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Regulation of the expression of the VEGF/VPS and its receptors: role in tumor angiogenesis

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Summary

Vascular endothelial growth factor (VEGF) / vascular permeability factor (VPS) plays a crucial role for the vascularization of tumors including breast cancers. Tumors produce ample amounts of VEGF, which stimulates the proliferation and migration of endothelial cells (ECs), thereby inducing tumor vascularization by a paracrine mechanism. VEGF receptors (VEGF-Rs) are highly expressed by the ECs in tumor blood vessels. VEGF expression can be induced in various cell types by a number of stimuli including hypoxia, differentiation, growth factors and tumor promoters of the phorbol ester class, such as TPA. The VEGF inductive pathways comprise kinases, oncogenes, tumor suppressor genes, and steroid hormone transcription factors, many of which seem to converge on the activator protein (AP-1) transcription factor. Much less is known about the regulation of VEGF-R expression, which is restricted to ECs. This expression is greatly enhanced in diseased tissue such as solid tumors. So far, it appears that growth factors, cytokines, and tumor promoters are involved in the control of VEGF-R expression. Here we review current knowledge about the regulation of the expression of VEGF and its receptors.

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References

  1. Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82:4–7, 1990

    Google Scholar 

  2. Folkman J: The role of angiogenesis in tumor growth. Semin Cancer Biol 3:65–71, 1992

    Google Scholar 

  3. Fox SB, Leek RD, Smith K, Hollyer J, Greenall M, Harris AL: Tumor angiogenesis in node-negative breast carcinomas: relationship with epidermal growth factor receptor, estrogen receptor, and survival. Breast Cancer Res Treat 29:109–116, 1994

    Google Scholar 

  4. Weidner N, Semple P, Welch W, Folkman J: Tumor angiogenesis and metastasis. Correlation in invasive breast carcinoma. New Engl J Med 324:1–6, 1991

    Google Scholar 

  5. Horak ER, Leek R, Klenk N, LeJeune S, Smith K, Stuart N, Greenall M, Stepniewska K, Harris AL: Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet 340:1120–1124, 1992

    Google Scholar 

  6. Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, Meli S, Gasparini G: Tumor angiogenesis: A new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst 84:1875–1888, 1992

    Google Scholar 

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

    Google Scholar 

  8. Bicknell R, Harris AL: Anticancer strategies involving the vasculature: vascular targeting and the inhibition of angiogenesis. Seminars in Cancer Biology 3:399–407, 1992

    Google Scholar 

  9. Klagsbrun M, Soker S: VEGF/VPS: the angiogenesis factor found? Current Biology 3:699–702, 1993

    Google Scholar 

  10. 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 266:11947–11954, 1991

    Google Scholar 

  11. Charnock Jones DS, Sharkey AM, Rajput Williams J, Burch D, Schofield JP, Fountain SA, Boocock CA, Smith SK: Identification and localization of alternatively spliced mRNAs for vascular endothelial growth factor in human uterus and estrogen regulation in endometrial carcinoma cell lines. Biol Reprod 48: 1120–1128, 1993

    Google Scholar 

  12. Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW: The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol 5:1806–1814, 1991

    Google Scholar 

  13. Ferrara N, Henzel WJ: Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161:851–858, 1989

    Google Scholar 

  14. Gospodarowicz D, Abraham JA, Schilling J: Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. Proc Natl Acad Sci USA 86:7311–7315, 1989

    Google Scholar 

  15. Connolly DT, Heuvelman DM, Nelson R, Olander JV, Epley BL, Delfino JJ, Siegel NR, Leimgruber RM, Feder J: Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest 84:1470–1478, 1989

    Google Scholar 

  16. 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 246:1309–1312, 1989

    Google Scholar 

  17. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N: Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309, 1989

    Google Scholar 

  18. Senger DR, Van de Water L, Brown LF, Nagy JA, Yeo KT, Yeo TK, Berse B, Jackman RW, Dvorak AM, Dvorak HF: Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Metastasis Rev 12: 303–324, 1993

    Google Scholar 

  19. Nagy JA, Brown LF, Senger DR, Lanir N, Van De Water L, Dvorak AM, Dvorak HF: Pathogenesis of tumor stroma generation: a critical role for leaky blood vessels and fibrin deposition. Biochim Biophys Acta 948:305–326, 1988

