B, Sukhatme VP. An important von Hippel-Lindau tumor suppressor domain mediates Sp1-binding and self-association. Biochem Biophys Res Commun. 1999; 266: 43–50.

    Article  CAS  PubMed  Google Scholar 

  81. Zhang L, Yu D, Hu M, Xiong S, Lang A, Ellis LM, Pollock RE. Wild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression. Cancer Res. 2000; 60: 3655–61.

    CAS  PubMed  Google Scholar 

  82. 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: 6952–57.

    CAS  PubMed  Google Scholar 

  83. Salimath B, Marme D, Finkenzeller G. Expression of the vascular endothelial growth factor gene is inhibited by p73. Oncogene. 2000; 19: 3470–76.

    Article  CAS  PubMed  Google Scholar 

  84. Mukhopadhyay D, Tsiokas L, Zhou XM, Foster D, Brugge JS, Sukhatme VP. Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation. Nature. 1995; 375(6532): 577–81.

    Article  CAS  PubMed  Google Scholar 

  85. Rak J, Filmus J, Finkenzeller G, Grugel S, Marme D, Kerbel RS. Oncogenes as inducers of tumor angiogenesis. Cancer Metastasis Rev. 1995; 14: 263–77.

    Article  CAS  PubMed  Google Scholar 

  86. Schafer G, Cramer T, Suske G, Kemmner W, Wiedenmann B, Hocker M. Oxidative stress regulates vascular endothelial growth factor-A gene transcription through Sp1- and Sp3-dependent activation of two proximal GC-rich promoter elements. J Biol Chem. 2003; 278: 8190–98.

    Article  PubMed  CAS  Google Scholar 

  87. Berra E, Milanini J, Richard DE, Le Gall M, Vinals F, Gothie E, Roux D, Pages G, Pouyssegur J. Signaling angiogenesis via p42/p44 MAP kinase and hypoxia. Biochem Pharmacol. 2000; 60: 1171–78.

    Article  CAS  PubMed  Google Scholar 

  88. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol. 2001; 21: 3995–4004.

    Article  CAS  PubMed  Google Scholar 

  89. Minet E, Arnould T, Michel G, Roland I, Mottet D, Raes M, Remacle J, Michiels C. ERK activation upon hypoxia: involvement in HIF-1 activation. FEBS Lett. 2000; 468: 53–58.

    Article  CAS  PubMed  Google Scholar 

  90. Wei LH, Kuo ML, Chen CA, Chou CH, Lai KB, Lee CN, Hsieh CY. Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene. 2003; 22: 1517–27.

    Article  CAS  PubMed  Google Scholar 

  91. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D, Heller R, Ellis LM, Karras J, Bromberg J, Pardoll D, Jove R, Yu H. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 2002; 21: 2000–2008.

    Article  CAS  PubMed  Google Scholar 

  92. Funamoto M, Fujio Y, Kunisada K, Negoro S, Tone E, Osugi T, Hirota H, Izumi M, Yoshizaki K, Walsh K, Kishimoto T, Yamauchi-Takihara K. Signal transducer and activator of transcription 3 is required for glycoprotein 130-mediated induction of vascular endothelial growth factor in cardiac myocytes. J Biol Chem. 2000; 275: 10561–66.

    Article  CAS  PubMed  Google Scholar 

  93. Buettner R, Mora LB, Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res. 2002; 8: 945–54.

    CAS  PubMed  Google Scholar 

  94. Leonard WJ. Role of Jak kinases and STATs in cytokine signal transduction. Int J Hematol. 2001; 73: 271–77.

    CAS  PubMed  Google Scholar 

  95. Turkson J, Jove R. STAT proteins: novel molecular targets for cancer drug discovery. Oncogene. 2000; 19: 6613–26.

    Article  CAS  PubMed  Google Scholar 

  96. Yahata Y, Shirakata Y, Tokumaru S, Yamasaki K, Sayama K, Hanakawa Y, Detmar M, Hashimoto K. Nuclear translocation of phosphorylated STAT3 is essential for vascular endothelial growth factor-induced human dermal microvascular endothelial cell migration and tube formation. J Biol Chem. 2003; 278: 40026–31.

    Article  CAS  PubMed  Google Scholar 

  97. Swannie HC, Kaye SB. Protein kinase C inhibitors. Curr Oncol Rep. 2002; 4: 37–46.

    Article  PubMed  Google Scholar 

  98. Neri LM, Borgatti P, Capitani S, Martelli AM. Protein kinase C isoforms and lipid second messengers: a critical nuclear partnership? Histol Histopathol. 2002; 17: 1311–16.

    CAS  PubMed  Google Scholar 

  99. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science. 1992; 258: 607–14.

    Article  CAS  PubMed  Google Scholar 

  100. Michiels C, Minet E, Michel G, Mottet D, Piret JP, Raes M. HIF-1 and AP-1 cooperate to increase gene expression in hypoxia: role of MAP kinases. IUBMB Life. 2001; 52: 49–53.

    Article  CAS  PubMed  Google Scholar 

  101. Karin M, Shaulian E. AP-1: linking hydrogen peroxide and oxidative stress to the control of cell proliferation and death. IUBMB Life. 2001; 52: 17–24.

    Article  CAS  PubMed  Google Scholar 

  102. Tsai JC, Teng LJ, Chen CT, Hong TM, Goldman CK, Gillespie GY. Protein kinase C mediates induced secretion of vascular endothelial growth factor by human glioma cells. Biochem Biophys Res Commun. 2003; 309: 952–60.

    Article  CAS  Google Scholar 

  103. Minet E, Michel G, Mottet D, Piret JP, Barbieux A, Raes M, Michiels C. c-JUN gene induction and AP-1 activity is regulated by a JNK-dependent pathway in hypoxic HepG2 cells. Exp Cell Res. 2001; 265: 114–24.

    Article  CAS  PubMed  Google Scholar 

  104. Karin M, Delhase M. JNK or IKK, AP-1 or NF-kappaB, which are the targets for MEK kinase 1 action? Proc Natl Acad Sci USA. 1998; 95: 9067–69.

    Article  CAS  PubMed  Google Scholar 

  105. Karin M, Liu Z, Zandi E. AP-1 function and regulation. Curr Opin Cell Biol. 1997; 9: 240–46.

    Article  CAS  PubMed  Google Scholar 

  106. Gille J, Swerlick RA, Caughman SW. Transforming growth factor-alpha-induced transcriptional ctivation of the vascular permeability factor (VPF/VEGF) gene requires AP-2-dependent DNA binding and transactivation. EMBO J. 1997; 16: 750–59.

    Google Scholar 

  107. Brenneisen P, Blaudschun R, Gille J, Schneider L, Hinrichs R, Wlaschek M, Eming S, Scharffetter-Kochanek K. Essential role of an activator protein-2 (AP-2)/specificity protein 1 (Sp1) cluster in the UVB-mediated induction of the human vascular endothelial growth factor in HaCaT keratinocytes. Biochem J. 2003; 369(Pt 2): 341–49.

    Article  CAS  PubMed  Google Scholar 

  108. Schwarte-Waldhoff I, Schmiegel W. Smad4 transcriptional pathways and angiogenesis. Int J Gastrointest Cancer. 2002; 31: 47–59.

    Article  CAS  PubMed  Google Scholar 

  109. Schwarte-Waldhoff I, Volpert OV, Bouck NP, Sipos B, Hahn SA, Klein-Scory S, Luttges J, Kloppel G, Graeven U, Eilert-Micus C, Hintelmann A, Schmiegel W. Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc Natl Acad Sci USA. 2000; 97: 9624–29.

    Article  CAS  PubMed  Google Scholar 

  110. Damert A, Ikeda E, Risau W. Activator-protein-1 binding potentiates the hypoxia-induciblefactor-1-mediated hypoxia-induced transcriptional activation of vascular-endothelial growth factor expression in C6 glioma cells. Biochem J. 1997; 327(Pt 2): 419–23.

    CAS  PubMed  Google Scholar 

  111. Milanini J, Vinals F, Pouyssegur J, Pages G. p42/p44 MAP kinase module plays a key role in the transcriptional regulation of the vascular endothelial growth factor gene in fibroblasts. J Biol Chem. 1998; 273: 18165–72.

    Article  CAS  PubMed  Google Scholar 

  112. Blaudschun R, Sunderkotter C, Brenneisen P, Hinrichs R, Peters T, Schneider L, Razi-Wolf Z, Hunzelmann N, Scharffetter-Kochanek K. Vascular endothelial growth factor causally contributes to the angiogenic response upon ultraviolet B irradiation in vivo. Br J Dermatol. 2002; 146: 581–87.

    Article  CAS  PubMed  Google Scholar 

  113. Levy AP, Levy NS, Goldberg MA. Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J Biol Chem. 1996; 271: 2746–53.

    Article  CAS  PubMed  Google Scholar 

  114. Levy NS, Chung S, Furneaux H, Levy AP. Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. J Biol Chem. 1998; 273: 6417–23.

