Platelet-Derived Growth Factor

Normal Function, Role in Disease, and Application of PDGF Antagonists
  • Tobias Sjöblom
  • Kristian Pietras
  • Arne östman
  • Carl-Henrik Heldin
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Platelet-derived growth factor (PDGF) is a family of isoforms that stimulate the growth, survival, and motility of fibroblasts, smooth muscle cells, and other cell types (reviewed in ref. 1) (Fig. 1). PDGF was originally identified in human platelets and purified from this source; however, subsequent studies have shown that PDGF is synthesized by a number of different cell types.


Imatinib Mesylate Derive Growth Factor Interstitial Fluid Pressure Chronic Myelomonocytic Leukemia Dermatofibrosarcoma Protuberans 
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  1. 1.
    Heldin C-H, Eriksson U, Östman A. New members of the platelet-derived growth factor family of mitogens. Arch Biochem Biophys 2002; 398:284–290.PubMedGoogle Scholar
  2. 2.
    Oefner C, D’Arcy A, Winkler FK, Eggimann B, Hosang M. Crystal structure of human platelet-derived growth factor BB. EMBO J 1992; 11:3921–3926.PubMedGoogle Scholar
  3. 3.
    Boström H, Willetts K, Pekny M, et al. PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell 1996; 85:863–873.PubMedGoogle Scholar
  4. 4.
    Soriano P. The PDGFα receptor is required for neural crest cell development and for normal patterning of the somites. Development 1997; 124:2691–2700.PubMedGoogle Scholar
  5. 5.
    Levéen P, Pekny M, Gebre-Medhin S, Swolin B, Larsson E, Betsholtz C. Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev 1994; 8:1875–1887.PubMedGoogle Scholar
  6. 6.
    Soriano P. Abnormal kidney development and hematological disorders in PDGF β-receptor mutant mice. Genes Dev 1994; 8:1888–1896.PubMedGoogle Scholar
  7. 7.
    Lindahl P, Karlsson L, Hellström M, et al. Alveogenesis failure in PDGF-A-deficient mice is coupled to lack of distal spreading of alveolar smooth muscle cell progenitors during lung development. Development 1997; 124:3943–3953.PubMedGoogle Scholar
  8. 8.
    Karlsson L, Lindahl P, Heath JK, Betsholtz C. Abnormal gastrointestinal development in PDGF-A and PDGFR-α deficient mice implicates a novel mesenchymal structure with putative instructive properties in villus morphogenesis. Development 2000; 127:3457–3466.PubMedGoogle Scholar
  9. 9.
    Gnessi L, Basciani S, Mariani S, et al. Leydig cell loss and spermatogenic arrest in platelet-derived growth factor (PDGF)-A-deficient mice. J Cell Biol 2000; 149:1019–1026.PubMedGoogle Scholar
  10. 10.
    Calver AR, Hall AC, Yu WP, et al. Oligodendrocyte population dynamics and the role of PDGF in vivo. Neuron 1998; 20:869–882.PubMedGoogle Scholar
  11. 11.
    Fruttiger M, Karlsson L, Hall AC, et al. Defective oligodendrocyte development and severe hypomyelination in PDGF-A knockout mice. Development 1999; 126:457–467.PubMedGoogle Scholar
  12. 12.
    Tallquist MD, Weismann KE, Hellstrom M, Soriano P. Early myotome specification regulates PDGFA expression and axial skeleton development. Development 2000; 127:5059–5070.PubMedGoogle Scholar
  13. 13.
    Tallquist MD, Soriano P. Cell autonomous requirement for PDGFRα in populations of cranial and cardiac neural crest cells. Development 2003; 3:507–518.Google Scholar
  14. 14.
    Hellström M, Kalén M, Lindahl P, Abramsson A, Betsholtz C. Role of PDGF-B and PDGFR-β in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 1999; 126:3047–3055.PubMedGoogle Scholar
  15. 15.
    Lindahl P, Johansson BR, Levéen P, Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 1997; 277:242–245.PubMedGoogle Scholar
  16. 16.
    Hellström M, Gerhardt H, Kalén M, et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 2001; 153:543–553.PubMedGoogle Scholar
  17. 17.
    Crosby JR, Seifert RA, Soriano P, Bowen-Pope DF. Chimaeric analysis reveals role of PDGF receptors in all muscle lineages. Nat Genet 1998; 18:385–388.PubMedGoogle Scholar
  18. 18.
    Enge M, Bjarnegard M, et al. Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy. EMBO J 2002; 21:4307–4316.PubMedGoogle Scholar
  19. 19.
    Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 1998; 125:1591–1598.PubMedGoogle Scholar
  20. 20.
    Ohlsson R, Falck P, Hellström M, et al. PDGFB regulates the development of the labyrinthine layer of the mouse fetal placenta. Dev Biol 1999; 212:124–136.PubMedGoogle Scholar
  21. 21.
    Kaminski WE, Lindahl P, Lin NL, et al. Basis of hematopoietic defects in platelet-derived growth factor (PDGF)-B and PDGF β-receptor null mice. Blood 2001; 97:1990–1998.PubMedGoogle Scholar
  22. 22.
