The Role of Angiogenesis in Breast Cancer Progression

  • Sandra W. McLeskey
  • Robert B. Dickson
Part of the Cardiovascular Molecular Morphogenesis book series (CARDMM)


Increasingly abundant evidence indicates that the ability of a tumor to command angiogenesis is an important determinant of its phenotype. The data that support this viewpoint were first gained in patients with carcinoma of the breast (Weidner et al, 1991), and confirmatory data have subsequently been obtained in studies conducted in breast and many other solid tumors (see Chapter 4). Additionally, the discovery of various proangiogenic and antiangiogenic molecules has led to the viewpoint that in the normally quiescent vasculature of an adult, the effects of angiogenesis inhibitors predominate for endothelial cells. Therefore, it follows that in angiogenic tumors, the balance between inhibition and stimulation of angiogenesis is disrupted so that endothelial stimulation is favored. Much effort has been directed toward identifying particular angiogenesis stimulators or inhibitors important in neoangiogenesis of breast cancer. Although a multiplicity of candidate stimulators and inhibitors have been investigated, and although vascular endothelial growth factor (VEGF) has been correlated with poor prognosis in breast cancer (Toi et al, 1995a; Gasparini et al, 1997; Relf et al, 1997; Eppenberger et al, 1998), it is becoming clear that we will probably not find any single angiogenic molecule that is responsible for the neovascularization of this disease. It appears more likely that tumors can influence expression of a large number of angiogenesis stimulators and inhibitors, and that this influence extends to molecules expressed by stromal cells as well as those expressed by the tumor cells themselves (reviewed in Pluda, 1997).


Breast Cancer Vascular Endothelial Growth Factor Angiogenic Factor Vascular Endothelial Growth Factor Expression Angiogenesis Inhibitor 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Agani, F., Kirsch, D. G., Friedman, S. L., Kastan, M. B., and Semenza, G. L. 1997. p53 does not repress hypoxia-induced transcription of the vascular endothelial growth factor gene. Cancer Res. 57:4474–4477.PubMedGoogle Scholar
  2. Akiri, G., Nahari, D., Finkelstein, Y., Le, S.-Y., Elroy-Stein, O., and Levi, B.-Z. 1998. Regulation of vascular endothelial growth factor (VEGF) expression is mediated by internal initiation of translation and alternative initiation of transcription. Oncogene 17:227–236.PubMedCrossRefGoogle Scholar
  3. Anthony, B., Carter, P., and de Benedetti, A. 1996. Overexpression of the protooncogene/translation factor 4E in breast-carcinoma cell lines. Int. J. Cancer 65:858–863.PubMedCrossRefGoogle Scholar
  4. Arany, Z., Huang, L. E., Eckner, R., Bhattacharya, S., Jiang, C., Goldberg, M. A., Bunn, H. F., and Livingston, D. M. 1996. An essential role for p300/CBP in the cellular response to hypoxia. Proc. Natl. Acad. Sci. USA 93:12969–12973.PubMedCrossRefGoogle Scholar
  5. Arbiser, J. L., Moses, M. A., Fernandez, C. A., Ghiso, N., Cao, Y., Klauber, N., Frank, D., Brownlee, M., Flynn, E., Parangi, S., Byers, H. R., and Folkman, J. 1997. Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways. Proc. Natl. Acad. Sci. USA 94:861–866.PubMedCrossRefGoogle Scholar