    Article  CAS  PubMed  Google Scholar 

  115. Nabors LB, Gillespie GY, Harkins L, King PH. HuR, a RNA stability factor, is expressed in malignant brain tumors and binds to adenine- and uridine-rich elements within the 3’ untranslated regions of cytokine and angiogenic factor mRNAs. Cancer Res. 2001; 61: 2154–61.

    CAS  PubMed  Google Scholar 

  116. Dibbens JA, Miller DL, Damert A, Risau W, Vadas MA, Goodall GJ. Hypoxic regulation of vascular endothelial growth factor mRNA stability requires the cooperation of multiple RNA elements. Mol Biol Cell. 1999; 10: 907–19.

    CAS  PubMed  Google Scholar 

  117. Pages G, Berra E, Milanini J, Levy AP, Pouyssegur J. Stress-activated protein kinases (JNK and p38/HOG) are essential for vascular endothelial growth factor mRNA stability. J Biol Chem. 2000; 275: 26484–91.

    Article  CAS  PubMed  Google Scholar 

  118. Prats AC, Prats H. Translational control of gene expression: role of IRESs and consequences for cell transformation and angiogenesis. Prog Nucleic Acid Res Mol Biol. 2002; 72: 367–413.

    Article  CAS  PubMed  Google Scholar 

  119. Guo P, Xu L, Pan S, Brekken RA, Yang ST, Whitaker GB, Nagane M, Thorpe PE, Rosenbaum JS, Su Huang HJ, Cavenee WK, Cheng SY. Vascular endothelial growth factor isoforms display distinct activities in promoting tumor angiogenesis at different anatomic sites. Cancer Res. 2001; 61: 8569–77.

    CAS  PubMed  Google Scholar 

  120. Stein I, Itin A, Einat P, Skaliter R, Grossman Z, Keshet E. Translation of vascular endothelial growth factor mRNA by internal ribosome entry: implications for translation under hypoxia. Mol Cell Biol. 1998; 18: 3112–19.

    CAS  PubMed  Google Scholar 

  121. Huez I, Creancier L, Audigier S, Gensac MC, Prats AC, Prats H. Two independent internal ribosome entry sites are involved in translation initiation of vascular endothelial growth factor mRNA. Mol Cell Biol. 1998; 18: 6178–90.

    CAS  PubMed  Google Scholar 

  122. Kevil CG, De Benedetti A, Payne DK, Coe LL, Laroux FS, Alexander JS. Translational regulation of vascular permeability factor by eukaryotic initiation factor 4E: implications for tumor angiogenesis. Int J Cancer. 1996; 65: 785–90.

    Article  CAS  PubMed  Google Scholar 

  123. Li BD, Liu L, Dawson M, De Benedetti A. Overexpression of eukaryotic initiation factor 4E (eIF4E) in breast carcinoma. Cancer. 1997; 79: 2385–90.

    Article  CAS  PubMed  Google Scholar 

  124. Crew JP, Fuggle S, Bicknell R, Cranston DW, de Benedetti A, Harris AL. Eukaryotic initiation factor-4E in superficial and muscle invasive bladder cancer and its correlation with vascular endothelial growth factor expression and tumour progression. Br J Cancer. 2000; 82: 161–66.

    Google Scholar 

  125. Kuwabara K, Matsumoto M, Ikeda J, Hori O, Ogawa S, Maeda Y, Kitagawa K, Imuta N, Kinoshita T, Stern DM, Yanagi H, Kamada T. Purification and characterization of a novel stress protein, the 150-kDa oxygen-regulated protein (ORP150), from cultured rat astrocytes and its expression in ischemic mouse brain. J Biol Chem. 1996; 271: 5025–32.

    Article  CAS  PubMed  Google Scholar 

  126. Ozawa K, Kondo T, Hori O, Kitao Y, Stern DM, Eisenmenger W, Ogawa S, Ohshima T. Expression of the oxygen-regulated protein ORP150 accelerates wound healing by modulating intracellular VEGF transport. J Clin Invest. 2001; 108: 41–50.

    CAS  PubMed  Google Scholar 

  127. Miyagi T, Hori O, Koshida K, Egawa M, Kato H, Kitagawa Y, Ozawa K, Ogawa S, Namiki M. Antitumor effect of reduction of 150-kDa oxygen-regulated protein expression on human prostate cancer cells. Int J Urol. 2002; 9: 577–85.

    Article  CAS  PubMed  Google Scholar 

  128. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000; 407(6801): 249–57.

    Article  CAS  PubMed  Google Scholar 

  129. Igarashi H, Esumi M, Ishida H, Okada K. Vascular endothelial growth factor overexpression is correlated with von Hippel-Lindau tumor suppressor gene inactivation in patients with sporadic renal cell carcinoma. Cancer. 2002; 95: 47–53.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  132. Larcher F, Robles AI, Duran H, Murillas R, Quintanilla M, Cano A, Conti CJ, Jorcano JL. Up-regulation of vascular endothelial growth factor/vascular permeability factor in mouse skin carcinogenesis correlates with malignant progression state and activated H-ras expression levels. Cancer Res. 1996; 56: 5391–96.

    CAS  PubMed  Google Scholar 

  133. D’Arcangelo G, Habas R, Wang S, Halegoua S, Salton SR. Activation of codependent transcription factors is required for transcriptional induction of the vgf gene by nerve growth factor and Ras. Mol Cell Biol. 1996; 16: 4621–31.

    CAS  PubMed  Google Scholar 

  134. White FC, Benehacene A, Scheele JS, Kamps M. VEGF mRNA is stabilized by ras and tyrosine kinase oncogenes, as well as by UV radiation – evidence for divergent stabilization pathways. Growth Factors. 1997; 14: 199–212.

    Article  CAS  PubMed  Google Scholar 

  135. Sodhi A, Montaner S, Miyazaki H, Gutkind JS. MAPK and Akt act cooperatively but independently on hypoxia inducible factor-1alpha in rasV12 upregulation of VEGF. Biochem Biophys Res Commun. 2001; 287: 292–300.

    Article  CAS  PubMed  Google Scholar 

  136. Milanini-Mongiat J, Pouyssegur J, Pages G. Identification of two Sp1 phosphorylation sites for p42/p44 mitogen-activated protein kinases: their implication in vascular endothelial growth factor gene transcription. J Biol Chem. 2002; 277: 20631–39.

    Article  CAS  PubMed  Google Scholar 

  137. Pal S, Datta K, Khosravi-Far R, Mukhopadhyay D. Role of protein kinase C-zeta in Ras-mediated transcriptional activation of vascular permeability factor/vascular endothelial growth factor expression. J Biol Chem. 2001; 276: 2395–403.

    Article  CAS  PubMed  Google Scholar 

  138. Pal S, Claffey KP, Cohen HT, Mukhopadhyay D. Activation of Sp1-mediated vascular permeability factor/vascular endothelial growth factor transcription requires specific interaction with protein kinase C-zeta. J Biol Chem. 1998; 273: 26277–80.

    Article  CAS  PubMed  Google Scholar 

  139. Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-i S, Wada H, Fujimoto J, Kohno M. Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene. 1999; 18: 813–22.

    Article  CAS  PubMed  Google Scholar 

  140. Salh B, Marotta A, Matthewson C, Ahluwalia M, Flint J, Owen D, Pelech S. Investigation of the Mek-MAP kinase-Rsk pathway in human breast cancer. Anticancer Res. 1999; 19(1B): 731–40.

    CAS  PubMed  Google Scholar 

  141. Schmidt CM, McKillop IH, Cahill PA, Sitzmann JV. Increased MAPK expression and activity in primary human hepatocellular carcinoma. Biochem Biophys Res Commun. 1997; 236: 54–58.

    Article  CAS  PubMed  Google Scholar 

  142. Govindarajan B, Bai X, Cohen C, Zhong H, Kilroy S, Louis G, Moses M, Arbiser JL. Malignant transformation of melanocytes to melanoma by constitutive activation of mitogen-activated protein kinase kinase (MAPKK) signaling. J Biol Chem. 2003; 278: 9790–95.

    Article  CAS  PubMed  Google Scholar 

  143. Cohen C, Zavala-Pompa A, Sequeira JH, Shoji M, Sexton DG, Cotsonis G, Cerimele F, Govindarajan B, Macaron N, Arbiser JL. Mitogen-actived protein kinase activation is an early event in melanoma progression. Clin Cancer Res. 2002; 8: 3728–33.

    CAS  PubMed  Google Scholar 

  144. Katsanakis KD, Owen C, Zoumpourlis V. JNK and ERK signaling pathways in multistage mouse carcinogenesis: studies in the inhibition of signaling cascades as a means to understand their in vivo biological role. Anticancer Res. 2002; 22: 755–59.

    CAS  PubMed  Google Scholar 

  145. Mazure NM, Chen EY, Laderoute KR, Giaccia AJ. Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element. Blood. 1997; 90: 3322–31.

    CAS  PubMed  Google Scholar 

  146. Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J Biol Chem. 1999; 274: 32631–37.