    Google Scholar 

  20. Dvorak HF, Nagy JA, Berse B, Brown LF, Yeo K, Yeo T, Dvorak AM, Van De Water L, Sioussat TM, Senger DR: Vascular permeability factor, fibrin, and the pathogenesis of tumor stroma function. Ann NY Acad Sci 667:101–111, 1992

    Google Scholar 

  21. Clauss M, Gerlach M, Gerlach H, Brett J, Wang F, Familletti PC, Pan YC, Olander JV, Connolly DT, Stern D: Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity and promotes monocyte migration. J Exp Med 172:1535–1545, 1990

    Google Scholar 

  22. Iijima K, Yoshikawa N, Connolly DT, Nakamura H: Human mesangial cells and peripheral blood mononuclear cells produce vascular permeability factor. Kidney Int 44:959–966, 1993

    Google Scholar 

  23. Sunderkotter C, Steinbrink K, Goebeler M, Bhardwaj R, Sorg C: Macrophages and angiogenesis. J Leukoc Biol 55:410–422, 1994

    Google Scholar 

  24. Shen H, Clauss M, Ryan J, Schmidt AM, Tijburg P, Borden L, Connolly D, Stern D, Kao J: Characterization of vascular permeability factor/vascular endothelial growth factor receptors on mononuclear phagocytes. Blood 81:2767–2773, 1993

    Google Scholar 

  25. Vaisman N, Gospodarowicz D, Neufeld G: Characterization of the receptors for vascular endothelial growth factor. J Biol Chem 265:19461–19466, 1990

    Google Scholar 

  26. Plouet J, Moukadiri H: Characterization of the receptor to vasculotropin on bovine adrenal cortexderived capillary endothelial cells. J Biol Chem 265: 22071–22074, 1990

    Google Scholar 

  27. Olander JV, Connolly DT, DeLarco JE: Specific binding of vascular permeability factor to endothelial cells. Biochem Biophys Res Commun 175:68–76, 1991

    Google Scholar 

  28. De Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT: The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255:989–991, 1992

    Google Scholar 

  29. Galland F, Karamysheva A, Pebusque M, Borg J, Rottapel R, Dubreuil P, Rosnet O, Birnbaum D: The flt4 gene encodes a transmembrane tyrosine kinase related to the vascular endothelial growth factor receptor. Oncogene 8:1233–1240, 1993

    Google Scholar 

  30. Terman BI, Dougher Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, Bohlen P: Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 187:1579–1586, 1992

    Google Scholar 

  31. Millauer B, Wizigmann Voos S, Schnurch H, Martinez R, Moller NP, Risau W, Ullrich A: High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 72:835–846, 1993

    Google Scholar 

  32. Pajusola K, Aprelikova O, Pelicci G, Weich H, Claesson-Welsh L, Alitalo K: Signalling properties of FLT4, a proteolytically processed receptor tyrosine kinase related to two VEGF receptors. Oncogene 9: 3545–3555, 1994

    Google Scholar 

  33. Senger DR, Perruzzi CA, Feder J, Dvorak HF: A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res 46:5629–5632, 1986

    Google Scholar 

  34. Dvorak HF, Sioussat TM, Brown LF, Berse B, Nagy JA, Sotrel A, Manseau EJ, Van De Water L, Senger DR: Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels. J Exp Med 174:1275–1278, 1991

    Google Scholar 

  35. Berkman RA, Merril MJ, Reinhold WC, Monacci WT, Saxena A, Clark WC, Robertson JT, Ali IU, Oldfield EH: Expression of the vascular permeability factor/ vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest 91:153–159, 1993

    Google Scholar 

  36. Berse B, Brown LF, Van de Water L, Dvorak HF, Senger DR: Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell 3:211–220, 1992

    Google Scholar 

  37. Plate KH, Breier G, Weich HA, Risau W: Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359: 845–848, 1992

    Google Scholar 

  38. Plate KH, Breier G, Millauer B, Ullrich A, Risau W: Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Res 53:5822–5827, 1993

    Google Scholar 

  39. Dvorak HF, Sioussat TM, Brown LF, Berse B, Nagy JA, Sotrel A, Manseau EJ, Van de Water L, Senger DR: Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels. J Exp Med 174:1275–1278, 1991