  6. Arnoletti, J. P., Albo, D., Granick, M. S., Solomon, M. P., Gastiglioni, A., Rothman, V. L., and Tuszynski, G. P. 1995. Thrombospondin and transforming growth factor-beta 1 increase expression of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in human MDA-MB-231 cells. Cancer 76:998–1005.PubMedCrossRefGoogle Scholar
  7. Bagavandoss, P., Kaytes, P., Vogeli, G., Wells, P. A., and Wilks, J. W. 1993. Recombinant truncated thrombospondin-1 monomer modulates endothelial cell plasminogen activator inhibitor 1 accumulation and proliferation in vitro. Biochem. Biophys. Res. Commun. 192:325–332.PubMedCrossRefGoogle Scholar
  8. Bernstein, J., Sella, O., Le, S.-Y., and Elroy-Stein, O. 1997. PDGF2/c-sis mRNA leader contains a differentiation-linked internal ribosomal entry site (D-IRES). J. Biol. Chem. 272:9356–9362.PubMedCrossRefGoogle Scholar
  9. Bernstein, J., Shefler, I., and Elroy-Stein, O. 1995. The translational repression mediated by the platelet-derived growth factor 21c-sis mRNA leader is relieved during megakaryocytic differentiation. J. Biol. Chem. 270:10559–10565.PubMedCrossRefGoogle Scholar
  10. Bertin, N., Clezardin, P., Kubiak, R., and Frappart, L. 1997. Thrombospondin-1 and -2 messenger RNA expression in normal, benign, and neoplastic human breast tissues: correlation with prognostic factors, tumor angiogenesis, and fibroblastic tlesmoplasia. Cancer Res. 57:396–399.PubMedGoogle Scholar
  11. Bikfalvi, A. 1995. Significance of angiogenesis in tumour progression and metastasis. Eur. J. Cancer 31A:1101–1104.PubMedCrossRefGoogle Scholar
  12. Birch, J. M., Blair, V., Kelsey, A. M., Evans, D. G., Harris, M., Tricker, K. J., and Varley, J. M. 1998. Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome. Oncogene 17:1061–1068.PubMedCrossRefGoogle Scholar
  13. Biscardi, J. S., Tice, D. A., and Parsons, S. J. 1999. c-Src, receptor tyrosine kinases, and human cancer. Adv. Cancer Res. 76:61–119.PubMedCrossRefGoogle Scholar
  14. Blagosklonny, M. V., An, W. G., Romanova, L. Y., Trepel, J., Fojo, T., and Neckers, L. 1998. p53 inhibits hypoxia-inducible factor-stimulated transcription. J. Biol. Chem. 273:11995–11998.PubMedCrossRefGoogle Scholar
  15. Blam, S. B., Mitchell, R., Tischer, E., Rubin, J. S., Silva, M., Silver, S., Fiddes, J. C., Abraham, J. A., and Aaronson, S. A. 1988. Addition of growth hormone secretion signal to basic fibroblast growth factor results in cell transformation and secretion of aberrant forms of the protein. Oncogene 3:129–136.PubMedGoogle Scholar
  16. Boehm, T., Folkman, J., Browder, T., and O’Reilly, M. S. 1997. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390:404–407.PubMedCrossRefGoogle Scholar
  17. Boehm, T., O’Reilly, M. S., Keough, K., Shiloach, J., Shapiro, R., and Folkman, J. 1998. Zinc-binding of endostatin is essential for its antiangiogenic activity. Biochem. Biophys. Res. Commun. 252:190–194.PubMedCrossRefGoogle Scholar
  18. Bornstein, P. 1995. Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1. J. Cell Biol. 130:503–506.PubMedCrossRefGoogle Scholar
  19. Bouvet, M., Ellis, L. M., Nishizaki, M., Fujiwara, T., Liu, W., Bucana, C. D., Fang, B., Lee, J. J., and Roth, J. A. 1998. Adenovirus-mediated wild-type p53 gene transfer down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human colon cancer. Cancer Res. 58:2288–2292.PubMedGoogle Scholar