    Article  CAS  PubMed  Google Scholar 

  147. Urata Y, Yamaguchi M, Higashiyama Y, Ihara Y, Goto S, Kuwano M, Horiuchi S, Sumikawa K, Kondo T. Reactive oxygen species accelerate production of vascular endothelial growth factor by advanced glycation end products in RAW264.7 mouse macrophages. Free Radic Biol Med. 2002; 32(8): 688–701.

    Article  CAS  PubMed  Google Scholar 

  148. Okajima E, Thorgeirsson UP. Different regulation of vascular endothelial growth factor expression by the ERK and p38 kinase pathways in v-ras, v-raf, and v-myc transformed cells. Biochem Biophys Res Commun. 2000; 270: 108–11.

    Article  CAS  PubMed  Google Scholar 

  149. Miao H, Wei BR, Peehl DM, Li Q, Alexandrou T, Schelling JR, Rhim JS, Sedor JR, Burnett E, Wang B. Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway. Nat Cell Biol. 2001; 3: 527–30.

    Article  CAS  PubMed  Google Scholar 

  150. Zhang X, Gaspard JP, Chung DC. Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Cancer Res. 2001; 61: 6050–54.

    CAS  PubMed  Google Scholar 

  151. Sheta EA, Harding MA, Conaway MR, Theodorescu D. Focal adhesion kinase, Rap1, and transcriptional induction of vascular endothelial growth factor. J Natl Cancer Inst. 2000; 92: 1065–73.

    Article  CAS  PubMed  Google Scholar 

  152. Thomas SM, Brugge JS. Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol. 1997; 13: 513–609.

    Article  CAS  PubMed  Google Scholar 

  153. Gruden G, Thomas S, Burt D, Lane S, Chusney G, Sacks S, Viberti G. Mechanical stretch induces vascular permeability factor in human mesangial cells: mechanisms of signal transduction. Proc Natl Acad Sci USA. 1997; 94: 12112–16.

    Article  CAS  PubMed  Google Scholar 

  154. Gruden G, Araf S, Zonca S, Burt D, Thomas S, Gnudi L, Viberti G. IGF-I induces vascular endothelial growth factor in human mesangial cells via a Src-dependent mechanism. Kidney Int. 2003; 63: 1249–55.

    Article  CAS  PubMed  Google Scholar 

  155. Mukhopadhyay D, Tsiokas L, Sukhatme VP. Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res. 1995; 55: 6161–65.

    CAS  PubMed  Google Scholar 

  156. 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: 501–07.

    Article  CAS  PubMed  Google Scholar 

  157. Ellis LM, Staley CA, Liu W, Fleming RY, Parikh NU, Bucana CD, Gallick GE. Down-regulation of vascular endothelial growth factor in a human colon carcinoma cell line transfected with an antisense expression vector specific for c-src. J Biol Chem. 1998; 273: 1052–57.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  159. Jiang BH, Agani F, Passaniti A, Semenza GL. V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res. 1997; 57: 5328–35.

    CAS  PubMed  Google Scholar 

  160. Lee SW, Kim WJ, Choi YK, Song HS, Son MJ, Gelman IH, Kim YJ, Kim KW. SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier. Nat Med. 2003; 9: 900–06.

    Article  CAS  PubMed  Google Scholar 

  161. Kumar R, Yarmand-Bagheri R. The role of HER2 in angiogenesis. Semin Oncol. 2001; 28(5 Suppl 16): 27–32.

    Article  CAS  PubMed  Google Scholar 

  162. 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 ndothelial 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: 1523–30.

    CAS  PubMed  Google Scholar 

  163. Koukourakis MI, Giatromanolaki A, O’Byrne KJ, Cox J, Krammer B, Gatter KC, Harris AL. bcl-2 and c-erbB-2 proteins are involved in the regulation of VEGF and of thymidine phosphorylase angiogenic activity in non-small-cell lung cancer. Clin Exp Metastasis. 1999; 17: 545–54.

    Article  CAS  PubMed  Google Scholar 

  164. Anan K, Morisaki T, Katano M, Ikubo A, Tsukahara Y, Kojima M, Uchiyama A, Kuroki S, Torisu M, Tanaka M. Assessment of c-erbB2 and vascular endothelial growth factor mRNA expression in fine-needle aspirates from early breast carcinomas: pre-operative determination of malignant potential. Eur J Surg Oncol. 1998; 24: 28–33.

    Article  CAS  PubMed  Google Scholar 

  165. 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: 2855–61.

    Article  CAS  PubMed  Google Scholar 

  166. Lee JS, Kim HS, Jung JJ, Kim YB, Lee MC, Park CS. Expression of vascular endothelial growth factor in invasive ductal carcinoma of the breast and the relation to angiogenesis and p53 and HER-2/neu protein expression. Appl Immunohistochem Mol Morphol. 2002; 10: 289–95.

    Article  CAS  PubMed  Google Scholar 

  167. Lee JS, Kim HS, Jung JJ, Lee MC, Park CS. Expression of vascular endothelial growth factor in adenocarcinomas of the uterine cervix and its relation to angiogenesis and p53 and c-erbB-2 protein expression. Gynecol Oncol. 2002; 85: 469–75.

    Google Scholar 

  168. Yen L, Benlimame N, Nie ZR, Xiao D, Wang T, Al Moustafa AE, Esumi H, Milanini J, Hynes NE, Pages G, Alaoui-Jamali MA. Differential regulation of tumor angiogenesis by distinct ErbB homo- and heterodimers. Mol Biol Cell. 2002; 13: 4029–44.

    Article  CAS  PubMed  Google Scholar 

  169. Mayerhofer M, Valent P, Sperr WR, Griffin JD, Sillaber C. BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood. 2002; 100: 3767–75.

    Article  CAS  PubMed  Google Scholar 

  170. Ebos JM, Tran J, Master Z, Dumont D, Melo JV, Buchdunger E, Kerbel RS. Imatinib mesylate (STI-571) reduces Bcr-Abl-mediated vascular endothelial growth factor secretion in chronic myelogenous leukemia. Mol Cancer Res. 2002; 1: 89–95.

    CAS  PubMed  Google Scholar 

  171. Lopez-Ocejo O, Viloria-Petit A, Bequet-Romero M, Mukhopadhyay D, Rak J, Kerbel RS. Oncogenes and tumor angiogenesis: the HPV-16 E6 oncoprotein activates the vascular endothelial growth factor (VEGF) gene promoter in a p53 independent manner. Oncogene. 2000; 19: 4611–20.

    Article  CAS  PubMed  Google Scholar 

  172. Fontanini G, Boldrini L, Vignati S, Chine S, Basolo F, Silvestri V, Lucchi M, Mussi A, Angeletti CA, Bevilacqua G. Bcl2 and p53 regulate vascular endothelial growth factor (VEGF)-mediated angiogenesis in non-small cell lung carcinoma. Eur J Cancer. 1998; 34: 718–23.

    Article  CAS  PubMed  Google Scholar 

  173. Kobayashi N, Ishii M, Ueno Y, Kisara N, Chida N, Iwasaki T, Toyota T. Co-expression of Bcl-2 protein and vascular endothelial growth factor in hepatocellular carcinomas treated by hemoembolization. Liver. 1999; 19: 25–31.

    Article  CAS  PubMed  Google Scholar 

  174. Biroccio A, Candiloro A, Mottolese M, Sapora O, Albini A, Zupi G, Del Bufalo D. Bcl-2 overexpression and hypoxia synergistically act to modulate vascular endothelial growth factor expression and in vivo angiogenesis in a breast carcinoma line. FASEB J. 2000; 14: 652–60.

    CAS  PubMed  Google Scholar 

  175. Wizigmann-Voos S, Breier G, Risau W, Plate KH. Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res. 1995; 55: 1358–64.

    CAS  PubMed  Google Scholar 

  176. Siemeister G, Weindel K, Mohrs K, Barleon B, Martiny-Baron G, Marme D. Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein. Cancer Res. 1996; 56: 2299–301.

    CAS  PubMed  Google Scholar 

  177. Ohh M, Takagi Y, Aso T, Stebbins CE, Pavletich NP, Zbar B, Conaway RC, Conaway JW, Kaelin WG Jr. Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel-Lindau protein. J Clin Invest. 1999; 104: 1583–91.

    Article  CAS  PubMed  Google Scholar 

  178. Gnarra JR, Zhou S, Merrill MJ, Wagner JR, Krumm A, Papavassiliou E, Oldfield EH, Klausner RD, Linehan WM. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc Natl Acad Sci USA. 1996; 93: 10589–94.

    Article  CAS  PubMed  Google Scholar 

  179. Iliopoulos O, Levy AP, Jiang C, Kaelin WG Jr, Goldberg MA. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci USA. 1996; 93: 10595–99.