    Google Scholar 

  40. Sunderkotter C, Steinbrink K, Goebeler M, Bhardwaj R, Sorg C: Macrophages and angiogenesis. J Leukoc Biol 55:410–422, 1994

    Google Scholar 

  41. Alvarez JA, Baird A, Tatum A, Daucher J, Chorsky R, Gonzalez AM, Stopa EG: Localization of basic fibroblast growth factor and vascular endothelial growth factor in human glial neoplasms. Mod Pathol 5:303–307, 1992

    Google Scholar 

  42. Weindel K, Moringlane JR, Marme D, Weich HA: Detection and quantification of vascular endothelial growth factor/vascular permeability factor in brain tumor tissue and cyst fluid: the key to angiogenesis? Neurosurgery 35:439–449, 1994

    Google Scholar 

  43. Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Dvorak HF, Senger DR: Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. Am J Pathol 143:1255–1262, 1993

    Google Scholar 

  44. Takahashi A, Sasaki H, Kim SJ, Tobisu K, Kakizoe T, Tsukamoto T, Kumamoto Y, Sugimura T, Terada M: Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res 54:4233–4237, 1994

    Google Scholar 

  45. Brown LF, Berse B, Jackman R, Tognazzi K, Manseau EJ, Senger DR, Dvorak HF: Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res 53:4727–4735, 1993

    Google Scholar 

  46. Toi M, Hoshima S, Takayanagi T, Tominaga T: Association of vascular endothelial growth factor expression with tumor angiogenesis and with early relapse in primary breast cancer. Jpn J Cancer Res 85:1045–1049, 1994

    Google Scholar 

  47. Criscuolo GR: The genesis of peritumoral vasogenic brain edema and tumor cysts: a hypothetical role for tumor-derived vascular permeability factor. Yale J Biol Med 66:277–314, 1993

    Google Scholar 

  48. Ferrara N, Winer J, Burton T, Rowland A, Siegel M, Phillips HS, Terrell T, Keller GA, Levinson AD: Expression of vascular endothelial growth factor does not promote transformation but confers a growth advantage in vivo to Chinese hamster ovary cells. J Clin Invest 91:160–170, 1993

    Google Scholar 

  49. Kondo S, Asano M, Suzuki H: Significance of vascular endothelial growth factor/vascular permeability factor for solid tumor growth, and its inhibition by the antibody. Biochem Biophys Res Commun 194: 1234–1241, 1993

    Google Scholar 

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

    Google Scholar 

  51. Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A: Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367:576–579, 1994

    Google Scholar 

  52. Breier G, Albrecht U, Sterrer S, Risau W: Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development 114:521–532, 1992

    Google Scholar 

  53. Peters KG, De Vries C, Williams LT: Vascular endothelial growth factor receptor expression during embryogenesis and tissue repair suggests a role in endothelial differentiation and blood vessel growth. Proc Natl Acad Sci USA 90:8915–8919, 1993

    Google Scholar 

  54. Risau W: Angiogenesis and endothelial cell function. Arzneimittelforschung 44:416–417, 1994

    Google Scholar 

  55. Jakeman LB, Armanini M, Phillips HS, Ferrara N: Developmental expression of binding sites and messenger ribonucleic acid for vascular endothelial growth factor suggests a role for this protein in vasculogenesis and angiogenesis. Endocrinology 133:848–859, 1993

    Google Scholar 

  56. Jakeman LB, Winer J, Bennett GL, Altar CA, Ferrara N: Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. J Clin Invest 89:244–253, 1992

    Google Scholar 

  57. 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 93:2490–2496, 1994

    Google Scholar 

  58. Midy V, Plouet J: Vasculotropin/vascular endothelial growth factor induces differentiation in cultured osteoblasts. Biochem Biophys Res Commun 199:380–386, 1994

    Google Scholar 

  59. Castellot JJ Jr, Kambe AM, Dobson DE, Spiegelman BM: Heparin potentiation of 3T3-adipocyte stimulated angiogenesis: mechanisms of action on endothelial cells. J Cell Physiol 127:323–329, 1986