    Lindahl P, Hellström M, Kalén M, et al. Paracrine PDGF-B/PDGF-Rβ signaling controls mesangial cell development in kidney glomeruli. Development 1998; 125:3313–3322.PubMedGoogle Scholar
  23. 23.
    Klinghoffer RA, Hamilton TG, Hoch R, Soriano P. An allelic series at the PDGFaR locus indicates unequal contributions of distinct signaling pathways during development. Dev Cell 2002; 2:103–113.PubMedGoogle Scholar
  24. 24.
    Heuchel R, Berg A, Tallquist M, et al. Platelet-derived growth factor β receptor regulates interstitial fluid homeostasis through phosphatidylinositol-3′ kinase signaling. Proc Natl Acad Sci USA 1999; 96:11410–11415.PubMedGoogle Scholar
  25. 25.
    Tallquist MD, Klinghoffer RA, Heuchel R, et al. Retention of PDGFR-β function in mice in the absence of phosphatidylinositol-3′ kinase and phospholipase Cγ signaling pathways. Genes Dev 2000; 14:3179–3190.PubMedGoogle Scholar
  26. 26.
    Hamilton TG, Klinghoffer RA, Corrin PD, Soriano P. Evolutionary divergence of platelet-derived growth factor α receptor signaling mechanisms. Mol Cell Biol 2003; 11:4013–4025.Google Scholar
  27. 27.
    Klinghoffer RA, Mueting-Nelsen PF, Faerman A, Shani M, Soriano P. The two PDGF receptors maintain conserved signaling in vivo despite divergent embryological functions. Mol Cell 2001; 7:343–354.PubMedGoogle Scholar
  28. 28.
    Grotendorst GR, Martin GR, Pancev D, Sodek J, Harvey AK. Stimulation of granulation tissue formation by platelet-derived growth factor in normal and diabetic rats. J Clin Invest 1985; 76:2323–2339.PubMedGoogle Scholar
  29. 29.
    Lepistö J, Laato M, Niinikoski J, Lundberg C, Gerdin B, Heldin C-H. Effects of homodimeric isoforms of platelet-derived growth factor (PDGF-AA and PDGF-BB) on wound healing in rat. J Surgi Res 1992; 53:596–601.Google Scholar
  30. 30.
    Sprugel KH, McPherson JM, Clowes AW, Ross R. Effects of growth factors in vivo. I. Cell ingrowth into porous subcutaneous chambers. Am J Pathol 1987; 129:601–613.PubMedGoogle Scholar
  31. 31.
    Robson MC, Phillips LG, Thomason A, Robson LE, Pierce GF. Platelet-derived growth factor BB for the treatment of chronic pressure ulcers. Lancet 1992; 339:23–25.PubMedGoogle Scholar
  32. 32.
    Crosby JR, Tappan KA, Seifert RA, Bowen-Pope DF. Chimera analysis reveals that fibroblasts and endothelial cells require platelet-derived growth factor receptor β expression for participation in reactive connective tissue formation in adults but not during development. Am J Pathol 1999; 154:1315–1321.PubMedGoogle Scholar
  33. 33.
    Buetow BS, Crosby JR, Kaminski WE, et al. Platelet-derived growth factor B-chain of hematopoietic origin is not necessary for granulation tissue formation and its absence enhances vascularization. Am J Pathol 2001; 159:1869–1876.PubMedGoogle Scholar
  34. 34.
    Rodt SÅ, Åhlén K, Berg A, Rubin K, Reed RK. A novel physiological function for platelet-derived growth factor-BB in rat dermis. J Physiol 1996; 495:193–200.PubMedGoogle Scholar
  35. 35.
    Östman A, Heldin C-H. Involvement of platelet-derived growth factor in disease: development of specific antagonists. Adv Cancer Res 2001; 80:1–38.PubMedGoogle Scholar
  36. 36.
    Green LS, Jellinek D, Jenison R, Östman A, Heldin C-H, Janjic N. Inhibitory DNA ligands to platelet-derived growth factor B-chain. Biochem 1996; 35:14413–14424.Google Scholar
  37. 37.
    Floege J, Ostendorf T, Janssen U, et al. Novel approach to specific growth factor inhibition in vivo. Antagonism of platelet-derived growth factor in glomerulonephritis by aptamers. Am J Pathol 1999; 154:169–179.PubMedGoogle Scholar
  38. 38.
    Leppänen O, Janjic N, Carlsson M-A, et al. Intimal hyperplasia recurs after removal of PDGF-AB and-BB inhibition in the rat carotid artery injury model. Arterioscler Thromb Vasc Biol 2000; 20:E89–E95.PubMedGoogle Scholar
  39. 39.
    Pietras K, Östman A, Sjöquist M, et al. Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res 2001; 61:2929–2934.PubMedGoogle Scholar
  40. 40.
    Pietras K, Rubin K, Sjöblom T, et al. Inhibition of PDGF receptor signaling in tumor stroma enhances anti-tumor effect of chemotherapy. Cancer Res 2002; 62:5476–5484.PubMedGoogle Scholar
  41. 41.
    Heidaran MA, Mahadevan D, Larochelle WJ. β PDGFR-IgG chimera demonstrates that human β PDGFR Ig-like domains 1 to 3 are sufficient for high affinity PDGF BB binding. FASEB J 1995; 9:140–145.PubMedGoogle Scholar
  42. 42.
