p53 and Angiogenesis

  • Jose G. Teodoro
  • Sara K. Evans
  • Michael R. Green
Part of the Cancer Genetics book series (CANGENETICS)


The TP53 gene is the most mutated gene in human cancer and as a consequence has been one of the most extensively studied genes in the human genome. Over half of all human cancers carry direct mutations of the p53 coding region. In addition to sporadic mutations in human cancer, inherited mutations in TP53 cause a genetic predisposition to cancer called Li–Fraumeni syndrome. Individuals with Li–Fraumeni exhibit early onset of a wide variety of cancers including soft-tissue sarcoma, leukemia, osteosarcoma, and tumors of the breast and brain (Li et al., 1988). The TP53 gene is not essential for development but seems to have evolved a primary function to prevent neoplasia in multicellular organisms. The p53 tumor suppressor protein has the structure of a classical transcription factor possessing a central domain with sequence-specific DNA binding activity and an N-terminal acidic region required for transcriptional regulation of target genes.


Vascular Endothelial Growth Factor Down Syndrome Vascular Endothelial Growth Factor Expression Angiogenesis Inhibitor Maspin Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Alvarez, A. A., Axelrod, J. R., Whitaker, R. S., Isner, P. D., Bentley, R. C., Dodge, R. K., and Rodriguez, G. C (2001) Thrombospondin-1 expression in epithelial ovarian carcinoma: Association with p53 status, tumor angiogenesis, and survival in platinum-treated patients. Gynecol. Oncol. 82:273–278.PubMedCrossRefGoogle Scholar
  2. Appella, E. and Anderson, C. W (2001) Post-translational modifications and activation of p53 by genotoxic stresses. Eur. J. Biochem. 268:2764–2772.Google Scholar
  3. Baker, S. J., Preisinger, A. C., Jessup, J. M., Paraskeva, C., Markowitz, S., Willson, J. K., Hamilton, S., and Vogelstein, B (1990) p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res. 50:7717–7722.PubMedGoogle Scholar
  4. Band, V., Dalal, S., Delmolino, L., and Androphy, E. J (1993) Enhanced degradation of p53 protein in HPV-6 and BPV-1 E6-immortalized human mammary epithelial cells. EMBO J. 12:1847–1852.PubMedGoogle Scholar
  5. Bian, J. and Sun, Y (1997) Transcriptional activation by p53 of the human type IV collagenase (gelatinase A or matrix metalloproteinase 2) promoter. Mol. Cell. Biol. 17:6330–6338.PubMedGoogle Scholar
  6. Black, W. C. and Welch, H. G (1993) Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy. N. Engl. J. Med. 328:1237–1243.PubMedCrossRefGoogle Scholar
  7. Brantley, D. M., Cheng, N., Thompson, E. J., Lin, Q., Brekken, R. A., Thorpe, P. E., Muraoka, R. S., Cerretti, D. P., Pozzi, A., Jackson, D., Lin, C., and Chen, J (2002) Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo. Oncogene 21:7011–7026.PubMedCrossRefGoogle Scholar
  8. Camphausen, K., Moses, M. A., Menard, C., Sproull, M., Beecken, W. D., Folkman, J., and O’Reilly, M. S (2003) Radiation abscopal antitumor effect is mediated through p53. Cancer Res. 63:1990–1993.PubMedGoogle Scholar
  9. Carmeliet, P., Dor, Y., Herbert, J. M., Fukumura, D., Brusselmans, K., Dewerchin, M., Neeman, M., Bono, F., Abramovitch, R., Maxwell, P., Koch, C. J., Ratcliffe, P., Moons, L., Jain, R. K., Collen, D., and Keshert, E (1998) Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490.PubMedCrossRefGoogle Scholar
  10. Chulada, P. C., Thompson, M. B., Mahler, J. F., Doyle, C. M., Gaul, B. W., Lee, C., Tiano, H. F., Morham, S. G., Smithies, O., and Langenbach, R (2000) Genetic disruption of Ptgs-1, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice. Cancer Res. 60:4705–4708.PubMedGoogle Scholar
  11. Coffman, K. T., Hu, M., Carles-Kinch, K., Tice, D., Donacki, N., Munyon, K., Kifle, G., Woods, R., Langermann, S., Kiener, P. A., and Kinch, M. S (2003) Differential EphA2 epitope display on normal versus malignant cells. Cancer Res. 63:7907–7912.PubMedGoogle Scholar
  12. Coussens, L. M., Fingleton, B., and Matrisian, L. M (2002) Matrix metalloproteinase inhibitors and cancer: Trials and tribulations. Science 295:2387–2392.PubMedCrossRefGoogle Scholar