    Google Scholar 

  60. Dobson DE, Kambe A, Block E, Dion T, Lu H, Castellot JJ Jr, Spiegelman BM: 1-butyryl-glycerol: a novel angiogenesis factor secreted by differentiating adipocytes. Cell 61:223–230, 1990

    Google Scholar 

  61. Green H, Kehinde O: Formation of normally differentiated subcutaneous fat pads by an established preadipose cell line. J Cell Physiol 101:169–171, 1979

    Google Scholar 

  62. Claffey KP, Wilkison WO, Spiegelman BM: Vascular endothelial growth factor. Regulation by cell differentiation and activated second messenger pathways. J Biol Chem 267:16317–16322, 1992

    Google Scholar 

  63. Kinasewitz GT, Groome LJ, Marshall RP, Leslie WK, Diana JN: Effect of hypoxia on permeability of pulmonary endothelium of canine visceral pleura. J Appl Physiol 61:554–560, 1986

    Google Scholar 

  64. Olesen SP: Rapid increase in blood-brain barrier permeability during severe hypoxia and metabolic inhibition. Brain Res 368:24–29, 1986

    Google Scholar 

  65. Adair TH, Gay WJ, Montani JP: Growth regulation of the vascular system: evidence for a metabolic hypothesis. Am J Physiol 259:R393-R404, 1990

    Google Scholar 

  66. Shweiki D, Itin A, Soffer D, Keshet E: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845, 1992

    Google Scholar 

  67. Goldberg MA, Schneider TJ: Similarities between the oxygen-sensing mechanisms regulating the expression of vascular endothelial growth factor and erythropoietin. J Biol Chem 269:4355–4359, 1994

    Google Scholar 

  68. Brogi E, Wu T, Namiki A, Isner JM: Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only. Circulation 90:649–652, 1994

    Google Scholar 

  69. Ladoux A, Frelin C: Hypoxia is a strong inducer of vascular endothelial growth factor mRNA expression in the heart. Biochem Biophys Res Commun 195: 1005–1010, 1993

    Google Scholar 

  70. Rondon IJ, MacMillan LA, Beckman BS, Goldberg MA, Schneider T, Bunn HF, Malter JS: Hypoxia upregulates the activity of a novel erythropoietin mRNA binding protein. J Biol Chem 266:16594–16598, 1991

    Google Scholar 

  71. Firth JD, Ebert BL, Pugh CW, Ratcliffe PJ: Oxygenregulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoietin 3′ enhancer. Proc Natl Acad Sci USA 91:6496–6500, 1994

    Google Scholar 

  72. McClure N, Healy DL, Rogers PA, Sullivan J, Beaton L, Haning RV Jr, Connolly DT, Robertson DM: Vascular endothelial growth factor as capillary permeability agent in ovarian hyperstimulation syndrome. Lancet 344:235–236, 1994

    Google Scholar 

  73. Webster KA, Discher DJ, Bishopric NH: Induction and nuclear accumulation of fos and jun proto-oncogenes in hypoxic cardiac myocytes. J Biol Chem 268: 16852–16858, 1993

    Google Scholar 

  74. Curran T, Franza BR: Fos and Jun: The AP-1 connection. Cell 55:395–397, 1988

    Google Scholar 

  75. Koong AC, Chen EY, Kim CY, Giaccia AJ: Activators of protein kinase C selectively mediate cellular cytotoxicity to hypoxic cells and not aerobic cells. Int J Radiat Oncol Biol Phys 29:259–265, 1994

    Google Scholar 

  76. Eckardt KU, Ring A, Maier M, Gess B, Fabbro D, Kurtz A: Hypoxia-induced accumulation of erythropoietin mRNA in isolated hepatocytes is inhibited by protein kinase C. Pflugers Arch 426:21–30, 1994

    Google Scholar 

  77. Davis RJ: MAPKs: new JNK expands the group. Trends in Bioch Sci 19:470–473, 1994

    Google Scholar 

  78. Findlay JK: Angiogenesis in reproductive tissues. J Endocrinol 111:357–366, 1986

    Google Scholar 

  79. Christianes GCM, Sixma JJ, Haspels AA: Hemostasis in menstrual endometrium: a review. Obstet Gynecol Survey 37:281–303, 1982