    Article  CAS  PubMed  Google Scholar 

  180. Levy AP, Levy NS, Goldberg MA. Hypoxia-inducible protein binding to vascular endothelial growth factor mRNA and its modulation by the von Hippel-Lindau protein. J Biol Chem. 1996; 271: 25492–97.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  182. Pioli PA, Rigby WF. The von Hippel-Lindau protein interacts with heteronuclear ribonucleoprotein a2 and regulates its expression. J Biol Chem. 2001; 276: 40346–52.

    CAS  PubMed  Google Scholar 

  183. Li Z, Wang D, Na X, Schoen SR, Messing EM, Wu G. The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity. EMBO J. 2003; 22: 1857–67.

    Article  CAS  PubMed  Google Scholar 

  184. Kieser A, Weich HA, Brandner G, Marme D, Kolch W. Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene. 1994; 9: 963–69.

    CAS  PubMed  Google Scholar 

  185. Bouvet M, Ellis LM, Nishizaki M, Fujiwara T, Liu W, Bucana CD, Fang B, Lee JJ, Roth JA. 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: 2288–92.

    CAS  PubMed  Google Scholar 

  186. Choi KS, Bae MK, Jeong JW, Moon HE, Kim KW. Hypoxia-induced angiogenesis during carcinogenesis. J Biochem Mol Biol. 2003; 36: 120–27.

    CAS  PubMed  Google Scholar 

  187. Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, Dillehay LE, Madan A, Semenza GL, Bedi A. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev. 2000; 14: 34–44.

    CAS  PubMed  Google Scholar 

  188. Bae MK, Ahn MY, Jeong JW, Bae MH, Lee YM, Bae SK, Park JW, Kim KR, Kim KW. Jab1 interacts directly with HIF-1alpha and regulates its stability. J Biol Chem. 2002; 277: 9–12.

    Article  CAS  PubMed  Google Scholar 

  189. Pugh CW, Ratcliffe PJ. The von Hippel-Lindau tumor suppressor, hypoxia-inducible factor-1 (HIF-1) degradation, and cancer pathogenesis. Semin Cancer Biol. 2003; 13: 83–89.

    Article  CAS  PubMed  Google Scholar 

  190. Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin WG Jr. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell. 2002; 1: 237–46.

    Article  CAS  PubMed  Google Scholar 

  191. Fontanini G, Vignati S, Lucchi M, Mussi A, Calcinai A, Boldrini L, Chine S, Silvestri V, Angeletti CA, Basolo F, Bevilacqua G. Neoangiogenesis and p53 protein in lung cancer: their prognostic role and their relation with vascular endothelial growth factor (VEGF) expression. Br J Cancer. 1997; 75: 1295–301.

    CAS  PubMed  Google Scholar 

  192. Kang SM, Maeda K, Onoda N, Chung YS, Nakata B, Nishiguchi Y, Sowa M. Combined analysis of p53 and vascular endothelial growth factor expression in colorectal carcinoma for determination of tumor vascularity and liver metastasis. Int J Cancer. 1997; 74: 502–07.

    Article  CAS  PubMed  Google Scholar 

  193. Takahashi Y, Bucana CD, Cleary KR, Ellis LM. p53, vessel count, and vascular endothelial growth factor expression in human colon cancer. Int J Cancer. 1998; 79: 34–38.

    Article  CAS  PubMed  Google Scholar 

  194. Kondo Y, Arii S, Furutani M, Isigami S, Mori A, Onodera H, Chiba T, Imamura M. Implication of vascular endothelial growth factor and p53 status for angiogenesis in noninvasive colorectal carcinoma. Cancer. 2000; 88: 1820–27.

    Article  CAS  PubMed  Google Scholar 

  195. 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: 900–10.

    Article  CAS  PubMed  Google Scholar 

  196. Uchida S, Shimada Y, Watanabe G, Tanaka H, Shibagaki I, Miyahara T, Ishigami S, Imamura M. In oesophageal squamous cell carcinoma vascular endothelial growth factor is associated with p53 mutation, advanced stage and poor prognosis. Br J Cancer. 1998; 77: 1704–09.

    CAS  PubMed  Google Scholar 

  197. Zietz C, Rossle M, Haas C, Sendelhofert A, Hirschmann A, Sturzl M, Lohrs U. MDM-2 oncoprotein overexpression, p53 gene mutation, and VEGF up-regulation in angiosarcomas. Am J Pathol. 1998; 153: 1425–33.

    CAS  PubMed  Google Scholar 

  198. Linderholm BK, Lindahl T, Holmberg L, Klaar S, Lennerstrand J, Henriksson R, Bergh J. The expression of vascular endothelial growth factor correlates with mutant p53 and poor prognosis in human breast cancer. Cancer Res. 2001; 61: 2256–60.

    CAS  PubMed  Google Scholar 

  199. Saito H, Tujitani S, Ikeguchi M, Maeta M, Kaibara N. Neoangiogenesis and relationship to nuclear p53 accumulation and vascular endothelial growth factor expression in advanced gastric carcinoma. Oncology. 1999; 57: 164–72.

    Article  CAS  PubMed  Google Scholar 

  200. Giatromanolaki A, Koukourakis MI, Kakolyris S, Turley H, O’Byrne K, Scott PA, Pezzella F, Georgoulias V, Harris AL, Gatter KC. Vascular endothelial growth factor, wild-type p53, and angiogenesis in early operable non-small cell lung cancer. Clin Cancer Res. 1998; 4: 3017–24.

    CAS  PubMed  Google Scholar 

  201. Ambs S, Bennett WP, Merriam WG, Ogunfusika MO, Oser SM, Khan MA, Jones RT, Harris CC. Vascular endothelial growth factor and nitric oxide synthase expression in human lung cancer and the elation to p53. Br J Cancer. 1998; 78: 233–39.

    CAS  PubMed  Google Scholar 

  202. Maeda T, Matsumura S, Hiranuma H, Jikko A, Furukawa S, Ishida T, Fuchihata H. Expression of vascular endothelial growth factor in human oral squamous cell carcinoma: its association with tumour progression and p53 gene status. J Clin Pathol. 1998; 51: 771–75.

    CAS  PubMed  Google Scholar 

  203. Rosa AR, Schirmer CC, Gurski RR, Meurer L, Edelweiss MI, Kruel CD. Prognostic value of p53 protein expression and vascular endothelial growth factor expression in resected squamous cell carcinoma of the esophagus. Dis Esophagus. 2003; 16: 112–18.

    Article  CAS  PubMed  Google Scholar 

  204. Cascinu S, Graziano F, Catalano V, Barni S, Giordani P, Baldelli AM, Staccioli MP, Rossi C, Brenna A, Valenti A, Muretto P, Catalano G. Vascular endothelial growth factor and p53 expressions in liver and abdominal metastases from colon cancer. Tumour Biol. 2003; 24: 77–81.

    Article  CAS  PubMed  Google Scholar 

  205. Agani F, Kirsch DG, Friedman SL, Kastan MB, Semenza GL. p53 does not repress hypoxia-induced transcription of the vascular endothelial growth factor gene. Cancer Res. 1997; 57: 4474–77.

    CAS  PubMed  Google Scholar 

  206. Vikhanskaya F, Bani MR, Borsotti P, Ghilardi C, Ceruti R, Ghisleni G, Marabese M, Giavazzi R, Broggini M, Taraboletti G. p73 overexpression increases VEGF and reduces thrombospondin-1 production: implications for tumor angiogenesis. Oncogene. 2001; 20: 7293–300.

    Article  CAS  PubMed  Google Scholar 

  207. Tsugawa K, Jones MK, Sugimachi K, Sarfeh IJ, Tarnawski AS. Biological role of phosphatase PTEN in cancer and tissue injury healing. Front Biosci. 2002; 7: e245–51.

    Google Scholar 

  208. Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, Gottschalk AR, Ryan HE, Johnson RS, Jefferson AB, Stokoe D, Giaccia AJ. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 2000; 14: 391–96.

    CAS  PubMed  Google Scholar 

  209. Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW, Semenza GL. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth actor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res. 2000; 60: 1541–45.

    CAS  PubMed  Google Scholar 

  210. Jiang BH, Jiang G, Zheng JZ, Lu Z, Hunter T, Vogt PK. Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell Growth Differ. 2001; 12: 363–69.

    CAS  PubMed  Google Scholar 

  211. Koul D, Shen R, Garyali A, Ke LD, Liu TJ, Yung WK. MMAC/PTEN tumor suppressor gene egulates vascular endothelial growth factor-mediated angiogenesis in prostate cancer. Int J Oncol. 2002; 21: 469–75.

    CAS  PubMed  Google Scholar 

  212. Gomez-Manzano C, Fueyo J, Jiang H, Glass TL, Lee HY, Hu M, Liu JL, Jasti SL, Liu TJ, Conrad CA, Yung WK. Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis. Ann Neurol. 2003; 53: 109–17.

    Article  CAS  PubMed  Google Scholar 

  213. Jiang YA, Fan LF, Jiang CQ, Zhang YY, Luo HS, Tang ZJ, Xia D, Wang M. Expression and significance of PTEN, hypoxia-inducible factor-1 alpha in colorectal adenoma and adenocarcinoma. World J Gastroenterol. 2003; 9: 491–94.