  13. Crawford, S. E., Stellmach, V., Murphy-Ullrich, J. E., Ribeiro, S. M., Lawler, J., Hynes, R. O., Boivin, G. P., and Bouck, N (1998) Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 93:1159–1170.PubMedCrossRefGoogle Scholar
  14. Crew, J. P., O’Brien, T., Bradburn, M., Fuggle, S., Bicknell, R., Cranston, D., and Harris, A. L (1997) Vascular endothelial growth factor is a predictor of relapse and stage progression in superficial bladder cancer. Cancer Res. 57:5281–5285.PubMedGoogle Scholar
  15. Dameron, K. M., Volpert, O. V., Tainsky, M. A., and Bouck, N (1994) Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265:1582–1584.PubMedCrossRefGoogle Scholar
  16. Dawson, D. W., Pearce, S. F., Zhong, R., Silverstein, R. L., Frazier, W. A., and Bouck, N. P (1997) CD36 mediates the In vitro inhibitory effects of thrombospondin-1 on endothelial cells. J. Cell Biol. 138:707–717.PubMedCrossRefGoogle Scholar
  17. Dejong, V., Degeorges, A., Filleur, S., Ait-Si-Ali, S., Mettouchi, A., Bornstein, P., Binetruy, B., and Cabon, F (1999) The Wilms’ tumor gene product represses the transcription of thrombospondin 1 in response to overexpression of c-Jun. Oncogene 18:3143–3151.PubMedCrossRefGoogle Scholar
  18. Derynck, R., Akhurst, R. J., and Balmain, A (2001) TGF-beta signaling in tumor suppression and cancer progression. Nat. Genet. 29:117–129.PubMedCrossRefGoogle Scholar
  19. Dobner, T., Horikoshi, N., Rubenwolf, S., and Shenk, T (1996) Blockage by adenovirus E4orf6 of transcriptional activation by the p53 tumor suppressor. Science 272:1470–1473.PubMedCrossRefGoogle Scholar
  20. Dodelet, V. C. and Pasquale, E. B (2000) Eph receptors and ephrin ligands: Embryogenesis to tumorigenesis. Oncogene 19:5614–5619.PubMedCrossRefGoogle Scholar
  21. Dohn, M., Jiang, J., and Chen, X (2001) Receptor tyrosine kinase EphA2 is regulated by p53-family proteins and induces apoptosis. Oncogene 20:6503–6515.PubMedCrossRefGoogle Scholar
  22. Easty, D. J. and Bennett, D. C (2000) Protein tyrosine kinases in malignant melanoma. Melanoma Res. 10:401–411.PubMedCrossRefGoogle Scholar
  23. Erkinheimo, T. L., Lassus, H., Finne, P., van Rees, B. P., Leminen, A., Ylikorkala, O., Haglund, C., Butzow, R., and Ristimaki, A (2004) Elevated cyclooxygenase-2 expression is associated with altered expression of p53 and SMAD4, amplification of HER-2/neu, and poor outcome in serous ovarian carcinoma. Clin. Cancer Res. 10:538–545.PubMedCrossRefGoogle Scholar
  24. Faviana, P., Boldrini, L., Spisni, R., Berti, P., Galleri, D., Biondi, R., Camacci, T., Materazzi, G., Pingitore, R., Miccoli, P., and Fontanini, G (2002) Neoangiogenesis in colon cancer: Correlation between vascular density, vascular endothelial growth factor (VEGF) and p53 protein expression. Oncol Rep. 9:617–620.PubMedGoogle Scholar
  25. Fingleton, B (2006) Matrix metalloproteinases: Roles in cancer and metastasis. Front. Biosci. 11:479–491.PubMedCrossRefGoogle Scholar
  26. Folkman, J. and Kalluri, R (2004) Cancer without disease. Nature 427:787.PubMedCrossRefGoogle Scholar
  27. Fontanini, G., Vignati, S., Lucchi, M., Mussi, A., Calcinai, A., Boldrini, L., Chine, S., Silvestri, V., Angeletti, C. A., Basolo, F., and Bevilacqua, G (1997) Neoangiogenesis and p53 protein in lung cancer: Their prognostic role and their relation with vascular endothelial growth factor (VEGF) expression. Br. J. Cancer 75:1295–1301.PubMedCrossRefGoogle Scholar
  28. Forsythe, J. A., Jiang, B. H., Iyer, N. V., Agani, F., Leung, S. W., Koos, R. D., and Semenza, G. L (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell. Biol. 16:4604–4613.PubMedGoogle Scholar
  29. Gabellini, C., Del Bufalo, D., and Zupi, G (2006) Involvement of RB gene family in tumor angiogenesis. Oncogene 25:5326–5332.PubMedCrossRefGoogle Scholar
  30. Gasparini, G., Weidner, N., Maluta, S., Pozza, F., Boracchi, P., Mezzetti, M., Testolin, A., and Bevilacqua, P (1993) Intratumoral microvessel density and p53 protein: Correlation with metastasis in head-and-neck squamous-cell carcinoma. Int. J. Cancer 55:739–744.PubMedCrossRefGoogle Scholar
