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Downmodulation of bFGF-binding protein expression following restoration of p53 function


Angiogenesis is a requirement for solid tumor growth. Therefore, inhibition of this neovascularization is one mechanism by which restoration of wtp53 function may lead to tumor regression. Here we report that adenoviral vector–mediated wild-type p53 transduction results in growth inhibition of squamous cell carcinoma of the head and neck tumor cells both in vitro and in a xenograft mouse model. This growth inhibition is associated with the down-regulation of the expression of fibroblast growth factor binding protein, a secreted protein required for the activation of angiogenic factor basic FGF. These findings suggest that wtp53-induced tumor regression is due, at least in part, to antiangiogenesis mediated by the downmodulation of fibroblast growth factor binding protein. Cancer Gene Therapy (2001) 8, 771–782


  1. 1

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

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Colville-Nash PR, Willoughby DA . Growth factors in angiogenesis: current interest and therapeutic potential Mol Med Today 1997 3: 14–23

    CAS  PubMed  Google Scholar 

  3. 3

    Fathallah-Shaykh HM, Zhao L-J, Kafrouni AI, et al . Gene transfer of IFN-γ into established brain tumors represses growth by antiangiogenesis J Immunol 2000 164: 217–222

    CAS  PubMed  Google Scholar 

  4. 4

    Shao R, Xia W, Hung MC . Inhibition of angiogenesis and induction of apoptosis are involved in E1A-mediated bystander effect and tumor suppression Cancer Res 2000 60: 3123–3126

    CAS  PubMed  Google Scholar 

  5. 5

    Chen CT, Lin J, Li Q, et al . Antiangiogenic gene therapy for cancer via systemic administration of adenoviral vectors expressing secretable endostatin Hum Gene Ther 2000 11: 1983–1996

    CAS  PubMed  Google Scholar 

  6. 6

    Eckhardt SG, Pluda JM . Development of angiogenesis inhibitors for cancer therapy Invest New Drugs 1997 15: 1–3

    CAS  PubMed  Google Scholar 

  7. 7

    Wieser R . The transforming growth factor-beta signaling pathway in tumorigenesis Curr Opin Oncol 2001 13: 70–77

    CAS  PubMed  Google Scholar 

  8. 8

    Yu Q, Stamenkovic I . Cell surface–localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis Genes Dev 2000 14: 163–176

    PubMed  PubMed Central  Google Scholar 

  9. 9

    Saaristo A, Karpanen T, Alitalo K . Mechanisms of angiogenesis and their use in the inhibition of tumor growth and metastasis Oncogene 2000 19: 6122–6129

    CAS  Google Scholar 

  10. 10

    Karkkainen MJ, Petrova TV . Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis Oncogene 2000 19: 5598–5605

    CAS  PubMed  Google Scholar 

  11. 11

    Rofstad EK, Halsor EF . Vascular endothelial growth factor, interleukin 8, platelet-derived endothelial cell growth factor, and basic fibroblast growth factor promote angiogenesis and metastasis in human melanoma xenografts Cancer Res 2000 60: 4932–4938

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Velculescu VE, el-Deiry WS . Biological and clinical importance of the p53 tumor suppressor gene Clin Chem 1996 42: 858–868

    CAS  PubMed  Google Scholar 

  13. 13

    Burgess WH, Maciag T . The heparin-binding (fibroblast) growth factor family of proteins Annu Rev Biochem 1989 58: 575–606

    CAS  PubMed  Google Scholar 

  14. 14

    Miyamoto M, Naruo K, Seko C, et al . Molecular cloning of a novel cytokine cDNA encoding the ninth member of the fibroblast growth factor family, which has a unique secretion property Mol Cell Biol 1993 13: 4251–4259

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Yamasaki M, Miyake A, Tagashira S, et al . Structure and expression of the rat mRNA encoding a novel member of the fibroblast growth factor family J Biol Chem 1996 271: 5918–5921

    Google Scholar 

  16. 16

    Klagsbrun M, Sasse J, Sullivan R, et al . Human tumor cells synthesize an endothelial cell growth factor that is structurally related to basic fibroblast growth factor Proc Natl Acad Sci USA 1986 83: 2448–2452

    CAS  PubMed  Google Scholar 

  17. 17

    Moscatelli D, Presta M, Joseph-Silverstein J, et al . Both normal and tumor cells produce basic fibroblast growth factor J Cell Physiol 1986 129: 273–276

    CAS  PubMed  Google Scholar 

  18. 18

    Schweigerer L, Neufeld G, Gospodarowicz D . Basic fibroblast growth factor as a growth inhibitor for cultured human tumor cells J Clin Invest 1987 80: 1516–1520