    CAS  PubMed  Google Scholar 

  214. Sharpless NE, DePinho RA. The INK4A/ARF locus and its two gene products. Curr Opin Genet Dev. 1999; 9: 22–30.

    Article  CAS  PubMed  Google Scholar 

  215. Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res. 1998; 72: 141–96.

    Article  CAS  PubMed  Google Scholar 

  216. David K, Ollert MW, Vollmert C, Heiligtag S, Eickhoff B, Erttmann R, Bredehorst R, Vogel CW. Human natural immunoglobulin M antibodies induce apoptosis of human neuroblastoma cells by binding to a Mr 260,000 antigen. Cancer Res. 1999; 59: 3768–75.

    CAS  PubMed  Google Scholar 

  217. Miki K, Shimizu E, Yano S, Tani K, Sone S. Demethylation by 5-aza-2’-deoxycytidine (5-azadC) of p16INK4A gene results in downregulation of vascular endothelial growth factor expression in human lung cancer cell lines. Oncol Res. 2000; 12: 335–42.

    CAS  Google Scholar 

  218. Gibson SL, Dai CY, Lee HW, DePinho RA, Gee MS, Lee WM, Furth EE, Brensinger C, Enders GH. Inhibition of colon tumor progression and angiogenesis by the Ink4a/Arf locus. Cancer Res. 2003; 63: 742–46.

    CAS  PubMed  Google Scholar 

  219. Senoo M, Matsumura Y, Habu S. TAp63gamma (p51A) and dNp63alpha (p73L), two major isoforms of the p63 gene, exert opposite effects on the vascular endothelial growth factor (VEGF) gene expression. Oncogene. 2002; 21: 2455–65.

    Article  CAS  PubMed  Google Scholar 

  220. Kawai H, Li H, Chun P, Avraham S, Avraham HK. Direct interaction between BRCA1 and the estrogen receptor regulates vascular endothelial growth factor (VEGF) transcription and secretion in breast cancer cells. Oncogene. 2002; 21: 7730–39.

    Article  CAS  PubMed  Google Scholar 

  221. Dent P, Yacoub A, Contessa J, Caron R, Amorino G, Valerie K, Hagan MP, Grant S, Schmidt-Ullrich R. Stress and radiation-induced activation of multiple intracellular signaling pathways. Radiat Res. 2003; 159: 283–300.

    Article  CAS  PubMed  Google Scholar 

  222. Danilkovitch-Miagkova A. Oncogenic signaling pathways activated by RON receptor tyrosine kinase. Curr Cancer Drug Targets. 2003 Feb; 3(1): 31–40. Review. Erratum in: Curr Cancer Drug Targets. 2003; 3: 161.

    Google Scholar 

  223. Ang KK, Berkey BA, Tu X, Zhang HZ, Katz R, Hammond EH, Fu KK, Milas L. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002; 62: 7350–56.

    Google Scholar 

  224. Arteaga CL. Overview of epidermal growth factor receptor biology and its role as a therapeutic target in human neoplasia. Semin Oncol. 2002; 29(5 Suppl 14): 3–9.

    Article  CAS  PubMed  Google Scholar 

  225. Fukuda R, Hirota K, Fan F, Jung YD, Ellis LM, Semenza GL. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J Biol Chem. 2002; 277: 38205–11.

    Article  CAS  PubMed  Google Scholar 

  226. Tanaka T, Kanai H, Sekiguchi K, Aihara Y, Yokoyama T, Arai M, Kanda T, Nagai R, Kurabayashi M. Induction of VEGF gene transcription by IL-1 beta is mediated through stress-activated MAP kinases and Sp1 sites in cardiac myocytes. J Mol Cell Cardiol. 2000; 32: 1955–67.

    Article  CAS  PubMed  Google Scholar 

  227. Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 1989; 49: 6449–65.

    CAS  PubMed  Google Scholar 

  228. Intaglietta M, Johnson PC, Winslow RM. Microvascular and tissue oxygen distribution. Cardiovasc Res. 1996; 32: 632–43.

    CAS  PubMed  Google Scholar 

  229. Jain RK. Determinants of tumor blood flow: a review. Cancer Res. 1988; 48: 2641–58.

    CAS  PubMed  Google Scholar 

  230. Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992; 359(6398): 843–45.

    Article  CAS  PubMed  Google Scholar 

  231. Minchenko A, Bauer T, Salceda S, Caro J. Hypoxic stimulation of vascular endothelial growth factor expression in vitro and in vivo. Lab Invest. 1994; 71: 374–79.

    CAS  PubMed  Google Scholar 

  232. Shima DT, Adamis AP, Ferrara N, Yeo KT, Yeo TK, Allende R, Folkman J, D’Amore PA. Hypoxic induction of endothelial cell growth factors in retinal cells: identification and characterization of vascular endothelial growth factor (VEGF) as the mitogen. Mol Med. 1995; 1: 182–93.

    CAS  PubMed  Google Scholar 

  233. Levy AP, Levy NS, Wegner S, Goldberg MA. Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem. 1995; 270: 13333–40.

    Article  CAS  PubMed  Google Scholar 

  234. Liu Y, Cox SR, Morita T, Kourembanas S. Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5’ enhancer. Circ Res. 1995; 77: 638–43.

    CAS  PubMed  Google Scholar 

  235. Madan A, Curtin PT. A 24-base-pair sequence 3’ to the human erythropoietin gene contains a hypoxia-responsive transcriptional enhancer. Proc Natl Acad Sci USA. 1993; 90: 3928–32.

    Article  CAS  PubMed  Google Scholar 

  236. Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, Maher ER, Pugh CW, Ratcliffe PJ, Maxwell PH. Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem. 2000; 275: 25733–41.

    Article  CAS  PubMed  Google Scholar 

  237. Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol. 2000; 2: 423–27.

    Article  CAS  PubMed  Google Scholar 

  238. Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW. Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci USA. 2000; 97: 10430–35.

    Article  CAS  PubMed  Google Scholar 

  239. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999; 399(6733): 271–75.

    Article  CAS  PubMed  Google Scholar 

  240. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001; 292(5516): 468–72

    Google Scholar 

  241. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996; 16: 4604–13.

    CAS  PubMed  Google Scholar 

  242. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999; 59: 5830–35.

    CAS  PubMed  Google Scholar 

  243. Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL. The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol. 2000; 157: 411–21.

    CAS  PubMed  Google Scholar 

  244. Ikeda E, Achen MG, Breier G, Risau W. Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem. 1995; 270: 19761–66.

    Google Scholar 

  245. Goldberg-Cohen I, Furneauxb H, Levy AP. A 40-bp RNA element that mediates stabilization of vascular endothelial growth factor mRNA by HuR. J Biol Chem. 2002; 277: 13635–40.

    Article  CAS  PubMed  Google Scholar 

  246. Akiri G, Nahari D, Finkelstein Y, Le SY, Elroy-Stein O, Levi BZ. Regulation of vascular endothelial growth factor (VEGF) expression is mediated by internal initiation of translation and alternative initiation of transcription. Oncogene. 1998; 17: 227–36.

    Article  CAS  PubMed  Google Scholar 

  247. Miller DL, Dibbens JA, Damert A, Risau W, Vadas MA, Goodall GJ. The vascular endothelial growth factor mRNA contains an internal ribosome entry site. FEBS Lett. 1998; 434: 417–20.

    Article  CAS  PubMed  Google Scholar 

  248. Wike-Hooley JL, Haveman J, Reinhold HS. The relevance of tumour pH to the treatment of malignant disease. Radiother Oncol. 1984; 2: 343–66.

    Article  CAS  PubMed  Google Scholar 

  249. Tannock IF, Rotin D. Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res. 1989; 49: 4373–84.

    CAS  PubMed  Google Scholar 

  250. Fukumura D, Xu L, Chen Y, Gohongi T, Seed B, Jain RK. Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res. 2001; 61: 6020–24.

    CAS  PubMed  Google Scholar 

  251. Xu L, Fukumura D, Jain RK. Acidic extracellular pH induces vascular endothelial growth factor (VEGF) in human glioblastoma cells via ERK1/2 MAPK signaling pathway: mechanism of low pH-induced VEGF. J Biol Chem. 2002; 277: 11368–74.

    Article  CAS  PubMed  Google Scholar 

  252. Brooks SE, Gu X, Kaufmann PM, Marcus DM, Caldwell RB. Modulation of VEGF production by pH and glucose in retinal Muller cells. Curr Eye Res. 1998; 17: 875–82.

    Google Scholar 

  253. Spector JA, Mehrara BJ, Greenwald JA, Saadeh PB, Steinbrech DS, Bouletreau PJ, Smith LP, Longaker MT. Osteoblast expression of vascular endothelial growth factor is modulated by the extracellular microenvironment. Am J Physiol Cell Physiol. 2001; 280: C72–80.