  31. Gasparini, G., Weidner, N., Bevilacqua, P., Maluta, S., Dalla Palma, P., Caffo, O., Barbareschi, M., Boracchi, P., Marubini, E., and Pozza, F (1994) Tumor microvessel density, p53 expression, tumor size, and peritumoral lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma. J. Clin. Oncol. 12:454–466.PubMedGoogle Scholar
  32. Gasparini, G., Toi, M., Gion, M., Verderio, P., Dittadi, R., Hanatani, M., Matsubara, I., Vinante, O., Bonoldi, E., Boracchi, P., Gatti, C., Suzuki, H., and Tominaga, T (1997) Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J. Natl. Cancer Inst. 89:139–147.PubMedCrossRefGoogle Scholar
  33. Gautam, A., Densmore, C. L., Melton, S., Golunski, E., and Waldrep, J. C (2002) Aerosol delivery of PEI-p53 complexes inhibits B16-F10 lung metastases through regulation of angiogenesis. Cancer Gene Ther. 9:28–36.PubMedCrossRefGoogle Scholar
  34. Giuriato, S., Ryeom, S., Fan, A. C., Bachireddy, P., Lynch, R. C., Rioth, M. J., van Riggelen, J., Kopelman, A. M., Passegue, E., Tang, F., Folkman, J., and Felsher, D. W (2006) Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch. Proc. Natl. Acad. Sci. USA 103:16266–16271.PubMedCrossRefGoogle Scholar
  35. Good, D. J., Polverini, P. J., Rastinejad, F., Le Beau, M. M., Lemons, R. S., Frazier, W. A., and Bouck, N. P (1990) A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc. Natl. Acad. Sci. USA 87:6624–6628.PubMedCrossRefGoogle Scholar
  36. Graeber, T. G., Peterson, J. F., Tsai, M., Monica, K., Fornace, A. J., Jr., and Giaccia, A. J (1994) Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol. Cell. Biol. 14:6264–6277.PubMedGoogle Scholar
  37. Graeber, T. G., Osmanian, C., Jacks, T., Housman, D. E., Koch, C. J., Lowe, S. W., and Giaccia, A. J (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379:88–91.PubMedCrossRefGoogle Scholar
  38. Grant, S. W., Kyshtoobayeva, A. S., Kurosaki, T., Jakowatz, J., and Fruehauf, J. P (1998) Mutant p53 correlates with reduced expression of thrombospondin-1, increased angiogenesis, and metastatic progression in melanoma. Cancer Detect. Prev. 22:185–194.PubMedCrossRefGoogle Scholar
  39. Grossfeld, G. D., Carroll, P. R., Lindeman, N., Meng, M., Groshen, S., Feng, A. C., Hawes, D., and Cote, R. J (2002) Thrombospondin-1 expression in patients with pathologic stage T3 prostate cancer undergoing radical prostatectomy: Association with p53 alterations, tumor angiogenesis, and tumor progression. Urology 59:97–102.PubMedCrossRefGoogle Scholar
  40. Harach, H. R., Franssila, K. O., and Wasenius, V. M (1985) Occult papillary carcinoma of the thyroid. A “normal” finding in Finland. A systematic autopsy study. Cancer 56:531–538.PubMedCrossRefGoogle Scholar
  41. Hartford, A. C., Gohongi, T., Fukumura, D., and Jain, R. K (2000) Irradiation of a primary tumor, unlike surgical removal, enhances angiogenesis suppression at a distal site: Potential role of host-tumor interaction. Cancer Res. 60:2128–2131.PubMedGoogle Scholar
  42. Herbst, R. S., Hess, K. R., Tran, H. T., Tseng, J. E., Mullani, N. A., Charnsangavej, C., Madden, T., Davis, D. W., McConkey, D. J., O’Reilly, M. S., Ellis, L. M., Pluda, J., Hong, W. K., and Abbruzzese, J. L (2002) Phase I study of recombinant human endostatin in patients with advanced solid tumors. J. Clin. Oncol. 20:3792–3803.PubMedCrossRefGoogle Scholar
  43. Holmgren, L., Jackson, G., and Arbiser, J (1998) p53 induces angiogenesis-restricted dormancy in a mouse fibrosarcoma. Oncogene 17:819–824.PubMedCrossRefGoogle Scholar
  44. Hsu, S. C., Volpert, O. V., Steck, P. A., Mikkelsen, T., Polverini, P. J., Rao, S., Chou, P., and Bouck, N. P (1996) Inhibition of angiogenesis in human glioblastomas by chromosome 10 induction of thrombospondin-1. Cancer Res. 56:5684–5691.PubMedGoogle Scholar
  45. Iyer, N. V., Kotch, L. E., Agani, F., Leung, S. W., Laughner, E., Wenger, R. H., Gassmann, M., Gearhart, J. D., Lawler, A. M., Yu, A. Y., and Semenza, G. L (1998) Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 12:149–162.PubMedCrossRefGoogle Scholar