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Kurtz A, Wang HG, Darwiche N, et al . Expression of a binding protein for FGF is associated with epithelial development and skin carcinogenesis Oncogene 1997 14: 2671–2681

    CAS  PubMed  Google Scholar 

  20. 20

    Hori A, Sasada R, Matsutani E, et al . Suppression of solid tumor growth by immunoneutralizing monoclonal antibody against human basic fibroblast growth factor Cancer Res 1991 51: 6180–6184

    CAS  PubMed  Google Scholar 

  21. 21

    Vlodavsky I, Folkman J, Sullivan R, et al . Endothelial cell–derived basic fibroblast growth factor: synthesis and deposition into subendothelial extracellular matrix Proc Natl Acad Sci USA 1987 84: 2292–2296

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Di Mario J, Buffinger N, Yamada S, et al . Fibroblast growth factor in the extracellular matrix of dystrophic (MDX) mouse muscle Science 1989 244: 688–690

    CAS  Google Scholar 

  23. 23

    Baird A, Ling N . Fibroblast growth factors are present in the extracellular matrix produced by endothelial cells in vitro : implications for a role of heparinase-like enzymes in the neovascular response Biochem Biophys Res Commun 1987 142: 428–435

    CAS  PubMed  Google Scholar 

  24. 24

    Bashkin P, Doctrow S, Klagsbrun M, et al . Basic fibroblast growth factor binds to subendothelian extracellular matrix is released by heparitinase and heparin-like molecules Biochemistry 1989 28: 1737–1743

    CAS  PubMed  Google Scholar 

  25. 25

    Czubayko F, Smith RV, Chung HC, et al . Tumor growth and angiogenesis induced by a secreted binding protein for fibroblast growth factors J Biol Chem 1994 269: 28243–28248

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Wu DQ, Kan MK, Sato GH, et al . Characterization and molecular cloning of a putative binding protein for heparin-binding growth factors J Biol Chem 1991 266: 16778–16785

    CAS  PubMed  Google Scholar 

  27. 27

    Aigner A, Malerczyk C, Houghtling R, et al . Tissue distribution and retinoid-mediated downregulation of an FGF-binding protein (FGF-BP) in the rat Growth Factors 2000 18: 51–62

    CAS  PubMed  Google Scholar 

  28. 28

    Lametsch R, Rasmussen JT, Johnsen LB, et al . Structural characterization of the fibroblast growth factor binding protein purified from bovine prepartum mammary gland secretion J Biol Chem 2000 275: 19469–19474

    CAS  PubMed  Google Scholar 

  29. 29

    Pirollo KF, Hao Z, Rait A, et al . P53-mediated sensitization of squamous cell carcinoma of the head and neck to radiotherapy Oncogene 1997 14: 1735–1746

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Asgari K, Sesterhenn IA, Mcleod DG, et al . Inhibition of the growth of pre-established subcutaneous tumor nodules of human prostate cancer cells by single injection of the recombinant adenovirus p53 expression vector Int J Cancer 1997 71: 377–382

    CAS  PubMed  Google Scholar 

  31. 31

    Freeman SM, Abboud CN, Whartenby KA, et al . The “bystander effect”: tumor regression when a fraction of the tumor mass is genetically modified Cancer Res 1993 53: 5274–5283

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Chen CY, Chang YN, Ryan P, et al . Effect of herpes simplex virus thymidine kinase expression levels on ganciclovir-mediated cytotoxicity and the “bystander effect.” Hum Gene Ther 1995 6: 1467–1476

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Kaneko Y, Tsukamoto A . Gene therapy of hepatoma: bystander effects and non-apoptotic cell death induced by thymidine kinase and ganciclovir Cancer Lett 1995 96: 105–110

    CAS  PubMed  Google Scholar 

  34. 34

    Marini FC III, Nelson JA, Lapeyre JN . Assessment of bystander effect potency produced by intratumoral implantation of hsvtk-expressing cells using surrogate marker secretion to monitor tumor growth kinetics Gene Ther 1995 2: 655–659

    PubMed  Google Scholar 

  35. 35

    Fick J, Barker FG II, Dazin P, et al . The extent of heterocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro Proc Natl Acad Sci USA 1995 92: 11071–11075

    CAS  Google Scholar 

  36. 36

    Kuriyama S, Nakatani T, Masui K, et al . Bystander effect caused by suicide gene expression indicates the feasibility of gene therapy for hepatocellular carcinoma Hepatology 1995 22: 1838–1846

    CAS  PubMed  Google Scholar 

  37. 37

    Elshami AA, Kucharczuk JC, Sterman DH, et al . The role of immunosuppression in the efficacy of cancer gene therapy using adenovirus transfer of the herpes simplex thymidine kinase gene Ann Surg 1995 222: 298–310