    CAS  PubMed  Google Scholar 

  254. D’Arcangelo D, Facchiano F, Barlucchi LM, Melillo G, Illi B, Testolin L, Gaetano C, Capogrossi MC. Acidosis inhibits endothelial cell apoptosis and function and induces basic fibroblast growth factor and vascular endothelial growth factor expression. Circ Res. 2000; 86: 312–18.

    CAS  PubMed  Google Scholar 

  255. Jang A, Hill RP. An examination of the effects of hypoxia, acidosis, and glucose starvation on the expression of metastasis-associated genes in murine tumor cells. Clin Exp Metastasis. 1997; 15: 469–83.

    Article  CAS  PubMed  Google Scholar 

  256. Scott PA, Gleadle JM, Bicknell R, Harris AL. Role of the hypoxia sensing system, acidity and reproductive hormones in the variability of vascular endothelial growth factor induction in human breast carcinoma cell lines. Int J Cancer. 1998; 75: 706–12.

    Article  CAS  PubMed  Google Scholar 

  257. Stein I, Neeman M, Shweiki D, Itin A, Keshet E. Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes. Mol Cell Biol. 1995; 15: 5363–68.

    CAS  PubMed  Google Scholar 

  258. Damert A, Machein M, Breier G, Fujita MQ, Hanahan D, Risau W, Plate KH. Up-regulation of vascular endothelial growth factor expression in a rat glioma is conferred by two distinct hypoxia-driven mechanisms. Cancer Res. 1997; 57: 3860–64.

    CAS  PubMed  Google Scholar 

  259. Claffey KP, Shih SC, Mullen A, Dziennis S, Cusick JL, Abrams KR, Lee SW, Detmar M. Identification of a human VPF/VEGF 3’ untranslated region mediating hypoxia-induced mRNA stability. Mol Biol Cell. 1998; 9: 469–81.

    CAS  PubMed  Google Scholar 

  260. Shi Q, Le X, Wang B, Abbruzzese JL, Xiong Q, He Y, Xie K. Regulation of vascular endothelial growth factor expression by acidosis in human cancer cells. Oncogene. 2001; 20: 3751–56.

    Article  CAS  PubMed  Google Scholar 

  261. Huang S, Robinson JB, Deguzman A, Bucana CD, Fidler IJ. Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. Cancer Res. 2000; 60: 5334–39.

    CAS  PubMed  Google Scholar 

  262. Xiong HQ, Abbruzzese JL, Lin E, Wang L, Zheng L, Xie K. NF-kappaB activity blockade impairs the angiogenic potential of human pancreatic cancer cells. Int J Cancer. 2004; 108: 181–88.

    Article  CAS  Google Scholar 

  263. Xie K, Fidler IJ. Therapy of cancer metastasis by activation of the inducible nitric oxide synthase. Cancer Metastasis Rev. 1998; 17: 55–75.

    Article  CAS  PubMed  Google Scholar 

  264. Dreher D, Junod AF. Role of oxygen free radicals in cancer development. Eur J Cancer. 1996; 32A: 30–38.

    Article  CAS  PubMed  Google Scholar 

  265. Lala PK, Chakraborty C. Role of nitric oxide in carcinogenesis and tumour progression. Lancet Oncol. 2001; 2: 149–56.

    Article  CAS  PubMed  Google Scholar 

  266. Cianchi F, Cortesini C, Fantappie O, Messerini L, Schiavone N, Vannacci A, Nistri S, Sardi I, Baroni G, Marzocca C, Perna F, Mazzanti R, Bechi P, Masini E. Inducible nitric oxide synthase expression in human colorectal cancer: correlation with tumor angiogenesis. Am J Pathol. 2003; 162: 793–801.

    CAS  PubMed  Google Scholar 

  267. Song ZJ, Gong P, Wu YE. Relationship between the expression of iNOS, VEGF, tumor angiogenesis and gastric cancer. World J Gastroenterol. 2002; 8: 591–95.

    CAS  PubMed  Google Scholar 

  268. Gallo O, Masini E, Morbidelli L, Franchi A, Fini-Storchi I, Vergari WA, Ziche M. Role of nitric oxide in angiogenesis and tumor progression in head and neck cancer. J Natl Cancer Inst. 1998; 90: 587–96.

    Article  CAS  PubMed  Google Scholar 

  269. Donnini S, Ziche M. Constitutive and inducible nitric oxide synthase: role in angiogenesis. Antioxid Redox Signal. 2002; 4: 817–23.

    Article  CAS  PubMed  Google Scholar 

  270. Kimura H, Esumi H. Reciprocal regulation between nitric oxide and vascular endothelial growth factor in angiogenesis. Acta Biochim Pol. 2003; 50: 49–59.

    CAS  PubMed  Google Scholar 

  271. Uneda S, Hata H, Matsuno F, Nagasaki A, Harada N, Mitsuya Y, Matsuzaki H, Mitsuya H. A nitric oxide synthase inhibitor, N(G)-nitro-l-arginine-methyl-ester, exerts potent antiangiogenic effects on lasmacytoma in a newly established multiple myeloma severe combined immunodeficient mouse model. Br J Haematol. 2003; 120: 396–404.

    Article  CAS  PubMed  Google Scholar 

  272. Frank S, Madlener M, Pfeilschifter J, Werner S. Induction of inducible nitric oxide synthase and its corresponding tetrahydrobiopterin-cofactor-synthesizing enzyme GTP-cyclohydrolase I during cutaneous wound repair. J Invest Dermatol. 1998; 111: 1058–64.

    Article  CAS  PubMed  Google Scholar 

  273. Frank S, Stallmeyer B, Kampfer H, Kolb N, Pfeilschifter J. Nitric oxide triggers enhanced induction of vascular endothelial growth factor expression in cultured keratinocytes (HaCaT) and during cutaneous wound repair. FASEB J. 1999; 13: 2002–14.

    CAS  PubMed  Google Scholar 

  274. Frank S, Stallmeyer B, Kampfer H, Schaffner C, Pfeilschifter J. Differential regulation of vascular endothelial growth factor and its receptor fms-like-tyrosine kinase is mediated by nitric oxide in rat renal mesangial cells. Biochem J. 1999; 338(Pt 2): 367–74.

    Article  CAS  PubMed  Google Scholar 

  275. Dulak J, Jozkowicz A, Dembinska-Kiec A, Guevara I, Zdzienicka A, Zmudzinska-Grochot D, Florek I, Wojtowicz A, Szuba A, Cooke JP. Nitric oxide induces the synthesis of vascular endothelial growth factor by rat vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2000; 20: 659–66.

    CAS  PubMed  Google Scholar 

  276. Leibovich SJ, Chen JF, Pinhal-Enfield G, Belem PC, Elson G, Rosania A, Ramanathan M, ontesinos C, Jacobson M, Schwarzschild MA, Fink JS, Cronstein B. Synergistic up-regulation of vascular endothelial growth factor expression in murine macrophages by adenosine A(2A) receptor agonists and endotoxin. Am J Pathol. 2002; 160: 2231–44.

    Google Scholar 

  277. Konopka TE, Barker JE, Bamford TL, Guida E, Anderson RL, Stewart AG. Nitric oxide synthase II gene disruption: implications for tumor growth and vascular endothelial growth factor production. Cancer Res. 2001; 61: 3182–87.

    Google Scholar 

  278. Chin K, Kurashima Y, Ogura T, Tajiri H, Yoshida S, Esumi H. Induction of vascular endothelial growth factor by nitric oxide in human glioblastoma and hepatocellular carcinoma cells. Oncogene. 1997; 15: 437–42.

    Article  CAS  PubMed  Google Scholar 

  279. Kimura H, Ogura T, Kurashima Y, Weisz A, Esumi H. Effects of nitric oxide donors on vascular endothelial growth factor gene induction. Biochem Biophys Res Commun. 2002; 296: 976–82.

    Article  CAS  PubMed  Google Scholar 

  280. Sandau KB, Faus HG, Brune B. Induction of hypoxia-inducible-factor 1 by nitric oxide is mediated via the PI3K pathway. Biochem Biophys Res Commun. 2000; 278: 263–67.

    Article  CAS  PubMed  Google Scholar 

  281. Sandau KB, Fandrey J, Brune B. Accumulation of HIF-1alpha under the influence of nitric oxide. Blood. 2001; 97: 1009–15.

    Article  CAS  PubMed  Google Scholar 

  282. Lander HM, Milbank AJ, Tauras JM, Hajjar DP, Hempstead BL, Schwartz GD, Kraemer RT, Mirza UA, Chait BT, Burk SC, Quilliam LA. Redox regulation of cell signalling. Nature 1996; 381: 380–81.

    Article  CAS  PubMed  Google Scholar 

  283. Mazure NM, Brahimi-Horn MC, Pouyssegur J. Protein kinases and the hypoxia-inducible factor-1, two switches in angiogenesis. Curr Pharm Des. 2003; 9: 531–41.