    Google Scholar 

  80. Cullinan Bove K, Koos RD: Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: rapid stimulation by estrogen correlates with estrogen-induced increases in uterine capillary permeability and growth. Endocrinology 133: 829–837, 1993

    Google Scholar 

  81. Shweiki D, Itin A, Neufeld G, Gitay Goren H, Keshet E: Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J Clin Invest 91:2235–2243, 1993

    Google Scholar 

  82. Phillips HS, Hains J, Leung DW, Ferrara N: Vascular endothelial growth factor is expressed in rat corpus luteum. Endocrinology 127:965–967, 1990

    Google Scholar 

  83. Garrido C, Saule S, Gospodarowicz D: Transcriptional regulation of vascular endothelial growth factor gene expression in ovarian bovine granulosa cells. Growth Factors 8:109–117, 1993

    Google Scholar 

  84. Imagawa M, Chiu R, Karin M: Transcription factor AP2 mediates induction by two different signaltransduction pathways: protein kinase C and cAMP. Cell 51:251–260, 1987

    Google Scholar 

  85. Aronica SM, Kraus WL, Katzenellenbogen BS: Estrogen action via the cAMP signaling pathway: stimulation of adenylate cyclase and cAMP-regulated gene transcription. Proc Natl Acad Sci USA 91:8517–8521, 1994

    Google Scholar 

  86. Weisz A, Cicatiello L, Persicot E, Scalone M, Bresciani F: Estrogen stimulates transcription of cjun protooncogene. Mol Endocrinol 4:1041–1050, 1990

    Google Scholar 

  87. Krasil'nikov MA, Shatskaya VA, Kuzmina ZV, Barinov VV, Letyagin VP, Bassalyk LS: Regulation of phospholipid turnover by steroid hormones in endometrial carcinoma and breast cancer cells. Acta Endocrinol Copenh 128:543–548, 1993

    Google Scholar 

  88. Etindi RN, Manni A, Martel J: The effects of TGF-alpha and 17 beta-estradiol on polyphosphoinositide metabolism in MCF-7 breast cancer cells. Breast Cancer Res Treat 24:61–70, 1992

    Google Scholar 

  89. Cantley L: Lipid second messengers. Cell 77:329–334, 1994

    Google Scholar 

  90. Migliaccio A, Pagano M, Auricchio F: Immediate and transient stimulation of protein tyrosine phosphorylation by estradiol in MCF-7 cells. Oncogene 8:2183–2191, 1993

    Google Scholar 

  91. Detmar M, Brown LF, Claffey KP, Yeo KT, Kocher O, Jackman RW, Berse B, Dvorak HF: Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med 180:1141–1146, 1994

    Google Scholar 

  92. 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 269:6271–6274, 1994

    Google Scholar 

  93. Goldman CK, Kim J, Wong WL, King V, Brock T, Gillespie GY: Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. Mol Biol Cell 4:121–133, 1993

    Google Scholar 

  94. Finkenzeller G, Marme D, Weich HA, Hug H: Platelet-derived growth factor-induced transcription of the vascular endothelial growth factor gene is mediated by protein kinase C. Cancer Res 52:4821–4823, 1992

    Google Scholar 

  95. Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH, et al: Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA 83:4167–4171, 1986

    Google Scholar 

  96. Heimark RL, Twardzik DR, Schwartz SM: Inhibition of endothelial regeneration by type-beta transforming growth factor from platelets. Science 233:1078–1080, 1986

    Google Scholar 

  97. Baird A, Durkin T: Inhibition of endothelial cell proliferation by type beta-transforming growth factor: interactions with acidic and basic fibroblast growth factors. Biochem Biophys Res Commun 138:476–482, 1986

    Google Scholar 

  98. Walker RA, Dearing SJ, Gallacher B: Relationship of transforming growth factor beta 1 to extracellular matrix and stromal infiltrates in invasive breast carcinoma. Br J Cancer 69:1160–1165, 1994

    Google Scholar 

  99. Murray PA, Barrett Lee P, Travers M, Luqmani Y, Powles T, Coombes RC: The prognostic significance of transforming growth factors in human breast cancer. Br J Cancer 67:1408–1412, 1993

    Google Scholar 

  100. Goto F, Goto K, Weindel K, Folkman J: Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels [see comments]. Lab Invest 69:508–517, 1993