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Freeman SM, Abboud CN, Whartenby KA, et al . The “bystander effect”: tumor regression when a fraction of the tumor mass is genetically modified Cancer Res 1993 53: 5274–5283

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Samejima Y, Meruelo D . “Bystander killing” induces apoptosis and is inhibited by forskolin Gene Ther 1995 2: 50–58

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Yamasaki H, Katoh F . Novel method for selective killing of transformed rodent cells through intracellular communication, with possible therapeutic applications Cancer Res 1988 48: 3203–3207

    CAS  PubMed  Google Scholar 

  41. 41

    Bi WL, Parysek LM, Warnick R, et al . In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSV tk retroviral gene therapy Hum Gene Ther 1993 4: 725–731

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Freeman SM, Zwiebel JA . Gene therapy of cancer Cancer Invest 1993 11: 676–688

    CAS  PubMed  Google Scholar 

  43. 43

    Caruso M, Panis Y, Gagandeep S, et al . Regression of established macroscopic liver metastases after in situ transduction of a suicide gene Proc Natl Acad Sci USA 1993 90: 7024–7028

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Waku T, Fujiwara T, Shao J, et al . Contribution of CD95 ligand-induced neutrophil infiltration to the bystander effect in p53 gene therapy for human cancer J Immunol 2000 165: 5884–5890

    CAS  PubMed  Google Scholar 

  45. 45

    Nishizaki M, Fujiwara T, Tanida T, et al . Recombinant adenovirus expressing wild-type p53 is antiangiogenic: a proposed mechanism for bystander effect Clin Cancer Res 1999 5: 1015–1023

    CAS  PubMed  Google Scholar 

  46. 46

    Xu M, Kumar D, Srinivas S, et al . Parenteral gene therapy with p53 inhibits human breast tumors in vivo through a bystander mechanism without evidence of toxicity Hum Gene Ther 1997 8: 177–185

    CAS  PubMed  Google Scholar 

  47. 47

    Frank D, Mitchell F, Liu T, et al . Bystander effect in the adenovirus-mediated wild-type p53 gene therapy model of human squamous cell carcinoma of the head and neck Clin Cancer Res 1998 4: 2521–2527

    CAS  PubMed  Google Scholar 

  48. 48

    Jung M, Notario V, Dritschilo A . Mutations in the p53 gene in radiation-sensitive and -resistant human squamous carcinoma cells Cancer Res 1992 52: 6390–6393

    CAS  PubMed  Google Scholar 

  49. 49

    Weichselbaum RR, Beckett MA, Schwartz JL, et al . Radioresistant tumor cells are present in head and neck carcinomas that recur after radiotherapy Int J Radiat Oncol Biol Phys 1988 15: 575–579

    CAS  PubMed  Google Scholar 

  50. 50

    Smith TA, Mehaftey MG, Kayda DB, et al . Adenovirus-mediated expression of therapeutic plasma levels of human Factor IX in mice Nat Genet 1993 5: 397–402

    CAS  Google Scholar 

  51. 51

    Trapnell BC . Adenoviral vectors for gene transfer Adv Drug Delivery Rev 1993 12: 185–199

    CAS  Google Scholar 

  52. 52

    Mittereder N, Yei S, Bachurski C, et al . Evaluation of the efficacy and safety of in vitro, adenovirus-mediated transfer of the human cystic fibrosis transmembrane conductance regulator cDNA Hum Gene Ther 1994 5: 717–729

    CAS  PubMed  Google Scholar 

  53. 53

    Janat MF, Srivastava S, Devadas K, et al . Inhibition of retinoblastoma (Rb) protein phosphorylation by the combined effect of interferon-α and tumor necrosis factor-α Mol Cell Diff 1994 2: 241–253

    CAS  Google Scholar 

  54. 54

    Buckbinder L, Talbott R, Velasco-Miguel S, et al . Induction of the growth inhibitor IGF-binding protein 3 by p53 Nature 1995 377: 646–649

    CAS  Google Scholar 

  55. 55

    Liu TJ, el-Naggar AK, McDonnell TJ, et al . Apoptosis induction mediated by wild-type p53 adenoviral gene transfer in squamous cell carcinoma of the head and neck Cancer Res 1995 55: 3117–3122

    CAS  PubMed  Google Scholar 

  56. 56

    Deffie A, Wu H, Reinke V, et al . The tumor suppressor p53 regulates its own transcription Mol Cell Biol 1993 13: 3415–3423

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Dameron KM, Volpert OV, Tainsky MA, et al . Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1 Science 1994 265: 1582–1584

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Bouck N, Stellmach V, Hsu SC . How tumors become angiogenic Adv Cancer Res 1996 69: 135–174