    Leppänen O, Miyazawa K, Bäckström G, et al. Predimerization of recombinant platelet-derived growth factor receptor extracellular domains increases antagonistic potency. Biochemistry 2000; 39:2370–2375.PubMedGoogle Scholar
  43. 43.
    Yoshida M, Sakuma-Mochizuki J, Abe Ky, et al. In vivo gene transfer of an extracellular domain of platelet-derived growth factor β receptor by the HVJ-liposome method amelio-rates bleomycin-induced pulmonary fibrosis. Biochem Biophys Res Commun 1999; 265:503–508.PubMedGoogle Scholar
  44. 44.
    Omura T, Heldin C-H, Östman A. Immunoglobulin-like domain 4-mediated receptor-receptor interactions contribute to platelet-derived growth factor-induced receptor dimerization. J Biol Chem 1997; 272:12676–12682.PubMedGoogle Scholar
  45. 45.
    Lokker NA, O’Hare JP, Barsoumian A, et al. Functional importance of platelet-derived growth factor (PDGF) receptor extracellular immunoglobulin-like domains. Identification of PDGF binding site and neutralizing monoclonal antibodies. J Biol Chem 1997; 272:33037–33044.PubMedGoogle Scholar
  46. 46.
    Shulman T, Sauer FG, Jackman RM, Chang CN, Landolfi NF. An antibody reactive with domain 4 of the platelet-derived growth factor β receptor allows BB binding while inhibiting proliferation by impairing receptor dimerization. J Biol Chem 1997; 272:17400–17404.PubMedGoogle Scholar
  47. 47.
    Kovalenko M, Gazit A, Böhmer A, et al. Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation. Cancer Res 1994; 54:6106–6114.PubMedGoogle Scholar
  48. 48.
    Bilder G, Wentz T, Leadley R, et al. Persons P, Page K, Perrone M, Dunwiddie C. Restenosis following angioplasty in the swine coronary artery is inhibited by an orally active PDGF-receptor tyrosine kinase inhibitor, RPR101511A. Circulation 1999; 99:3292–3299.PubMedGoogle Scholar
  49. 49.
    Pandey A, Volkots DL, Seroogy JM, et al. Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family. J Med Chem 2002; 45:3772–3793.PubMedGoogle Scholar
  50. 50.
    Cools J, Stover EH, Boulton CL, et al. PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease. Cancer Cell 2003; 5:459–469.Google Scholar
  51. 51.
    Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003; 1:327–337.Google Scholar
  52. 52.
    Yamasaki Y, Miyoshi K, Oda N, et al. Weekly dosing with the platelet-derived growth factor receptor tyrosine kinase inhibitor SU9518 significantly inhibits arterial stenosis. Circ Res 2001; 88:630–636.PubMedGoogle Scholar
  53. 53.
    Yu JC, Lokker NA, Hollenbach S, et al. Efficacy of the novel selective platelet-derived growth factor receptor antagonist CT52923 on cellular proliferation, migration, and suppression of neointima following vascular injury. J Pharmacol Exp Ther 2001; 298:1172–1178.PubMedGoogle Scholar
  54. 54.
    Sawyers CL. Finding the next Gleevec: FLT3 targeted kinase inhibitor therapy for acute myeloid leukemia. Cancer Cell 2002; 1:413–415.PubMedGoogle Scholar
  55. 55.
    Rubin K, Tingström A, Hansson GK, et al. Induction of B-type receptors for platelet-derived growth factor in vascular inflammation. possible implications for development of vascular proliferative lesions. Lancet 1988; 1:1353–1356.PubMedGoogle Scholar
  56. 56.
    Tanizawa S, Ueda M, Van der Loos CM, Van der Wal AC, Becker AE. Expression of platelet derived growth factor B chain and β receptor in human coronary arteries after percutaneous transluminal coronary angioplasty. An immunohistochemical study. Br Heart J 1996; 75:549–556.Google Scholar
  57. 57.
    Ross R, Masuda J, Raines EW, et al. Localization of PDGF-B protein in macrophages in all phases of atherogenesis. Science 1990; 248:1009–1012.PubMedGoogle Scholar
  58. 58.
    Ueda M, Becker AE, Kasayuki N, Kojima A, Morita Y, Tanaka S. In situ detection of platelet-derived growth factor-A and-B chain mRNA in human coronary arteries after percutaneous transluminal coronary angioplasty. Am J Pathol 1996; 149:831–843.PubMedGoogle Scholar
  59. 59.
    Jawien A, Bowen-Pope DF, Lindner V, Schwartz SM, Clowes AW. Platelet-derived growth factor promotes smooth muscle migration and intimal thickening in a rat model of balloon angioplasty. J Clin Invest 1992; 89:507–511.PubMedGoogle Scholar
  60. 60.
    Nabel EG, Yang Z, Liptay S, et al. Recombinant platelet-derived growth factor B gene expression in porcine arteries induce intimal hyperplasia in vivo. J Clin Invest 1993;91:1822–1829.PubMedGoogle Scholar
  61. 61.
    Ferns GA, Raines EW, Sprugel KH, Motani AS, Reidy MA, Ross R: Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF. Science 1991;253:1129–1132.PubMedGoogle Scholar
  62. 62.