  46. Janz, A., Sevignani, C., Kenyon, K., Ngo, C. V., and Thomas-Tikhonenko, A (2000) Activation of the myc oncoprotein leads to increased turnover of thrombospondin-1 mRNA. Nucleic Acids Res. 28:2268–2275.PubMedCrossRefGoogle Scholar
  47. Jia, H. and Kling, J (2006) China offers alternative gateway for experimental drugs. Nat. Biotechnol. 24:117–118.PubMedCrossRefGoogle Scholar
  48. Jiang, D., Srinivasan, A., Lozano, G., and Robbins, P. D (1993) SV40 T antigen abrogates p53-mediated transcriptional activity. Oncogene 8:2805–2812.PubMedGoogle Scholar
  49. Jimenez, B., Volpert, O. V., Crawford, S. E., Febbraio, M., Silverstein, R. L., and Bouck, N (2000) Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat. Med. 6:41–48.Google Scholar
  50. Kalluri, R (2003) Basement membranes: Structure, assembly and role in tumour angiogenesis. Nat. Rev. Cancer 3:422–433.PubMedCrossRefGoogle Scholar
  51. Kaluzova, M., Kaluz, S., Lerman, M. I., and Stanbridge, E. J (2004) DNA damage is a prerequisite for p53-mediated proteasomal degradation of HIF-1alpha in hypoxic cells and downregulation of the hypoxia marker carbonic anhydrase IX. Mol. Cell. Biol. 24:5757–5766.PubMedCrossRefGoogle Scholar
  52. Kang, S. M., Maeda, K., Onoda, N., Chung, Y. S., Nakata, B., Nishiguchi, Y., and Sowa, M (1997) Combined analysis of p53 and vascular endothelial growth factor expression in colorectal carcinoma for determination of tumor vascularity and liver metastasis. Int. J. Cancer 74:502–507.PubMedCrossRefGoogle Scholar
  53. Kaur, B., Brat, D. J., Devi, N. S., and Van Meir, E. G (2005) Vasculostatin, a proteolytic fragment of brain angiogenesis inhibitor 1, is an antiangiogenic and antitumorigenic factor. Oncogene 24:3632–3642.PubMedCrossRefGoogle Scholar
  54. Kawahara, N., Ono, M., Taguchi, K., Okamoto, M., Shimada, M., Takenaka, K., Hayashi, K., Mosher, D. F., Sugimachi, K., Tsuneyoshi, M., and Kuwano, M (1998) Enhanced expression of thrombospondin-1 and hypovascularity in human cholangiocarcinoma. Hepatology 28:1512–1517.PubMedCrossRefGoogle Scholar
  55. Khalkhali-Ellis, Z (2006) Maspin: The new frontier. Clin. Cancer Res. 12:7279–7283.CrossRefGoogle Scholar
  56. Khwaja, F. W., Svoboda, P., Reed, M., Pohl, J., Pyrzynska, B., and Van Meir, E. G (2006) Proteomic identification of the wt-p53-regulated tumor cell secretome. Oncogene 25:7650–7661.PubMedCrossRefGoogle Scholar
  57. Kinch, M. S. and Carles-Kinch, K (2003) Overexpression and functional alterations of the EphA2 tyrosine kinase in cancer. Clin. Exp. Metastasis 20:59–68.PubMedCrossRefGoogle Scholar
  58. Koumenis, C., Alarcon, R., Hammond, E., Sutphin, P., Hoffman, W., Murphy, M., Derr, J., Taya, Y., Lowe, S. W., Kastan, M., and Giaccia, A (2001) Regulation of p53 by hypoxia: Dissociation of transcriptional repression and apoptosis from p53-dependent transactivation. Mol. Cell. Biol. 21:1297–1310.PubMedCrossRefGoogle Scholar
  59. Kulke, M. H., Bergsland, E. K., Ryan, D. P., Enzinger, P. C., Lynch, T. J., Zhu, A. X., Meyerhardt, J. A., Heymach, J. V., Fogler, W. E., Sidor, C., Michelini, A., Kinsella, K., Venook, A. P., and Fuchs, C. S (2006) Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors. J. Clin. Oncol. 24:3555–3561.PubMedCrossRefGoogle Scholar
  60. Kwak, C., Jin, R. J., Lee, C., Park, M. S., and Lee, S. E (2002) Thrombospondin-1, vascular endothelial growth factor expression and their relationship with p53 status in prostate cancer and benign prostatic hyperplasia. BJU Int. 89:303–309.PubMedCrossRefGoogle Scholar
  61. Li F. P., Fraumeni J. F., Jr., Mulvihill J. J., Blattner W. A., Dreyfus M. G., Tucker M. A., and Miller R. W (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48:5358–5362.PubMedGoogle Scholar
  62. Linderholm, B., Lindh, B., Tavelin, B., Grankvist, K., and Henriksson, R (2000) p53 and vascular-endothelial-growth-factor (VEGF) expression predicts outcome in 833 patients with primary breast carcinoma. Int. J. Cancer 89:51–62.PubMedCrossRefGoogle Scholar