  20. Brem, S. S., Gullino, P. M., and Medina, D. 1977. Angiogenesis: a marker for neoplastic transformation of papillary hyperplasia. Science 195:880–881.PubMedCrossRefGoogle Scholar
  21. Brown, L. F., Berse, B., Jackman, R. W., Tognazzi, K., Guidi, A. J., Dvorak, H. F., Senger, D. R., Connolly, J. L., and Schnitt, S. J. 1995. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum. Pathol. 26:86–91.PubMedCrossRefGoogle Scholar
  22. Brown, N. S., and Bicknell, R. 1998. Thymidine phosphorylase, 2-deoxy-ribose and angiogenesis. Biochem. J. 334:1–8.PubMedGoogle Scholar
  23. Bullocks, J., Zhang, L., Ding, I. Y. F., McLeskey, S. W, Tobias, C. A., Miller, D. L., and Kern, F. G. 1997. Overexpression of vascular endothelial cell growth factor (VEGF) in MCF-7 breast carcinoma cells facilitates growth in tamoxifen-treated nude mice and tumor cell dissemination. Proc. Am. Assoc. Cancer Res. 38:3521.Google Scholar
  24. Canfield, A. E., and Schor, A. M. 1995. Evidence that tenascin and thrombospondin-1 modulate sprouting of endothelial cells. J. Cell Sci. 108:797–809.PubMedGoogle Scholar
  25. Cao, Y., O’Reilly, M. S., Marshall, B., Flynn, E., Ji, R.-W, and Folkman, J. 1998. Expression of angiostatin cDNA in a murine fibrosarcoma suppresses primary tumor growth and produces long-term dormancy of metastases. J. Clin. Invest. 101:1055–1063.PubMedCrossRefGoogle Scholar
  26. Caré, A., Silvani, A., Meccia, E., Mattia, G., Peschle, C., and Colombo, M. P. 1998. Transduction of the SkBr3 breast carcinoma cell line with the HOXB7 gene induces bFGF expression, increases cell proliferation and reduces growth factor dependence. Oncogene 16:3285–3289.PubMedCrossRefGoogle Scholar
  27. Caré, A., Silvani, A., Meccia, E., Mattia, G., Stoppacciaro, A., Parmiani, G., Peschle, C., and Colombo, M. P. 1996. HOXB7 constitutively activates basic fibroblast growth factor in melanomas. Mol. Cell. Biol. 16:4842–4851.PubMedGoogle Scholar
  28. Carmeliet, P., Dor, Y., Herbert, J. M., et al. 1998. Role of HIF-lalpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490.PubMedCrossRefGoogle Scholar
  29. Chariot, A., Senterre-Lesenfants, S., Sobel, M. E., and Castronovo, V. 1998. Molecular cloning of a mutated HOXB7 cDNA encoding a truncated transactivating homeodomain-containing protein. J. Cell Biochem. 71:46–54.PubMedCrossRefGoogle Scholar
  30. Chen, Q. R., Kumar, D., Stass, S. A., and Mixson, A. J. 1999. Liposomes complexed to plasmids encoding angiostatin and endostatin inhibit breast cancer in nude mice. Cancer Res. 59:3308–3312.PubMedGoogle Scholar
  31. Chen, T. K., Smith, L. M., Gebhardt, D. K., Birrer, M. J., and Brown, P. H. 1996a. Activation and inhibition of the AP-1 complex in human breast cancer cells. Mol. Carcinog. 15:215–226.PubMedCrossRefGoogle Scholar
  32. Chen, Z.-S., Pohl, J., Lawley, T. J., and Swerlick, R. A. 1996b. Human microvascular endothelial cells adhere to thrombospondin-1 via an RGD/CSVTCG domain independent mechanism. J. Invest. Dermatol. 106:215–220.PubMedCrossRefGoogle Scholar
  33. Claesson-Welsh, L., Welsh, M., Ito, N., Anand-Apte, B., Soker, S., Zetter, B., O’Reilly, M., and Folkman, J. 1998. Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin-binding motif RGD. Proc. Natl. Acad. Sci. USA 95:5579–5583.PubMedCrossRefGoogle Scholar