    Sirois MG, Simons M, Edelman ER. Antisense oligonucleotide inhibition of PDGFR-β receptor subunit expression directs suppression of intimal thickening. Circulation 1997; 95:669–676.PubMedGoogle Scholar
  63. 63.
    Myllarniemi M, Calderon L, Lemström K, Buchdunger E, Hayry P. Inhibition of platelet-derived growth factor receptor tyrosine kinase inhibits vascular smooth muscle cell migration and proliferation. FASEB J 1997; 11:1119–1126.PubMedGoogle Scholar
  64. 64.
    Banai S, Wolf Y, Golomb G, et al. PDGF-receptor tyrosine kinase blocker AG1295 selectively attenuates smooth muscle cell growth in vitro and reduces neointimal formation after balloon angioplasty in swine. Circulation 1998; 97:1960–1969.PubMedGoogle Scholar
  65. 65.
    Bilder G, Amin D, Morgan L, et al. Stent-induced restenosis in the swine coronary artery is inhibited by a platelet-derived growth factor receptor tyrosine kinase inhibitor, TKI963. J Cardiovasc Pharmacol 2003; 41:817–829.PubMedGoogle Scholar
  66. 66.
    Giese NA, Marijianowski MMH, McCook O, et al. The role of α and β platelet-derived growth factor receptor in the vascular response to injury in nonhuman primates. Arterioscler. Thromb Vasc Biol 1999; 19:900–909.Google Scholar
  67. 67.
    Hart CE, Kraiss LW, Vergel S, et al. PDGFβ receptor blockade inhibits intimal hyperplasia in the baboon. Circulation 1999; 99:564–569.PubMedGoogle Scholar
  68. 68.
    Rutherford C, Martin W, Salame M, Carrier M, Änggård E, Ferns G. Substantial inhibition of neo-intimal response to balloon injury in the rat carotid artery using a combination of antibodies to platelet-derived growth factor-BB and basic fibroblast growth factor. Atherosclerosis 1997; 130:45–51.PubMedGoogle Scholar
  69. 69.
    Leppänen O, Rutanen J, Hiltunen MO, et al. Oral imatinib mesylate (STI571/Gleevec) improves the efficacy of local intravasular endothetial growth factor-c gene transfer in reducing neointimal growth in hypercholesterolemic rabbits. Circulation 2004; 109:1140–1146.PubMedGoogle Scholar
  70. 70.
    Sano H, Sudo T, Yokode M, et al. Functional blockade of platelet-derived growth factor receptor-β but not of receptor-α prevents vascular smooth muscle cell accumulation in fibrous cap lesions in apolipoprotein E-deficient mice. Circulation 2001; 103:2955–2960.PubMedGoogle Scholar
  71. 71.
    Kozaki K, Kaminski WE, Tang J, et al. Blockade of platelet-derived growth factor or its receptors transiently delays but does not prevent fibrous cap formation in ApoE null mice. Am J Pathol 2002; 161:1395–1407.PubMedGoogle Scholar
  72. 72.
    Sihvola R, Koskinen P, Myllärniemi M, et al. Prevention of cardiac allograft arteriosclerosis by protein tyrosine kinase inhibitor selective for platelet-derived growth factor receptor. Circulation 1999; 99:2295–2301.PubMedGoogle Scholar
  73. 73.
    Sihvola RK, Tikkanen JM, Krebs R, et al. Platelet-derived growth factor receptor inhibition reduces allograft arteriosclerosis of heart and aorta in cholesterol-fed rabbits. Transplantation 2003; 75:334–339.PubMedGoogle Scholar
  74. 74.
    Floege J, Ostendorf T. Platelet-derived growth factor: a new clinical target on the horizon. Kidney Int 2001; 59:1592–1593.PubMedGoogle Scholar
  75. 75.
    Aase K, Abramsson A, Karlsson L, Betsholtz C, Eriksson U. Expression analysis of PDGF-C in adult and developing mouse tissues. Mech Dev 2002; 110:187–191.PubMedGoogle Scholar
  76. 76.
    Changsirikulchai S, Hudkins KL, Goodpaster TA, et al. Platelet-derived growth factor-D expression in developing and mature human kidneys. Kidney Int 2002; 62:2043–2054.PubMedGoogle Scholar
  77. 77.
    Eitner F, Ostendorf T, Van Roeyen C, et al. Expression of a novel PDGF isoform, PDGF-C, in normal and diseased rat kidney. J Am Soc Nephrol 2002; 13:910–917.PubMedGoogle Scholar
  78. 78.
    Eitner F, Ostendorf T, Kretzler M, et al. PDGF-C expression in the developing and normal adult human kidney and in glomerular diseases. J Am Soc Nephrol 2003; 14:1145–1153.PubMedGoogle Scholar
  79. 79.
    Gilbert RE, Kelly DJ, McKay T, et al. PDGF signal transduction inhibition ameliorates experimental mesangial proliferative glomerulonephritis. Kidney Int 2001; 59:1324–1332.PubMedGoogle Scholar
  80. 80.
    Ostendorf T, Kunter U, Grone HJ, et al. Specific antagonism of PDGF prevents renal scarring in experimental glomerulonephritis. J Am Soc Nephrol 2001; 12:909–918.PubMedGoogle Scholar
  81. 81.