    Article  CAS  PubMed  Google Scholar 

  284. Chen Y, Maguire T, Hileman RE, Fromm JR, Esko JD, Linhardt RJ, Marks RM. Dengue virus infectivity depends on envelope protein binding to target cell heparan sulfate. Nat Med. 1997; 3: 866–71.

    Article  CAS  PubMed  Google Scholar 

  285. Tuder RM, Flook BE, Voelkel NF. Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia: modulation of gene expression by nitric oxide. J Clin Invest. 1995; 95: 1798–807.

    Article  CAS  PubMed  Google Scholar 

  286. Liu Y, Christou H, Morita T, Laughner E, Semenza GL, Kourembanas S. Carbon monoxide and nitric oxide suppress the hypoxic induction of vascular endothelial growth factor gene via the 5’ enhancer. J Biol Chem. 1998; 273: 15257–62.

    Article  CAS  PubMed  Google Scholar 

  287. Yin JH, Yang DI, Ku G, Hsu CY. iNOS expression inhibits hypoxia-inducible factor-1 activity. Biochem Biophys Res Commun. 2000; 279: 30–34.

    Article  CAS  PubMed  Google Scholar 

  288. Ghiso N, Rohan RM, Amano S, Garland R, Adamis AP. Suppression of hypoxia-associated vascular endothelial growth factor gene expression by nitric oxide via cGMP. Invest Ophthalmol Vis Sci. 1999; 40: 1033–39.

    CAS  PubMed  Google Scholar 

  289. Xie K, Huang S. Contribution of nitric oxide-mediated apoptosis to cancer metastasis inefficiency. Free Radic Biol Med. 2003; 34: 969–86.

    Article  CAS  PubMed  Google Scholar 

  290. Ambs S, Merriam WG, Ogunfusika MO, Bennett WP, Ishibe N, Hussain SP, Tzeng EE, Geller DA, Billiar TR, Harris CC. p53 and vascular endothelial growth factor regulate tumor growth of NOS2-expressing human carcinoma cells. Nat Med. 1998; 4: 1371–76.

    Article  CAS  PubMed  Google Scholar 

  291. Tsurumi Y, Murohara T, Krasinski K, Chen D, Witzenbichler B, Kearney M, Couffinhal T, Isner JM. Reciprocal relation between VEGF and NO in the regulation of endothelial integrity. Nat Med. 1997; 3: 879–86.

    Article  CAS  PubMed  Google Scholar 

  292. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000; 408(6809): 239–47.

    Article  CAS  PubMed  Google Scholar 

  293. Sundaresan M, Yu ZX, Ferrans VJ, Sulciner DJ, Gutkind JS, Irani K, Goldschmidt-Clermont PJ, Finkel T. Regulation of reactive-oxygen-species generation in fibroblasts by Rac1. Biochem J. 1996; 318(Pt 2): 379–82.

    CAS  PubMed  Google Scholar 

  294. Woo CH, Eom YW, Yoo MH, You HJ, Han HJ, Song WK, Yoo YJ, Chun JS, Kim JH. Tumor necrosis factor-alpha generates reactive oxygen species via a cytosolic phospholipase A2-linked cascade. J Biol Chem. 2000; 275: 32357–62.

    Article  CAS  PubMed  Google Scholar 

  295. Sundaresan M, Yu ZX, Ferrans VJ, Irani K, Finkel T. Requirement for generation of H2O2for platelet-derived growth factor signal transduction. Science. 1995; 270: 296–99.

    Article  CAS  PubMed  Google Scholar 

  296. Pani G, Colavitti R, Bedogni B, Anzevino R, Borrello S, Galeotti T. A redox signaling mechanism for density-dependent inhibition of cell growth. J Biol Chem. 2000; 275: 38891–99.

    Article  CAS  PubMed  Google Scholar 

  297. Pani G, Colavitti R, Borrello S, Galeotti T. Endogenous oxygen radicals modulate protein tyrosine phosphorylation and JNK-1 activation in lectin-stimulated thymocytes. Biochem J. 2000; 347(Pt 1): 173–81.

    Article  CAS  PubMed  Google Scholar 

  298. Finkel T. Oxygen radicals and signaling. Curr Opin Cell Biol. 1998; 10: 248–53.

    Article  CAS  PubMed  Google Scholar 

  299. Rhee SG, Bae YS, Lee SR, Kwon J. Hydrogen peroxide: a key messenger that modulates protein phosphorylation through cysteine oxidation. Sci STKE. 2000; 2000(53): PE1.

    Google Scholar 

  300. Maulik N, Das DK. Redox signaling in vascular angiogenesis. Free Radic Biol Med. 2002; 33: 1047–60.

    Article  CAS  PubMed  Google Scholar 

  301. Deshpande SS, Irani K. Oxidant signalling in carcinogenesis: a commentary. Hum Exp Toxicol. 2002; 21: 63–64.

    Google Scholar 

  302. Arbiser JL, Petros J, Klafter R, Govindajaran B, McLaughlin ER, Brown LF, Cohen C, Moses M, Kilroy S, Arnold RS, Lambeth JD. Reactive oxygen generated by Nox1 triggers the angiogenic switch. Proc Natl Acad Sci USA. 2002; 99: 715–20.

    Article  CAS  PubMed  Google Scholar 

  303. Zhu JW, Yu BM, Ji YB, Zheng MH, Li DH. Upregulation of vascular endothelial growth factor by hydrogen peroxide in human colon cancer. World J Gastroenterol. 2002; 8: 153–57.

    CAS  PubMed  Google Scholar 

  304. Chua CC, Hamdy RC, Chua BH. Upregulation of vascular endothelial growth factor by H2O2in rat heart endothelial cells. Free Radic Biol Med. 1998; 25: 891–97.

    Article  CAS  PubMed  Google Scholar 

  305. Gabbita SP, Robinson KA, Stewart CA, Floyd RA, Hensley K. Redox regulatory mechanisms of cellular signal transduction. Arch Biochem Biophys. 2000; 376: 1–13.

    Article  CAS  PubMed  Google Scholar 

  306. Michiels C, Minet E, Mottet D, Raes M. Regulation of gene expression by oxygen: NF-kappaB and HIF-1, two extremes. Free Radic Biol Med. 2002; 33: 1231–42.

    Article  CAS  PubMed  Google Scholar 

  307. Maulik N. Redox signaling of angiogenesis. Antioxid Redox Signal. 2002; 4: 805–15.

    Article  CAS  PubMed  Google Scholar 

  308. Sen CK, Khanna S, Babior BM, Hunt TK, Ellison EC, Roy S. Oxidant-induced vascular endothelial growth factor expression in human keratinocytes and cutaneous wound healing. J Biol Chem. 2002; 277: 33284–90.

    Article  CAS  PubMed  Google Scholar 

  309. Gao N, Ding M, Zheng JZ, Zhang Z, Leonard SS, Liu KJ, Shi X, Jiang BH. Vanadate-induced expression of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor through phosphatidylinositol 3-kinase/Akt pathway and reactive oxygen species. J Biol Chem. 2002; 277: 31963–71.

    Article  CAS  PubMed  Google Scholar 

  310. Esposito F, Chirico G, Montesano Gesualdi N, Posadas I, Ammendola R, Russo T, Cirino G, Cimino F. Protein kinase B activation by reactive oxygen species is independent of tyrosine kinase receptor phosphorylation and requires SRC activity. J Biol Chem. 2003; 278: 20828–34.

    Article  CAS  PubMed  Google Scholar 

  311. Kosmidou I, Xagorari A, Roussos C, Papapetropoulos A. Reactive oxygen species stimulate VEGF production from C(2)C(12) skeletal myotubes through a PI3K/Akt pathway. Am J Physiol Lung Cell Mol Physiol. 2001; 280: L585–92.

    CAS  PubMed  Google Scholar 

  312. Colavitti R, Pani G, Bedogni B, Anzevino R, Borrello S, Waltenberger J, Galeotti T. Reactive oxygen species as downstream mediators of angiogenic signaling by vascular endothelial growth factor receptor-2/KDR.J Biol Chem. 2002; 277: 3101–08.

    Article  CAS  Google Scholar 

  313. Frank S, Hubner G, Breier G, Longaker MT, Greenhalgh DG, Werner S. Regulation of vascular endothelial growth factor expression in cultured keratinocytes: implications for normal and impaired wound healing. J Biol Chem. 1995; 270: 12607–13.

    Article  CAS  PubMed  Google Scholar 

  314. Pertovaara L, Kaipainen A, Mustonen T, Orpana A, Ferrara N, Saksela O, Alitalo K. Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. J Biol Chem. 1994; 269: 6271–74.

    CAS  PubMed  Google Scholar 

  315. Stavri GT, Zachary IC, Baskerville PA, Martin JF, Erusalimsky JD. Basic fibroblast growth factor upregulates the expression of vascular endothelial growth factor in vascular smooth muscle cells: synergistic interaction with hypoxia. Circulation. 1995; 92: 11–14.