  63. Linderholm, B. K., Lindahl, T., Holmberg, L., Klaar, S., Lennerstrand, J., Henriksson, R., and Bergh, J (2001) The expression of vascular endothelial growth factor correlates with mutant p53 and poor prognosis in human breast cancer. Cancer Res. 61:2256–2260.PubMedGoogle Scholar
  64. Masferrer, J. L., Leahy, K. M., Koki, A. T., Zweifel, B. S., Settle, S. L., Woerner, B. M., Edwards, D. A., Flickinger, A. G., Moore, R. J., and Seibert, K (2000) Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res. 60:1306–1311.PubMedGoogle Scholar
  65. Mietz, J. A., Unger, T., Huibregtse, J. M., and Howley, P. M (1992) The transcriptional transactivation function of wild-type p53 is inhibited by SV40 large T-antigen and by HPV-16 E6 oncoprotein. EMBO J. 11:5013–5020.PubMedGoogle Scholar
  66. Miled, C., Pontoglio, M., Garbay, S., Yaniv, M., and Weitzman, J. B (2005) A genomic map of p53 binding sites identifies novel p53 targets involved in an apoptotic network. Cancer Res. 65:5096–5104.PubMedCrossRefGoogle Scholar
  67. Minami, T., Horiuchi, K., Miura, M., Abid, M. R., Takabe, W., Noguchi, N., Kohro, T., Ge, X., Aburatani, H., Hamakubo, T., Kodama, T., and Aird, W. C (2004) Vascular endothelial growth factor- and thrombin-induced termination factor, Down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis. J. Biol. Chem. 279:50537–50554.PubMedCrossRefGoogle Scholar
  68. Miyazaki, T., Kato, H., Fukuchi, M., Nakajima, M., and Kuwano, H (2003) EphA2 overexpression correlates with poor prognosis in esophageal squamous cell carcinoma. Int. J. Cancer 103:657–663.PubMedCrossRefGoogle Scholar
  69. Mukhopadhyay, D., Tsiokas, L., and Sukhatme, V. P. (1995a) Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res. 55:6161–6165.PubMedGoogle Scholar
  70. Mukhopadhyay, D., Tsiokas, L., Zhou, X. M., Foster, D., Brugge, J. S., and Sukhatme, V. P. (1995b) Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation. Nature 375:577–581.PubMedCrossRefGoogle Scholar
  71. Nielsen, M., Thomsen, J. L., Primdahl, S., Dyreborg, U., and Andersen, J. A (1987) Breast cancer and atypia among young and middle-aged women: A study of 110 medicolegal autopsies. Br. J. Cancer 56:814–819.PubMedCrossRefGoogle Scholar
  72. Nishimori, H., Shiratsuchi, T., Urano, T., Kimura, Y., Kiyono, K., Tatsumi, K., Yoshida, S., Ono, M., Kuwano, M., Nakamura, Y., and Tokino, T (1997) A novel brain-specific p53-target gene, BAI1, containing thrombospondin type 1 repeats inhibits experimental angiogenesis. Oncogene 15:2145–2150.PubMedCrossRefGoogle Scholar
  73. Nissi, R., Autio-Harmainen, H., Marttila, P., Sormunen, R., and Kivirikko, K. I (2001) Prolyl 4-hydroxylase isoenzymes I and II have different expression patterns in several human tissues. J. Histochem. Cytochem. 49:1143–1153.PubMedCrossRefGoogle Scholar
  74. Noblitt, L. W., Bangari, D. S., Shukla, S., Knapp, D. W., Mohammed, S., Kinch, M. S., and Mittal, S. K (2004) Decreased tumorigenic potential of EphA2-overexpressing breast cancer cells following treatment with adenoviral vectors that express EphrinA1. Cancer Gene Ther. 11:757–766.PubMedCrossRefGoogle Scholar
  75. Nor, J. E., Mitra, R. S., Sutorik, M. M., Mooney, D. J., Castle, V. P., and Polverini, P. J (2000) Thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway. J. Vasc. Res. 37:209–218.PubMedCrossRefGoogle Scholar
  76. O’Reilly, M. S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M., Lane, W. S., Cao, Y., Sage, E. H., and Folkman, J (1994) Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79:315–328.PubMedCrossRefGoogle Scholar
  77. Obermair, A., Kucera, E., Mayerhofer, K., Speiser, P., Seifert, M., Czerwenka, K., Kaider, A., Leodolter, S., Kainz, C., and Zeillinger, R (1997) Vascular endothelial growth factor (VEGF) in human breast cancer: Correlation with disease-free survival. Int. J. Cancer 74:455–458.PubMedCrossRefGoogle Scholar
  78. Ogawa, K., Pasqualini, R., Lindberg, R. A., Kain, R., Freeman, A. L., and Pasquale, E. B (2000) The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene 19:6043–6052.PubMedCrossRefGoogle Scholar