    Yi ES, Lee H, Yin S, et al. Platelet-derived growth factor causes pulmonary cell proliferation and collagen deposition in vivo. Am J Pathol 1996; 149:539–548.PubMedGoogle Scholar
  82. 82.
    Gurujeyalakshmi G, Hollinger MA, Giri SN. Pirfenidone inhibits PDGF isoforms in bleomycin hamster model of lung fibrosis at the translational level. Am J Physiol Lung Cell Mol Physiol 1999; 276:L311–L318.Google Scholar
  83. 83.
    Rice PL, Porter SE, Koski KM, Ramakrishna G, Chen A, Schrump D, Kazlauskas A, Malkinson AM. Reduced receptor expression for platelet-derived growth factor and epidermal growth factor in dividing mouse lung epithelial cells. Mol Carcinog 1999; 25:285–294.PubMedGoogle Scholar
  84. 84.
    Doolittle RF, Hunkapiller MW, Hood LE, et al. Simian sarcoma virus onc gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. Science 1983; 221:275–277.PubMedGoogle Scholar
  85. 85.
    Waterfield MD, Scrace GT, Whittle N, et al. Platelet-derived growth factor is structurally related to the putative transforming protein p28sis of simian sarcoma virus. Nature (London) 1983; 304:35–39.Google Scholar
  86. 86.
    Westermark B, Johnsson A, Betsholtz C, Heldin C-H. Biological properties of simian sarcoma virus and its oncogene product. Contr. Oncol., vol. 24. Basel. Karger, 1987:51–61.Google Scholar
  87. 87.
    Beckmann MP, Betsholtz C, Heldin C-H, et al. Comparison of biological properties and transforming potential of human PDGF-A and PDGF-B chains. Science 1988; 241:1346–1349.PubMedGoogle Scholar
  88. 88.
    Li H, Fredriksson L, Li X, Eriksson U. PDGF-D is a potent transforming and angiogenic growth factor. Oncogene 2003; 22:1501–1510.PubMedGoogle Scholar
  89. 89.
    Pietras K, Sjöblom T, Rubin K, Heldin C, Östman A. PDGF receptors as cancer drug targets. Cancer Cell 2003; 3:439–443.PubMedGoogle Scholar
  90. 90.
    Hermanson M, Funa K, Koopmann J, et al. Association of loss of heterozygosity on chromosome 17p with high platelet-derived growth factor a receptor expression in human malignant gliomas. Cancer Res 1996; 56:164–171.PubMedGoogle Scholar
  91. 91.
    LaRochelle WJ, Jeffers M, Corvalan JR, et al. Platelet-derived growth factor D. tumorigenicity in mice and dysregulated expression in human cancer. Cancer Res 2002; 62:2468–2473.PubMedGoogle Scholar
  92. 92.
    Lokker NA, Sullivan CM, Hollenbach SJ, Israel MA, Giese NA. Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res 2002; 62:3729–3735.PubMedGoogle Scholar
  93. 93.
    Fleming TP, Matsui T, Heidaran MA, Molloy CJ, Artrip J, Aaronson SA. Demonstration of an activated platelet-derived growth factor autocrine pathway and its role in human tumor cell proliferation in vitro. Oncogene 1992; 7:1355–1359.PubMedGoogle Scholar
  94. 94.
    Kumabe T, Sohma Y, Kayama T, Yoshimoto T, Yamamoto T. Amplification of α-platelet-derived growth factor receptor gene lacking an exon coding for a portion of the extracellular region in a primary brain tumor of glial origin. Oncogene 1992; 7:627–633.PubMedGoogle Scholar
  95. 95.
    Clarke ID, Dirks PB. A human brain tumor-derived PDGFR-α deletion mutant is transforming. Oncogene 2003; 22:722–733.PubMedGoogle Scholar
  96. 96.
    Deinhardt F. The biology of primate retrovirus. In: Klein, G, ed. Viral Oncology, Vol. New York: Raven Press, 1980:359–398.Google Scholar
  97. 97.
    Uhrbom L, Hesselager G, Nistér M, Westermark B. Induction of brain tumors in mice using a recombinant platelet-derived growth factor B-chain retrovirus. Cancer Res 1998; 58:5275–5279.PubMedGoogle Scholar
  98. 98.
    Shamah SM, Stiles CD, Guha A. Dominant-negative mutants of platelet-derived growth factor revert the transformed phenotype of human astrocytoma cells. Mol Cell Biol 1993; 13:7203–7212.PubMedGoogle Scholar
  99. 99.
    Strawn LM, Mann E, Elliger SS, et al. Inhibition of glioma cell growth by a truncated platelet-derived growth factor-β receptor. J Biol Chem 1994; 269:21215–21222.PubMedGoogle Scholar
  100. 100.
    Kilic T, Alberta JA, Zdunek PR, et al. Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine class. Cancer Res 2000; 60:5143–5150.PubMedGoogle Scholar
  101. 101.
    Smits A, Funa K, Vassbotn FS, et al. Expression of platelet-derived growth factor and its receptors in proliferative disorders of fibroblastic origin. Am J Pathol 1992; 140:639–648.PubMedGoogle Scholar
  102. 102.
    Zwerner JP, May WA. PDGF-C is an EWS/FLI induced transforming growth factor in Ewing family tumors. Oncogene 2001; 20:626–633.PubMedGoogle Scholar
  103. 103.