    Google Scholar 

  101. Arteaga CL, Hurd SD, Winnier AR, Johnson MD, Fendly BM, Forbes JT: Anti-transforming growth factor (TGF)-beta antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity. Implications for a possible role of tumor cell/host TGF-beta interactions in human breast cancer progression. J Clin Invest 92:2569–2576, 1993

    Google Scholar 

  102. Stewart AJ, Westley BR, May FE: Modulation of the proliferative response of breast cancer cells to growth factors by oestrogen. Br J Cancer 66:640–648, 1992

    Google Scholar 

  103. Leon SP, Zhu J, Black PM: Genetic aberrations in human brain tumors. Neurosurgery 34:708–722, 1994

    Google Scholar 

  104. Chrysogelos SA, Dickson RB: EGF receptor expression, regulation, and function in breast cancer. Breast Cancer Res Treat 29:29–40, 1994

    Google Scholar 

  105. Normanno N, Ciardiello F, Brandt R, Salomon DS: Epidermal growth factor-related peptides in the pathogenesis of human breast cancer. Breast Cancer Res Treat 29:11–27, 1994

    Google Scholar 

  106. Klijn JG, Look MP, Portengen H, Alexieva Figusch J, van Putten WL, Foekens JA: The prognostic value of epidermal growth factor receptor (EGF-R) in primary breast cancer: results of a 10 year follow-up study. Breast Cancer Res Treat 29:73–83, 1994

    Google Scholar 

  107. McCormick F: Signal transduction. How receptors turn Ras on. Nature 363:15–16, 1993

    Google Scholar 

  108. Seymour L, Dajee D, Bezwoda WR: Tissue platelet derived-growth factor (PDGF) predicts for shortened survival and treatment failure in advanced breast cancer. Breast Cancer Res Treat 26:247–252, 1993

    Google Scholar 

  109. Pertovaara L, Sistonen L, Bos TJ, Vogt PK, Keski Oja J, Alitalo K: Enhanced jun gene expression is an early genomic response to transforming growth factor beta stimulation. Mol Cell Biol 9:1255–1262, 1989

    Google Scholar 

  110. Konig H, Ponta H, Rahmsdorf HJ, Herrlich P: Interference between pathway-specific transcription factors: glucocorticoids antagonize phorbol esterinduced AP-1 activity without altering AP-1 site occupation in vivo. EMBO J 11:2241–2246, 1992

    Google Scholar 

  111. Ponta H, Cato AC, Herrlich P: Interference of pathway specific transcription factors. Biochim Biophys Acta 1129:255–261, 1992

    Google Scholar 

  112. Folkman J, Ingber D: Inhibition of angiogenesis. Semin Cancer Biol 3:89–96, 1992

    Google Scholar 

  113. Fava RA, Olsen NJ, Spencer Green G, Yeo KT, Yeo TK, Berse B, Jackman RW, Senger DR, Dvorak HF, Brown LF: Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J Exp Med 180:341–346, 1994

    Google Scholar 

  114. Koch AE, Harlow LA, Haines GK, Amento EP, Unemori EN, Wong WL, Pope RM, Ferrara N: Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol 152:4149–4156, 1994

    Google Scholar 

  115. Angel P, Baumann I, Stein B, Delius H, Rahmsdorf HJ, Herrlich P: 12-O-tetradecanoyl-phorbol-13-acetate induction of the human collagenase gene is mediated by an inducible enhancer element located in the 5′-flanking region. Mol Cell Biol 7:2256–2266, 1987

    Google Scholar 

  116. Goodnight J, Mushinski JF, Mischak H: Protein kinase C in differentiation and transformation. Adv Cancer Res 64:160–209, 1994

    Google Scholar 

  117. Mischak H, Goodnight J, Kolch W, Martiny-Baron G, Schaechtele C, Kazanietz MG, Blumberg PM, Pierce JH, Mushinski JF: Overexpression of PKCδ and -ε in NIH 3T3 cells induces opposite effects on growth, morphology, anchorage dependence and tumorigenicity. J Biol Chem 268:6090–6096, 1993

    Google Scholar 

  118. Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, Mischak H, Finkenzeller G, Marme D, Rapp UR: PKCα activates Raf-1 by direct phosphorylation. Nature 364:249–251, 1993