  79. Oshima, M., Dinchuk, J. E., Kargman, S. L., Oshima, H., Hancock, B., Kwong, E., Trzaskos, J. M., Evans, J. F., and Taketo, M. M (1996) Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87:803–809.PubMedCrossRefGoogle Scholar
  80. Pal, S., Datta, K., and Mukhopadhyay, D (2001) Central role of p53 on regulation of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) expression in mammary carcinoma. Cancer Res. 61:6952–6957.PubMedGoogle Scholar
  81. Pan, Y., Oprysko, P. R., Asham, A. M., Koch, C. J., and Simon, M. C (2004) p53 cannot be induced by hypoxia alone but responds to the hypoxic microenvironment. Oncogene 23:4975–4983.PubMedCrossRefGoogle Scholar
  82. Pasquale, E. B (2005) Eph receptor signalling casts a wide net on cell behaviour. Nat. Rev. Mol. Cell Biol. 6:462–475.PubMedCrossRefGoogle Scholar
  83. Pelengaris, S., Littlewood, T., Khan, M., Elia, G., and Evan, G (1999) Reversible activation of c-Myc in skin: Induction of a complex neoplastic phenotype by a single oncogenic lesion. Mol. Cell 3:565–577.PubMedCrossRefGoogle Scholar
  84. Prehn, R. T (1991) The inhibition of tumor growth by tumor mass. Cancer Res. 51:2–4.PubMedGoogle Scholar
  85. Ragimov, N., Krauskopf, A., Navot, N., Rotter, V., Oren, M., and Aloni, Y (1993) Wild-type but not mutant p53 can repress transcription initiation in vitro by interfering with the binding of basal transcription factors to the TATA motif. Oncogene 8:1183–1193.PubMedGoogle Scholar
  86. Rak, J., Mitsuhashi, Y., Sheehan, C., Tamir, A., Viloria-Petit, A., Filmus, J., Mansour, S. J., Ahn, N. G., and Kerbel, R. S (2000) Oncogenes and tumor angiogenesis: Differential modes of vascular endothelial growth factor up-regulation in ras-transformed epithelial cells and fibroblasts. Cancer Res. 60:490–498.PubMedGoogle Scholar
  87. Ravi, R., Mookerjee, B., Bhujwalla, Z. M., Sutter, C. H., Artemov, D., Zeng, Q., Dillehay, L. E., Madan, A., Semenza, G. L., and Bedi, A (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev. 14:34–44.PubMedGoogle Scholar
  88. Rempe, D. A., Lelli, K. M., Vangeison, G., Johnson, R. S., and Federoff, H. J (2007) In cultured astrocytes, p53 and MDM2 do not alter hypoxia-inducible factor-1alpha function regardless of presence of DNA damage. J. Biol. Chem. 282:16187–16201.PubMedCrossRefGoogle Scholar
  89. Riccioni, T., Cirielli, C., Wang, X., Passaniti, A., and Capogrossi, M. C (1998) Adenovirus-mediated wild-type p53 overexpression inhibits endothelial cell differentiation in vitro and angiogenesis in vivo. Gene Ther. 5:747–754.PubMedCrossRefGoogle Scholar
  90. Ryan, H. E., Lo, J., and Johnson, R. S (1998) HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J. 17:3005–3015.PubMedCrossRefGoogle Scholar
  91. Saez, E., Rutberg, S. E., Mueller, E., Oppenheim, H., Smoluk, J., Yuspa, S. H., and Spiegelman, B. M (1995) c-fos is required for malignant progression of skin tumors. Cell 82:721–732.PubMedCrossRefGoogle Scholar
  92. Sckell, A., Safabakhsh, N., Dellian, M., and Jain, R. K (1998) Primary tumor size-dependent inhibition of angiogenesis at a secondary site: An intravital microscopic study in mice. Cancer Res. 58:5866–5869.PubMedGoogle Scholar
  93. Seto, E., Usheva, A., Zambetti, G. P., Momand, J., Horikoshi, N., Weinmann, R., Levine, A. J., and Shenk, T (1992) Wild-type p53 binds to the TATA-binding protein and represses transcription. Proc. Natl. Acad. Sci. USA 89:12028–12032.PubMedCrossRefGoogle Scholar
  94. Sherif, Z. A., Nakai, S., Pirollo, K. F., Rait, A., and Chang, E. H (2001) Downmodulation of bFGF-binding protein expression following restoration of p53 function. Cancer Gene Ther. 8:771–782.PubMedCrossRefGoogle Scholar
  95. Slack, J. L. and Bornstein, P (1994) Transformation by v-src causes transient induction followed by repression of mouse thrombospondin-1. Cell Growth Differ. 5:1373–1380.PubMedGoogle Scholar
  96. Somasundaram, K. and El-Deiry, W. S (1997) Inhibition of p53-mediated transactivation and cell cycle arrest by E1A through its p300/CBP-interacting region. Oncogene 14:1047–1057.PubMedCrossRefGoogle Scholar