    Zwerner JP, May WA. Dominant negative PDGF-C inhibits growth of Ewing family tumor cell lines. Oncogene 2002; 21:3847–3854.PubMedGoogle Scholar
  104. 104.
    Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003; 299:708–710.PubMedGoogle Scholar
  105. 105.
    Heinrich MC, Corless CL, von Mehren M, et al. PDGFRA and KIT mutations correlate with the clinical responses to imatinib mesylate in patients with advanced gastrointestinal stromal tumors (GIST). In Proceedings of ASCO, 2003.Google Scholar
  106. 106.
    Mandahl N, Heim S, Willen H, Rydholm A, Mitelman F. Supernumerary ring chromosome as the sole cytogenetic abnormality in a dermatofibrosarcoma protuberans. Cancer Genet Cytogenet 1990; 49:273–275.PubMedGoogle Scholar
  107. 107.
    Naeem R, Lux ML, Huang SF, Naber SP, Corson JM, Fletcher JA. Ring chromosomes in dermatofibrosarcoma protuberans are composed of interspersed sequences from chromosomes 17 and 22. Am J Pathol 1995; 147:1553–1558.PubMedGoogle Scholar
  108. 108.
    Craver RD, Correa H, Kao YS, Van Brunt T, Golladay ES. Aggressive giant cell fibroblastoma with a balanced 17; 22 translocation. Cancer Genet Cytogenet 1995; 80:20–22.PubMedGoogle Scholar
  109. 109.
    Pedeutour F, Simon MP, Minoletti F, et al. Translocation, t(17;22)(q22;q13), in dermatofibrosarcoma protuberans. a new tumor-associated chromosome rearrangement. Cytogenet Cell Genet 1996; 72:171–174.PubMedGoogle Scholar
  110. 110.
    Simon M-P, Pedeutour F, Sirvent N, et al. Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nature Genet 1997; 15:95–98.PubMedGoogle Scholar
  111. 111.
    Sheng WQ, Hashimoto H, Okamoto S, et al. Expression of COL1A1-PDGFB fusion transcripts in superficial adult fibrosarcoma suggests a close relationship to dermatofibrosarcoma protuberans. J Pathol 2001; 194:88–94.PubMedGoogle Scholar
  112. 112.
    Wang J, Hisaoka M, Shimajiri S, Morimitsu Y, Hashimoto H. Detection of COL1A1-PDGFB fusion transcripts in dermatofibrosarcoma protuberans by reverse transcription-polymerase chain reaction using archival formalin-fixed, paraffin-embedded tissues. Diagn Mol Pathol 1999; 8:113–119.PubMedGoogle Scholar
  113. 113.
    Shimizu A, O’Brien KP, Sjöblom T, et al. The dermatofibrosarcoma protuberans-associated collagen type Iα1/platelet-derived growth factor (PDGF) B-chain fusion gene generates a transforming protein that is processed to functional PDGF-BB. Cancer Res 1999; 59:3719–3723.PubMedGoogle Scholar
  114. 114.
    Greco A, Fusetti L, Villa R, et al. Transforming activity of the chimeric sequence formed by the fusion of collagen gene COL1A1 and the platelet derived growth factor b-chain gene in dermatofibrosarcoma protuberans. Oncogene 1998; 17:1313–1319.PubMedGoogle Scholar
  115. 115.
    Sjöblom T, Shimizu A, O’Brien KP, et al. Growth inhibition of dermatofibrosarcoma protuberans tumors by the platelet-derived growth factor receptor antagonist STI571 through induction of apoptosis. Cancer Res 2001; 61:5778–5783.PubMedGoogle Scholar
  116. 116.
    Rubin BP, Schuetze SM, Eary JF, et al. Molecular targeting of platelet-derived growth factor B by imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J Clin Oncol 2002; 20:3586–3591.PubMedGoogle Scholar
  117. 117.
    Maki RG, Awan RA, Dixon RH, Jhanwar S, Antonescu CR. Differential sensitivity to imatinib of 2 patients with metastatic sarcoma arising from dermatofibrosarcoma protuberans. Int J Cancer 2002; 100:623–626.PubMedGoogle Scholar
  118. 117a.
    McArthur GA, Demetri GD, van Oosterom A, et al. Molecular and clinical analysis of locally advanced dermatofibrosarcoma protuberans treated with imatinib: Imatinib Target Exploration Consortium Study B2225. J Clin Oncol 2005; 23: 866–873.PubMedGoogle Scholar
  119. 118.
    Ganser A, Hoelzer D. Clinical course of myelodysplastic syndromes. Hematol Oncol Clin North Am 1992; 6:607–618.PubMedGoogle Scholar
  120. 119.
    Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor β to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994; 77:307–316.PubMedGoogle Scholar
  121. 120.
    Kulkarni S, Heath C, Parker S, et al. Fusion of H4/D10S170 to the platelet-derived growth factor receptor β in BCR-ABL-negative myeloproliferative disorders with a t(5;10)(q33;q21). Cancer Res 2000; 60:3592–3598.PubMedGoogle Scholar
  122. 121.