  34. Clark, G. J., and Der, C. J. 1995. Aberrant function of the Ras signal transduction pathway in human breast cancer. Breast Cancer Res. Treat. 35:133–144.PubMedCrossRefGoogle Scholar
  35. Cornelius, L. A., Nehring, L. C., Harding, E., Bolanowski, M., Welgus, H. G., Kobayashi, D. K., Pierce, R. A., and Shapiro, S. D. 1998. Matrix metalloproteinases generate angiostatin: effects on neovascularization. J. Immunol. 161:6845–6852.PubMedGoogle Scholar
  36. Czubayko, F., Liaudet-Coopman, E. D. E., Aigner, A., Tuveson, A. T., Berchem, G. J., and Wellstein, A. 1997. A secreted FGF-binding protein can serve as the angiogenic switch in human cancer. Nat. Med. 10:1137–1140.CrossRefGoogle Scholar
  37. D’Amore, P. A., and Shima, D. T. 1996. Tumor angiogenesis: a physiological process or genetically determined? Cancer Metastasis Rev. 15:205–212.PubMedCrossRefGoogle Scholar
  38. Dameron, K. M., Volpert, O. V., Tainsky, M. A., and Bouck, N. 1994a. The p53 tumor suppressor gene inhibits angiogenesis by stimulating the production of thrombospondin. Cold Spring Harb. Symp. Quant. Biol. 59:483–489.PubMedCrossRefGoogle Scholar
  39. Dameron, K. M., Volpert, O. V., Tainsky, M. A., and Bouck, N. 1994b. Control of angio-genesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265:1582–1584.PubMedCrossRefGoogle Scholar
  40. Damert, A., Ikeda, E., and Risau, W. 1997. Activator-protein-1 binding potentiates the hypoxia-inducible factor-1-mediated hypoxia-induced transcriptional activation of vascular-endothelial growth factor expression in C6 glioma cells. Biochem. J. 327:419–423.PubMedGoogle Scholar
  41. de Jong, J. S., van Diest, P. J., van der Valk, P., and Baak, J. P. A. 1998. Expression of growth factors, growth inhibiting factors, and their receptors in invasive breast cancer. I: An inventory in search of autocrine and paracrine loops. J. Pathol. 184:44–52.PubMedCrossRefGoogle Scholar
  42. Delli-Bovi, P., Curatola, A. M., Kern, F. G., Greco, A., Ittmann, M., and Basilico, C. 1987. An oncogene isolated by transfection of Kaposi’s sarcoma DNA encodes a growth factor that is member of the FGF family. Cell 50:729–737.PubMedCrossRefGoogle Scholar
  43. Dhanabal, M., Ramchandran, R., Volk, R., Stillman, I. E., Lombardo, M., Iruela-Arispe, M. L., Simons, M., and Sukhatme, V. P. 1999. Endostatin: yeast production, mutants, and antitumor effect in renal cell carcinoma. Cancer Res. 59:189–197.PubMedGoogle Scholar
  44. Dickson, C., Smith, R., Brookes, S., and Peters, G. 1984. Tumorigenesis by mouse mammary tumor virus: proviral activation of a cellular gene in the common integration region int-2. Cell 37:529–536.PubMedCrossRefGoogle Scholar
  45. Dong, Z., Kumar, R., Yang, X., and Fidler, I. J. 1997. Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell 88:801–810.PubMedCrossRefGoogle Scholar
  46. Duan, D. R., Pause, A., Burgess, W. H., Aso, T., Chen, D. Y. T., Garrett, K. P., Conaway, R. C., Conaway, J. W., Linehan, W. M., and Klausner, R. D. 1995. Inhibition of transcription elongation by the VHL tumor suppressor protein. Science 269:1402–1406.PubMedCrossRefGoogle Scholar