    Google Scholar 

  119. Sözeri O, Vollmer K, Liyanage M, Frith D, Kour G, Mark GE III, Stabel S: Activation of the c-Raf protein kinase by protein kinase C phosphorylation. Oncogene 7:2259–2262, 1992

    Google Scholar 

  120. Carroll MP, May WS: Protein kinase C-mediated serine phosphorylation directly activates Raf-1 in murine hematopoietic cells. J Biol Chem 269:1249–1256, 1994

    Google Scholar 

  121. Hallberg B, Ryter SI, Downward J: Interaction of Ras and Raf in intact mammalian cells upon extracellular stimulation. J Biol Chem 269:3913–3916, 1994

    Google Scholar 

  122. Koide H, Satoh K, Nakafuku M, Kaziro Y: GTP-dependent association of Raf-1 with Ha-Ras: identification of Ras as a target downstream of Ras in mammalian cells. Proc Natl Acad Sci USA 90:8683–8686, 1993

    Google Scholar 

  123. Moodie SA, Willumsen BM, Weber MJ, Wolfman A: Complexes of Ras/GTP with Raf-1 and mitogenactivated protein kinase kinase. Science 260:1658–1661, 1993

    Google Scholar 

  124. Bruder JT, Heidecker G, Rapp UR: Serum-, TPA-, and Ras-induced expression from AP-1/Ets-driven promoters requires Raf-1 kinase. Genes Dev 6:545–556, 1992

    Google Scholar 

  125. Diaz-Laviada I, Larrodera P, Diaz-Meco MC, Cornet ME, Guttal PM, Johansen T, Moscat J: Evidence for a role of phosphatidylcholine-hydrolyzing phospholipase C in the regulation of protein kinase C by ras and src oncogenes. EMBO J 9:3907–3912, 1990

    Google Scholar 

  126. Kolch W, Heidecker G, Lloyd P, Rapp UR: Raf-1 protein kinase is required for growth of induced NIH/3T3 cells. Nature 349:426–428, 1991

    Google Scholar 

  127. Kolch W, Heidecker G, Troppmair J, Yanagihara K, Bassin RH, Rapp UR: Raf revertant cells resist transformation by non-nuclear oncogenes and are deficient in the induction of early response genes by TPA and serum. Oncogene 8:361–370, 1993

    Google Scholar 

  128. Egan SE, Weinberg RA: The pathway to signal achievement. Nature 365:781–783, 1993

    Google Scholar 

  129. Pulverer BJ, Kyriakis JM, Avruch J, Nikolakaki E, Woodgett JR: Phosphorylation of c-jun mediated by MAP kinases. Nature 353:670–674, 1991

    Google Scholar 

  130. Gille HG, Sharrocks AD, Shaw PE: Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter. Nature 358:414–417, 1992

    Google Scholar 

  131. Troppmair J, Bruder JT, Munoz H, Lloyd PA, Kyriakis J, Banerjee P, Avruch J, Rapp UR: Mitogenactivated protein kinase / extracellular signalregulated kinase activation by oncogenes, serum, and 12-O-tetradecanoylphorbol-13-acetate requires Raf and is necessary for transformation. J Biol Chem 269:7030–7035, 1994

    Google Scholar 

  132. Vogelstein B, Kinzler KW: The multistep nature of cancer. Trends Genet 9:138–141, 1993

    Google Scholar 

  133. Sidransky D, Mikkelsen T, Schwechheimer K, Rosenblum ML, Cavanee W, Vogelstein B: Clonal expansion of p53 mutant cells is associated with brain tumour progression. Nature 355:846–847, 1992

    Google Scholar 

  134. Kieser A, Weich HA, Brandner G, Marme D, Kolch W: Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 9:963–969, 1994

    Google Scholar 

  135. Smith HS, Lu Y, Deng G, Martinez O, Krams S, Ljung BM, Thor A, Lagios M: Molecular aspects of early stages of breast cancer progression. J Cell Biochem Suppl 17G:144–152, 1993

    Google Scholar 

  136. Li FP, Fraumeni JF Jr: Soft tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome. Ann Intern Med 71:747–752, 1969