    Schwaller J, Anastasiadou E, Cain D, et al. H4(D10S170), a gene frequently rearranged in papillary thyroid carcinoma, is fused to the platelet-derived growth factor receptor β gene in atypical chronic myeloid leukemia with t(5;10)(q33;q22). Blood 2001; 97:3910–3918.PubMedGoogle Scholar
  123. 122.
    Ross TS, Bernard OA, Berger R, Gilliland DG. Fusion of Huntingtin Interacting protein 1 to platelet-derived growth factor β receptor (PDGFβR) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2). Blood 1998; 91:4419–4426.PubMedGoogle Scholar
  124. 123.
    Ross TS, Gilliland DG. Transforming properties of the Huntingtin interacting protein 1/platelet-derived growth factor β receptor fusion protein. J Biol Chem 1999; 274:22328–22336.PubMedGoogle Scholar
  125. 124.
    Magnusson MK, Meade KE, Brown KE, et al. Rabaptin-5 is a novel fusion partner to platelet-derived growth factor β receptor in chronic myelomonocytic leukemia. Blood 2001; 98:2518–2525.PubMedGoogle Scholar
  126. 125.
    Steer EJ, Cross NC. Myeloproliferative disorders with translocations of chromosome 5q31-35: role of the platelet-derived growth factor receptor β. Acta Haematol 2002; 107:113–122.PubMedGoogle Scholar
  127. 126.
    Carroll M, Tomasson MH, Barker GF, Golub TR, Gilliland DG. The TEL/platelet-derived growth factor β receptor (PDGFβR) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGFβR kinase-dependent signaling pathways. Proc Natl Acad Sci USA 1996; 93:14845–14850.PubMedGoogle Scholar
  128. 127.
    Jousset C, Carron C, Boureux A, et al. A domain of TEL conserved in a subset of ETS proteins defines a specific oligomerization interface essential to the mitogenic properties of the TEL-PDGFRβ oncoprotein. EMBO J 1997; 16:69–82.PubMedGoogle Scholar
  129. 128.
    Sternberg DW, Tomasson MH, Carroll M, et al. The TEL/PDGFβR fusion in chronic myelomonocytic leukemia signals through STAT5-dependent and STAT5-independent pathways. Blood 2001; 98:3390–3397.PubMedGoogle Scholar
  130. 129.
    Carroll M, Ohno-Jones S, Tamura S, et al. CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood 1997; 90:4947–4952.PubMedGoogle Scholar
  131. 130.
    Sjöblom T, Boureux A, Rönnstrand L, Heldin C-H, Ghysdael J, Östman A. Characterization of the chronic myelomonocytic leukemia associated TEL-PDGFβR fusion protein. Oncogene 1999; 18:7055–7062.PubMedGoogle Scholar
  132. 131.
    Tomasson MH, Williams IR, Hasserjian R, et al. TEL/PDGFβR induces hematologic malignancies in mice that respond to a specific tyrosine kinase inhibitor. Blood 1999; 93:1707–1714.PubMedGoogle Scholar
  133. 132.
    Tomasson MH, Sternberg DW, Williams IR, et al. Fatal myeloproliferation, induced in mice by TEL/PDGFβR expression, depends on PDGFβR tyrosines 579/581. J Clin Invest 2000; 105:423–432.PubMedGoogle Scholar
  134. 133.
    Apperley JF, Gardembas M, Melo JV, et al. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor β. N Engl J Med 2002; 347:481–487.PubMedGoogle Scholar
  135. 134.
    Pitini V, Arrigo C, Teti D, Barresi G, Righi M, Alo G. Response to ST1571 in chronic myelomonocytic leukemia with platelet derived growth factor β receptor involvement. a new case report. Haematologica 2003; 88:ECR18.PubMedGoogle Scholar
  136. 135.
    Magnusson MK, Meade KE, Nakamura R, Barrett J, Dunbar CE. Activity of ST1571 in chronic myelomonocytic leukemia with a platelet-derived growth factor β receptor fusion oncogene. Blood 2002; 100:1088–1091.PubMedGoogle Scholar
  137. 136.
    Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood 1994; 83:2759–2779.PubMedGoogle Scholar
  138. 137.
    Gleich GJ, Leiferman KM, Pardanani A, Tefferi A, Butterfield JH. Treatment of hypereosinophilic syndrome with imatinib mesylate. Lancet 2002; 359:1577–1578.PubMedGoogle Scholar
  139. 138.
    Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003; 348:1201–1214.PubMedGoogle Scholar
  140. 139.
    Griffin JH, Leung J, Bruner RJ, Caligiuri MA, Briesewitz R. Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome. Proc Natl Acad Sci USA 2003; 100:7830–7835.PubMedGoogle Scholar
  141. 140.
    Pardanani A, Ketterling RP, Brockman SR, et al. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib therapy. Blood 2003; 102:3093–3096.PubMedGoogle Scholar
  142. 141.
    Bhardwaj B, Klassen J, Cossette N, et al. Localization of platelet-derived growth factor β receptor expression in the periepithelial stroma of human breast carcinoma. Clin Cancer Res 1996; 2:773–782.PubMedGoogle Scholar
  143. 142.
    Sundberg C, Branting M, Gerdin B, Rubin K. Tumor cell and connective tissue cell interactions in human colorectal adenocarcinoma—Transfer of platelet-derived growth factor-AB/BB to stromal cells. Am J Pathol 1997; 151:479–492.PubMedGoogle Scholar
  144. 143.