    Google Scholar 

  316. Deroanne CF, Hajitou A, Calberg-Bacq CM, Nusgens BV, Lapiere CM. Angiogenesis by fibroblast growth factor 4 is mediated through an autocrine up-regulation of vascular endothelial growth factor expression. Cancer Res. 1997; 57: 5590–97.

    CAS  PubMed  Google Scholar 

  317. Wang D, Huang HJ, Kazlauskas A, Cavenee WK. Induction of vascular endothelial growth factor expression in endothelial cells by platelet-derived growth factor through the activation of phosphatidylinositol 3-kinase. Cancer Res. 1999; 59: 1464–72.

    CAS  PubMed  Google Scholar 

  318. Wojta J, Kaun C, Breuss JM, Koshelnick Y, Beckmann R, Hattey E, Mildner M, Weninger W, Nakamura T, Tschachler E, Binder BR. Hepatocyte growth factor increases expression of vascular endothelial growth factor and plasminogen activator inhibitor-1 in human keratinocytes and the vascular endothelial growth factor receptor flk-1 in human endothelial cells. Lab Invest. 1999; 79: 427–38.

    CAS  PubMed  Google Scholar 

  319. Li J, Perrella MA, Tsai JC, Yet SF, Hsieh CM, Yoshizumi M, Patterson C, Endege WO, Zhou F, Lee ME. Induction of vascular endothelial growth factor gene expression by interleukin-1 beta in rat aortic smooth muscle cells. J Biol Chem. 1995; 270: 308–12.

    Article  CAS  PubMed  Google Scholar 

  320. Ben-Av P, Crofford LJ, Wilder RL, Hla T. Induction of vascular endothelial growth factor expression in synovial fibroblasts by prostaglandin E and interleukin-1: a potential mechanism for inflammatory angiogenesis. FEBS Lett. 1995; 372: 83–87.

    Article  CAS  PubMed  Google Scholar 

  321. Cohen T, Nahari D, Cerem LW, Neufeld G, Levi BZ. Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem. 1996; 271: 736–41.

    Article  CAS  PubMed  Google Scholar 

  322. Warren RS, Yuan H, Matli MR, Ferrara N, Donner DB. Induction of vascular endothelial growth factor by insulin-like growth factor 1 in colorectal carcinoma. J Biol Chem. 1996; 271: 29483–88.

    Article  CAS  PubMed  Google Scholar 

  323. Samaniego F, Markham PD, Gendelman R, Watanabe Y, Kao V, Kowalski K, Sonnabend JA, Pintus A, Gallo RC, Ensoli B. Vascular endothelial growth factor and basic fibroblast growth factor present in Kaposi’s sarcoma (KS) are induced by inflammatory cytokines and synergize to promote vascular permeability and KS lesion development. Am J Pathol. 1998; 152: 1433–43.

    CAS  PubMed  Google Scholar 

  324. Yamaguchi R, Yano H, Iemura A, Ogasawara S, Haramaki M, Kojiro M. Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology. 1998; 28: 68–77.

    Article  CAS  PubMed  Google Scholar 

  325. Bolling B, Fandrey J, Frosch PJ, Acker H. VEGF production, cell proliferation and apoptosis of human IGR 1 melanoma cells under nIFN-alpha/beta and rIFN-gamma treatment. Exp Dermatol. 2000; 9: 327–35.

    Article  CAS  PubMed  Google Scholar 

  326. Xiong M, Elson G, Legarda D, Leibovich SJ. Production of vascular endothelial growth factor by murine macrophages: regulation by hypoxia, lactate, and the inducible nitric oxide synthase pathway. Am J Pathol. 1998; 153: 587–98.

    CAS  PubMed  Google Scholar 

  327. Yamamoto S, Yasui W, Kitadai Y, Yokozaki H, Haruma K, Kajiyama G, Tahara E. Expression of vascular endothelial growth factor in human gastric carcinomas. Pathol Int. 1998; 48: 499–506.

    CAS  PubMed  Google Scholar 

  328. Salven P, Anttonen K, Repo H, Joensuu H, Orpana A. Endotoxins induce and interferon alpha suppresses vascular endothelial growth factor (VEGF) production in human peripheral blood mononuclear cells. FASEB J. 2001; 15: 1318–20.

    CAS  PubMed  Google Scholar 

  329. von Marschall Z, Scholz A, Cramer T, Schafer G, Schirner M, Oberg K, Wiedenmann B, Hocker M, Rosewicz S. Effects of interferon alpha on vascular endothelial growth factor gene transcription and tumor angiogenesis. J Natl Cancer Inst. 2003; 95: 437–48.

    Article  Google Scholar 

  330. Tosato G. Interferon-alpha is implicated in the transcriptional regulation of vascular endothelial growth factor. J Natl Cancer Inst. 2003; 95: 420–21.

    CAS  PubMed  Google Scholar 

  331. Mori K, Tani M, Kamata K, Kawamura H, Urata Y, Goto S, Kuwano M, Shibata S, Kondo T. Mitogen-activated protein kinase, ERK1/2, is essential for the induction of vascular endothelial growth factor by ionizing radiation mediated by activator protein-1 in human glioblastoma cells. Free Radic Res. 2000; 33: 157–66.

    Article  CAS  PubMed  Google Scholar 

  332. Jung YD, Nakano K, Liu W, Gallick GE, Ellis LM. Extracellular signal-regulated kinase activation is required for up-regulation of vascular endothelial growth factor by serum starvation in human colon carcinoma cells. Cancer Res. 1999; 59: 4804–07.

    CAS  PubMed  Google Scholar 

  333. Harada S, Nagy JA, Sullivan KA, Thomas KA, Endo N, Rodan GA, Rodan SB. Induction of vascular endothelial growth factor expression by prostaglandin E2 and E1 in osteoblasts. J Clin Invest. 1994; 93: 2490–96.

    Article  CAS  PubMed  Google Scholar 

  334. Bamba H, Ota S, Kato A, Kawamoto C, Fujiwara K. Prostaglandins up-regulate vascular endothelial growth factor production through distinct pathways in differentiated U937 cells. Biochem Biophys Res Commun. 2000; 273: 485–91.

    Article  CAS  PubMed  Google Scholar 

  335. Liu XH, Kirschenbaum A, Lu M, Yao S, Dosoretz A, Holland JF, Levine AC. Prostaglandin E2 induces hypoxia-inducible factor-1alpha stabilization and nuclear localization in a human prostate cancer cell line. J Biol Chem. 2002; 277: 50081–86.

    Google Scholar 

  336. Wakiya K, Shibuya M. Okadaic acid stimulates the expression of vascular endothelial growth factor gene. Biochem Biophys Res Commun. 1999; 265: 584–88.

    Article  CAS  PubMed  Google Scholar 

  337. Shweiki D, Neeman M, Itin A, Keshet E. Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: implications for tumor angiogenesis. Proc Natl Acad Sci USA. 1995; 92: 768–72.

    Article  CAS  PubMed  Google Scholar 

  338. Satake S, Kuzuya M, Miura H, Asai T, Ramos MA, Muraguchi M, Ohmoto Y, Iguchi A. Up-regulation of vascular endothelial growth factor in response to glucose deprivation. Biol Cell. 1998; 90: 161–68.

    Article  CAS  PubMed  Google Scholar 

  339. Beerepoot LV, Shima DT, Kuroki M, Yeo KT, Voest EE. Up-regulation of vascular endothelial growth factor production by iron chelators. Cancer Res. 1996; 56: 3747–51.

    CAS  PubMed  Google Scholar 

  340. Clauss M, Schaper W. Vascular endothelial growth factor: A Jack-of-all-trades or a nonspecific stress gene? Circ Res. 2000; 86: 251–52.

    CAS  PubMed  Google Scholar 

  341. Spyridopoulos I, Brogi E, Kearney M, Sullivan AB, Cetrulo C, Isner JM, Losordo DW. Vascular endothelial growth factor inhibits endothelial cell apoptosis induced by tumor necrosis factor-alpha: balance between growth and death signals. J Mol Cell Cardiol. 1997; 29: 1321–30.

    Google Scholar 

  342. Watanabe Y, Dvorak HF. Vascular permeability factor/vascular endothelial growth factor inhibits anchorage-disruption-induced apoptosis in microvessel endothelial cells by inducing scaffold formation. Exp Cell Res. 1997; 233: 340–49.

    Article  CAS  PubMed  Google Scholar 

  343. Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, Ferrara N. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway: requirement for Flk-1/KDR activation. J Biol Chem. 1998; 273: 30336–43.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastrointestinal Medical Oncology, The University of Texas,MD Anderson Cancer Center, TX 77030, USA

    Keping Xie

Authors
  1. Keping Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

    Menashe Bar-Eli (Dr) (Dr)

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Xie, K., Yao, J. (2008). Molecular Basis for Vascular Endothelial Growth Factor Expression in Tumor. In: Bar-Eli, M. (eds) Regulation of Gene Expression in the Tumor Environment. TTME, vol 2. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-8341-9_6

Download citation

Publish with us

Policies and ethics

Search

Navigation