    Google Scholar 

  137. Malkin D, Li FP, Strong LC, Fraumeni JF, Nelson CE, Kim DH, Kassell J, Gryka MA, Bischoff FZ, Tainsky MA, Friend SH: Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas and other neoplasms. Science 250:1233–1238, 1990

    Google Scholar 

  138. Shibuya M, Yamaguchi S, Yamane A, Ikeda T, Tojo A, Matsushime H, Sato M: Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene 5:519–524, 1990

    Google Scholar 

  139. Terman BI, Carrion ME, Kovacs E, Rasmussen BA, Eddy RL, Shows TB: Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 6:1677–1683, 1991

    Google Scholar 

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

    Google Scholar 

  141. Sarzani R, Arnaldi G, De Pirro R, Moretti P, Schiaffino S, Rappelli A: A novel endothelial tyrosine kinase cDNA homologous to platelet-derived growth factor receptor cDNA. Biochem Biophys Res Commun 186:706–714, 1992

    Google Scholar 

  142. Eichmann A, Marcelle C, Breant C, Le Douarin NM: Two molecules related to the VEGF receptor are expressed in early endothelial cells during avian embryonic development. Mech Dev 42:33–48, 1993

    Google Scholar 

  143. Pajusola K, Aprelikova O, Korhonen J, Kaipainen A, Pertovaara L, Alitalo R, Alitalo K: FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines [published erratum appears in Cancer Res 53:3845, 1993]. Cancer Res 52:5738–5743, 1992

    Google Scholar 

  144. Kendall RL, Thomas KA: Inhibition of vascular endothelial growth factor by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA 90:10705–10709, 1993

    Google Scholar 

  145. Park JE, Chen HH, Winer J, Houck KA, Ferrara N: Placenta growth factor. J Biol Chem 269:25646–25654, 1994

    Google Scholar 

  146. Kendall RL, Wang G, DiSalvo J, Thomas KA: Specificity of vascular endothelial cell growth factor receptor ligand binding domains. Biochem Biophys Res Commun 201:326–330, 1994

    Google Scholar 

  147. Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH: Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 269:26988–26995, 1994

    Google Scholar 

  148. Barleon B, Hauser S, Schollmann C, Weindel K, Marme D, Yayon A, Weich HA: Differential expression of the two VEGF receptors flt and KDR in placenta and vascular endothelial cells. J Cell Biochem 54:56–66, 1994

    Google Scholar 

  149. Oberg C, Waltenberger J, Claesson Welsh L, Welsh M: Expression of protein tyrosine kinases in islet cells: possible role of the Flk-1 receptor for beta-cell maturation from duct cells. Growth Factors 10:115–126, 1994

    Google Scholar 

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

    Google Scholar 

  151. Yamaguchi TP, Dumont DJ, Conlon RA, Breitman ML, Rossant J: flk-1, an flt-related receptor tyrosine kinase, is an early marker for endothelial cell precursors. Development 118:489–498, 1993

    Google Scholar 

  152. Fong G, Rossant J, Breitman ML: Requirement of the VEGF receptor Flt-1 for the normal embryonic development. VIIIth Intern Symp on the Biology of Vascular Cells, Abstracts, 1994

  153. Shalaby F, Rossant J, Breitman ML, Schuh AC: The role of flk-1 in endothelial cell development. VIIIth Intern Symp on the Biology of Vascular Cells, Abstracts, 1994

  154. Barleon B, Weich HA, Martiny-Baron G, Marme D: Control of the two VEGF receptor genes KDR and flt-1 by cytokines and growth factors. Cancer Res, submitted

  155. Soutter AD, Nguyen M, Watanabe H, Folkman J: Basic fibroblast growth factor secreted by an animal tumor is detectable in urine. Cancer Res 53:5297–5299, 1993

    Google Scholar 

  156. Sato TN, Qin Y, Kozak CA, Audus KL: Tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system. Proc Natl Acad Sci USA 90:9355–9358, 1993

    Google Scholar 

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Kolch, W., Martiny-Baron, G., Kieser, A. et al. Regulation of the expression of the VEGF/VPS and its receptors: role in tumor angiogenesis. Breast Cancer Res Tr 36, 139–155 (1995). https://doi.org/10.1007/BF00666036

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