  97. Song, S. Y., Lee, S. K., Kim, D. H., Son, H. J., Kim, H. J., Lim, Y. J., Lee, W. Y., Chun, H. K., and Rhee, J. C (2002) Expression of maspin in colon cancers: Its relationship with p53 expression and microvessel density. Dig. Dis. Sci. 47:1831–1835.PubMedCrossRefGoogle Scholar
  98. Soussi T., Ishioka C., Claustres M., and Beroud C (2006) Locus-specific mutation databases: Pitfalls and good practice based on the p53 experience. Nat Rev Cancer 6:83–90.PubMedCrossRefGoogle Scholar
  99. Steegenga, W. T., van Laar, T., Riteco, N., Mandarino, A., Shvarts, A., van der Eb, A. J., and Jochemsen, A. G (1996) Adenovirus E1A proteins inhibit activation of transcription by p53. Mol. Cell. Biol. 16:2101–2109.PubMedGoogle Scholar
  100. Stellmach, V., Volpert, O. V., Crawford, S. E., Lawler, J., Hynes, R. O., and Bouck, N (1996) Tumour suppressor genes and angiogenesis: The role of TP53 in fibroblasts. Eur. J. Cancer 32A:2394–2400.PubMedCrossRefGoogle Scholar
  101. Subbaramaiah, K., Altorki, N., Chung, W. J., Mestre, J. R., Sampat, A., and Dannenberg, A. J (1999) Inhibition of cyclooxygenase-2 gene expression by p53. J. Biol. Chem. 274:10911–10915.PubMedCrossRefGoogle Scholar
  102. Sund, M., Hamano, Y., Sugimoto, H., Sudhakar, A., Soubasakos, M., Yerramalla, U., Benjamin, L. E., Lawler, J., Kieran, M., Shah, A., and Kalluri, R (2005) Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors. Proc. Natl. Acad. Sci. USA 102:2934–2939.PubMedCrossRefGoogle Scholar
  103. Sussan, T. E., Yang, A., Li, F., Ostrowski, M. C., and Reeves, R. H (2008) Trisomy represses Apc(Min)-mediated tumours in mouse models of Down’s syndrome. Nature 451:73–75.PubMedCrossRefGoogle Scholar
  104. Takahashi, Y., Bucana, C. D., Cleary, K. R., and Ellis, L. M (1998) p53, vessel count, and vascular endothelial growth factor expression in human colon cancer. Int. J. Cancer 79:34–38.PubMedCrossRefGoogle Scholar
  105. Teodoro, J. G., Parker, A. E., Zhu, X., and Green, M. R (2006) p53-mediated inhibition of angiogenesis through up-regulation of a collagen prolyl hydroxylase. Science 313:968–971.PubMedCrossRefGoogle Scholar
  106. Tikhonenko, A. T., Black, D. J., and Linial, M. L (1996) Viral Myc oncoproteins in infected fibroblasts down-modulate thrombospondin-1, a possible tumor suppressor gene. J. Biol. Chem. 271:30741–30747.PubMedCrossRefGoogle Scholar
  107. Tokino, T., Thiagalingam, S., el-Deiry, W. S., Waldman, T., Kinzler, K. W., and Vogelstein, B (1994) p53 tagged sites from human genomic DNA. Hum. Mol. Genet. 3:1537–1542.PubMedCrossRefGoogle Scholar
  108. Tokunaga, T., Nakamura, M., Oshika, Y., Tsuchida, T., Kazuno, M., Fukushima, Y., Kawai, K., Abe, Y., Kijima, H., Yamazaki, H., Tamaoki, N., and Ueyama, Y (1998) Alterations in tumour suppressor gene p53 correlate with inhibition of thrombospondin-1 gene expression in colon cancer cells. Virchows Arch. 433:415–418.PubMedCrossRefGoogle Scholar
  109. Tolsma, S. S., Volpert, O. V., Good, D. J., Frazier, W. A., Polverini, P. J., and Bouck, N (1993) Peptides derived from two separate domains of the matrix protein thrombospondin-1 have anti-angiogenic activity. J. Cell Biol. 122:497–511.CrossRefGoogle Scholar
  110. Tsujii, M., Kawano, S., Tsuji, S., Sawaoka, H., Hori, M., and DuBois, R. N (1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93:705–716.PubMedCrossRefGoogle Scholar
  111. Ueba, T., Nosaka, T., Takahashi, J. A., Shibata, F., Florkiewicz, R. Z., Vogelstein, B., Oda, Y., Kikuchi, H., and Hatanaka, M (1994) Transcriptional regulation of basic fibroblast growth factor gene by p53 in human glioblastoma and hepatocellular carcinoma cells. Proc. Natl. Acad. Sci. USA 91:9009–9013.PubMedCrossRefGoogle Scholar
  112. Van Meir, E. G., Polverini, P. J., Chazin, V. R., Su Huang, H. J., de Tribolet, N., and Cavenee, W. K (1994) Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells. Nat. Genet. 8:171–176.PubMedCrossRefGoogle Scholar
  113. Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., Fotouhi, N., and Liu, E. A (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303:844–848.PubMedCrossRefGoogle Scholar