    Franklin WA, Christison WH, Colley M, Montag AG, Stephens JK, Hart CE. In situ distribution of the β-subunit of platelet-derived growth factor receptor in nonneoplastic tissue and in soft tissue tumors. Cancer Res 1990; 50:6344–6348.PubMedGoogle Scholar
  145. 144.
    Hermanson M, Nistér M, Betsholtz C, Heldin C-H, Westermark B, Funa K. Endothelial cell hyperplasia in human glioblastoma: coexpression of mRNA for platelet-derived growth factor (PDGF) B chain and PDGF receptor suggests autocrine growth stimulation. Proc Natl Acad Sci USA 1988; 85:7748–7752.Google Scholar
  146. 145.
    Plate KH, Breier G, Farrell CL, Risau W. Platelet-derived growth factor receptor-β is induced during tumor development and upregulated during tumor progression in endothelial cells in human gliomas. Lab Invest 1992; 67:529–534.PubMedGoogle Scholar
  147. 146.
    Sundberg C, Ljungström M, Lindmark G, Gerdin B, Rubin K. Microvascular pericytes express platelet-derived growth factor-β receptors in human healing wounds and colorectal adenocarcinoma. Am J Pathol 1993; 143:1377–1388.PubMedGoogle Scholar
  148. 147.
    Abramsson A, Berlin O, Papayan H, Paulin D, Shani M, Betsholtz C. Analysis of mural cell recruitment to tumor vessels. Circulation 2002; 105:112–117.PubMedGoogle Scholar
  149. 148.
    Oikawa T, Onozawa C, Sakaguchi M, Morita I, Murota S. Three isoforms of platelet-derived growth factors all have the capability to induce angiogenesis in vivo. Biol Pharm Bull 1994; 17:1686–1688.PubMedGoogle Scholar
  150. 149.
    Risau W, Drexler H, Mironov V, et al. Platelet-derived growth factor is angiogenic in vivo. Growth Factors 1992; 7:261–266.PubMedGoogle Scholar
  151. 150.
    Oh SJ, Kurz H, Christ B, Wilting J. Platelet-derived growth factor-B induces transformation of fibrocytes into spindle-shaped myofibroblasts in vivo. Histochem Cell Biol 1998; 109:349–357.PubMedGoogle Scholar
  152. 151.
    Wilting J, Christ B, Bokeloh M, Weich HA. In vivo effects of vascular endothelial growth factor on the chicken chorioallantoic membrane. Cell Tissue Res 1993; 274:163–172.PubMedGoogle Scholar
  153. 152.
    Cao R, Bråkenhielm E, Li X, et al. Angiogenesis stimulated by PDGF-CC, a novel member in the PDGF family, involves activation of PDGFR-αα and-αβ receptors. FASEB J 2002; 16:1575–1583.PubMedGoogle Scholar
  154. 153.
    Guo P, Hu B, Gu W, Xu L, et al. Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment. Am J Pathol 2003; 162:1083–1093.PubMedGoogle Scholar
  155. 153a.
    Furnhashi M, Sjöblom T, Abramsson A, et al. Platelet-derived growth factor production by B16 melanoma cells leads to increased pericyte abundance in tumors and an associated increase in tumor growth rate. Cancer Res 2004; 64:2725–2733.Google Scholar
  156. 154.
    Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003; 111:1287–1295.PubMedGoogle Scholar
  157. 155.
    Uehara HK, Karashima T, Shepherd DL, et al. Effects of blocking platelet-derived growth factor-receptor signaling in a mouse model of experimental prostate cancer bone metastases. J Natl Cancer Inst 2003; 95:458–470.PubMedGoogle Scholar
  158. 156.
    Forsberg K, Valyi-Nagy I, Heldin C-H, Herlyn M, Westermark B. Platelet-derived growth factor (PDGF) in oncogenesis: development of a vascular connective tissue stroma in xenotransplanted human melanoma producing PDGF-BB. Proc Natl Acad Sci USA 1993; 90:393–397.PubMedGoogle Scholar
  159. 157.
    Skobe M, Fusenig NE. Tumorigenic conversion of immortal human keratinocytes through stromal cell activation. Proc Natl Acad Sci USA 1998; 95:1050–1055.PubMedGoogle Scholar
  160. 158.
    Shao Z-M, Nguyen M, Barsky SH. Human breast carcinoma desmoplasia is PDGF initiated. Oncogene 2000; 19:4337–4345.PubMedGoogle Scholar
  161. 159.
    Pietras K, Hubert M, Buchdunger E, et al. ST1571 enhances the therapeutic index of Epothilone B by a tumor-selective increase of drug uptake. Clin Cancer Res 2003; 3779–3787.Google Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Tobias Sjöblom
    • 1
  • Kristian Pietras
    • 2
  • Arne östman
    • 3
  • Carl-Henrik Heldin
    • 4
  1. 1.The Sydney Kimmel Comprehensive Cancer CenterJohns Hopkins UniversityBaltimore
  2. 2.Ludwig Institute for Cancer ResearchStockholmSweden
  3. 3.Cancer Center KarolinskaKarolinska InstituteStockholmSweden
  4. 4.Ludwig Institute for Cancer ResearchUppsalaSweden

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