    CAS  PubMed  Google Scholar 

  59. 59

    Volpert OV, Dameron KM, Bouck N . Sequential development of an angiogenic phenotype by human fibroblasts progressing to tumorigenicity Oncogene 1997 14: 1495–1502

    CAS  PubMed  Google Scholar 

  60. 60

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

    CAS  PubMed  Google Scholar 

  61. 61

    Liu Y, Thor A, Shtivelman E, et al . Systemic gene delivery expands the repertoire of effective antiangiogenic agents J Bio Chem 1999 274: 13338–13344

    CAS  Google Scholar 

  62. 62

    Nguyen M, Watanabe H, Budson AE, et al . Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers J Natl Cancer Inst 1994 86: 356–361

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Czubayko F, Liaudet-Coopman DE, Aigner A, et al . A secreted FGF-binding protein can serve as the angiogenic switch for squamous cell carcinoma Nat Med 1997 3: 1137–1140

    CAS  PubMed  Google Scholar 

  64. 64

    O'Brien T, Cranston D, Fuggle S, et al . Two mechanisms of basic fibroblast growth factor–induced angiogenesis in bladder cancer Cancer Res 1997 57: 136–140

    CAS  PubMed  Google Scholar 

  65. 65

    Harris VK, Coticchia CM, Kagan BL, et al . Induction of the angiogenic modulator fibroblast growth factor binding protein by epidermal growth factor is mediated through both MEK/ERK and p38 signal transduction pathways J Biol Chem 2000 275: 10802–10811

    CAS  PubMed  Google Scholar 

  66. 66

    Harris VK, Liaudet-Coopman EDE, Boyle B, et al . Phorbol ester–induced transcription of a fibroblast growth factor binding protein is modulated by a complex interplay of positive and negative regulatory promoter elements J Biol Chem 1998 273: 19130–19139

    CAS  PubMed  Google Scholar 

  67. 67

    Rajah R, Valentinis B, Cohen P . Insulin-like growth factor (IGF) binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-beta 1 on programmed cell death through a p53- and IGF-independent mechanism J Biol Chem 1997 272: 12181–12188

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Tolsma SS, Volpert OV, Good DJ, et al . Peptides derived from two separate domains of the matrix protein thrombospondin-1 have anti-angiogenic activity J Cell Biol 1993 122: 497–511

    CAS  PubMed  Google Scholar 

  69. 69

    Bertherat J . Insulin-like growth factor binding protein 3 (IGFBP-3): a novel target of the tumor suppressor p53 inhibiting cell growth Eur J Endocrinol 1996 134: 426–427

    CAS  PubMed  Google Scholar 

  70. 70

    Rizk NP, Chang MY, El Kouri C, et al . The evaluation of adenoviral p53-mediated bystander effect in gene therapy of cancer Cancer Gene Ther 1999 6: 291–301

    CAS  PubMed  Google Scholar 

  71. 71

    Swisher SG, Roth JA, Nemunaitis J, et al . Adenovirus-mediated p53 gene transfer in advanced non-small cell lung cancer J Natl Cancer Inst 1999 91: 763–771

    CAS  PubMed  Google Scholar 

  72. 72

    Ogawa N, Fujiwara T, Kagawa S, et al . Novel combination therapy for human colon cancer with adenovirus-mediated wild-type p53 gene transfer and DNA-damaging chemotherapeutic agent Int J Cancer 1997 73: 367–370

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Clayman GL, el-Naggar AK, Lippman SM, et al . Adenovirus-mediated p53 gene transfer in patients with advanced recurrent head and neck squamous cell carcinoma J Clin Oncol 1998 16: 2221–2232

    CAS  PubMed  Google Scholar 

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We thank Anton Wellstein for helpful discussion of this manuscript; Ralph Weichselbaum for his kind gift of the SCCHN cell line JSQ-3; Yawen Chiang (formerly at GTI/NOVARTIS and currently at RPR/Aventis) for the adenoviral constructs; Paulette Hubbard for assistance in preparation of this manuscript; the Lombardi Cancer Center's Macromolecular Synthesis and Sequencing Shared Resource, and the Department of Comparative Medicine's animal facility, which are supported in part by US Public Health Service Grant P03 CA51008. This work was supported, in part, by NCI Grant RO1 CA45158 (to E.C.) and the National Foundation for Cancer Research Grant HU 0001 (to E.C.).

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Correspondence to Esther H Chang.

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Sherif, Z., Nakai, S., Pirollo, K. et al. Downmodulation of bFGF-binding protein expression following restoration of p53 function. Cancer Gene Ther 8, 771–782 (2001).

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  • p53
  • bFGF-binding protein
  • antiangiogenesis
  • tumor regression

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