  114. Volpert, O. V., Dameron, K. M., and Bouck, N (1997) Sequential development of an angiogenic phenotype by human fibroblasts progressing to tumorigenicity. Oncogene 14:1495–1502.PubMedCrossRefGoogle Scholar
  115. Walker-Daniels, J., Coffman, K., Azimi, M., Rhim, J. S., Bostwick, D. G., Snyder, P., Kerns, B. J., Waters, D. J., and Kinch, M. S (1999) Overexpression of the EphA2 tyrosine kinase in prostate cancer. Prostate 41:275–280.PubMedCrossRefGoogle Scholar
  116. Watnick, R. S., Cheng, Y. N., Rangarajan, A., Ince, T. A., and Weinberg, R. A (2003) Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. Cancer Cell 3:219–231.PubMedCrossRefGoogle Scholar
  117. Wei, C. L., Wu, Q., Vega, V. B., Chiu, K. P., Ng, P., Zhang, T., Shahab, A., Yong, H. C., Fu, Y., Weng, Z., Liu, J., Zhao, X. D., Chew, J. L., Lee, Y. L., Kuznetsov, V. A., Sung, W. K., Miller, L. D., Lim, B., Liu, E. T., Yu, Q., Ng, H. H., and Ruan, Y (2006) A global map of p53 transcription-factor binding sites in the human genome. Cell 124:207–219.PubMedCrossRefGoogle Scholar
  118. Weinstat-Saslow, D. L., Zabrenetzky, V. S., VanHoutte, K., Frazier, W. A., Roberts, D. D., and Steeg, P. S (1994) Transfection of thrombospondin 1 complementary DNA into a human breast carcinoma cell line reduces primary tumor growth, metastatic potential, and angiogenesis. Cancer Res. 54:6504–6511.PubMedGoogle Scholar
  119. Williams, C. S., Tsujii, M., Reese, J., Dey, S. K., and DuBois, R. N (2000) Host cyclooxygenase-2 modulates carcinoma growth. J. Clin. Invest. 105:1589–1594.PubMedCrossRefGoogle Scholar
  120. Yang, J. C., Haworth, L., Sherry, R. M., Hwu, P., Schwartzentruber, D. J., Topalian, S. L., Steinberg, S. M., Chen, H. X., and Rosenberg, S. A (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N. Engl. J. Med. 349:427–434.PubMedCrossRefGoogle Scholar
  121. Yew, P. R. and Berk, A. J (1992) Inhibition of p53 transactivation required for transformation by adenovirus early 1B protein. Nature 357:82–85.PubMedCrossRefGoogle Scholar
  122. Yu, E. Y., Yu, E., Meyer, G. E., and Brawer, M. K (1997) The relation of p53 protein nuclear accumulation and angiogenesis in human prostatic carcinoma. Prostate Cancer Prostatic Dis. 1:39–44.PubMedCrossRefGoogle Scholar
  123. Yu, J. L., Rak, J. W., Coomber, B. L., Hicklin, D. J., and Kerbel, R. S (2002) Effect of p53 status on tumor response to antiangiogenic therapy. Science 295:1526–1528.PubMedCrossRefGoogle Scholar
  124. Zelinski, D. P., Zantek, N. D., Stewart, J. C., Irizarry, A. R., and Kinch, M. S (2001) EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res. 61:2301–2306.PubMedGoogle Scholar
  125. Zhang, L., Yu, D., Hu, M., Xiong, S., Lang, A., Ellis, L. M., and Pollock, R. E (2000a) Wild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression. Cancer Res. 60:3655–3661.PubMedGoogle Scholar
  126. Zhang, M., Volpert, O., Shi, Y. H., and Bouck, N (2000b) Maspin is an angiogenesis inhibitor. Nat Med 6:196–199.PubMedCrossRefGoogle Scholar
  127. Zorick, T. S., Mustacchi, Z., Bando, S. Y., Zatz, M., Moreira-Filho, C. A., Olsen, B., and Passos-Bueno, M. R (2001) High serum endostatin levels in Down syndrome: Implications for improved treatment and prevention of solid tumours. Eur. J. Hum. Genet. 9:811–814.PubMedCrossRefGoogle Scholar
  128. Zou, Z., Anisowicz, A., Hendrix, M. J., Thor, A., Neveu, M., Sheng, S., Rafidi, K., Seftor, E., and Sager, R (1994) Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells. Science 263:526–529.PubMedCrossRefGoogle Scholar
  129. Zou, Z., Gao, C., Nagaich, A. K., Connell, T., Saito, S., Moul, J. W., Seth, P., Appella, E., and Srivastava, S (2000) p53 regulates the expression of the tumor suppressor gene maspin. J. Biol. Chem. 275:6051–6054.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Jose G. Teodoro
    • 1
  • Sara K. Evans
    • 2
  • Michael R. Green
    • 2
  1. 1.McGill Cancer Centre and Department of BiochemistryMcGill UniversityMontrealCanada
  2. 2.University of MassachusettsProgram in Molecular MedicineWorcesterUSA

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