  47. Dumont, J. A., Bitonti, A. J., Wallace, C. D., Baumann, R. J., Cashman, E. A., GrossDoersen, D. E., and Cross-Doersen, D. E. 1996. Progression of MCF-7 breast cancer cells to antiestrogen-resistant phenotype is accompanied by elevated levels of AP-1 DNA binding activity. Cell Growth Differ. 7:351–359.PubMedGoogle Scholar
  48. Ellis, L. M., Staley, C. A., Liu, W., Fleming, R. Y. D., Parikh, N. U., Bucana, C. D., and Gallick, G. E. 1998. Down-regulation of vascular endothelial growth factor in a human colon carcinoma cell line transfected with an antisense expression vector specific for csrc. J. Biol. Chem. 273:1052–1057.CrossRefGoogle Scholar
  49. Ema, M., Taya, S., Yokotani, N., Sogawa, K., Matsuda, Y., and Fujii-Kuriyama, Y. 1997. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1 alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc. Natl. Acad. Sci. USA 94:4273–4278.PubMedCrossRefGoogle Scholar
  50. Engels, K., Fox, S. B., Whitehouse, R. M., Gatter, K. C., and Harris, A. L. 1997a. Up-regulation of thymidine phosphorylase expression is associated with a discrete pattern of angiogenesis in ductal carcinomas in situ of the breast. J. Pathol. 182:414–420.PubMedCrossRefGoogle Scholar
  51. Engels, K., Fox, S. B., Whitehouse, R. M., Gatter, K. C., and Harris, A. L. 1997b. Distinct angiogenic patterns are associated with high-grade in situ ductal carcinomas of the breast. J. Pathol. 181:207–212.PubMedCrossRefGoogle Scholar
  52. Eppenberger, U., Kueng, W., Schlaeppi, J. M., Roesel, J. L., Benz, C., Mueller, H., Matter, A., Zuber, M., Luescher, K., Litschgi, M., Schmitt, M., Foekens, J. A., and EppenbergerCastori, S. 1998. Markers of tumor angiogenesis and proteolysis independently define high-and low-risk subsets of node-negative breast cancer patients. J. Clin. Oncol. 16:3129–3136.PubMedGoogle Scholar
  53. Feldkamp, M. M., Lau, N., Rak, J., Kerbel, R. S., and Guha, A. 1999. Normoxic and hypoxic regulation of vascular endothelial growth factor (VEGF) by astrocytoma cells is mediated by Ras. Int. J. Cancer 81:118–124.PubMedCrossRefGoogle Scholar
  54. Feldser, D., Agani, F., Iyer, N. V., Pak, B., Ferreira, G., and Semenza, G. L. 1999. Reciprocal positive regulation of hypoxia-inducible factor 1 alpha and insulin-like growth factor 2. Cancer Res. 59:3915–3918.PubMedGoogle Scholar
  55. Flamme, I., Krieg, M., and Plate, K. H. 1998. Up-regulation of vascular endothelial growth factor in stromal cells of hemangioblastomas is correlated with up-regulation of the transcription factor HRF/HIF-2a. Am. J. Pathol. 153:25–29.PubMedCrossRefGoogle Scholar
  56. Folkman, J., Watson, K., Ingber, D., and Hanahan, D. 1989. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339:58–61.PubMedCrossRefGoogle Scholar
  57. Forough, R., Zhan, X., MacPhee, M., Friedman, S., Engleka, K. A., Sayers, T., Wiltrout, R. H., and Maciag, T. 1993. Differential transforming abilities of non-secreted and secreted forms of human fibroblast growth factor-1. J. Biol. Chem. 268:2960–2968.PubMedGoogle Scholar
  58. 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
  59. Fox, S. B., Westwood, M., Moghaddam, A., Comley, M., Turley, H., Whitehouse, R. M., Bicknell, R., Gatter, K. C., and Harris, A. L. 1996. The angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase is upregulated in breast cancer epithelium and endothelium. Br. J. Cancer 73:275–280.PubMedCrossRefGoogle Scholar
  60. Freeman, M. R., Schneck, F. X., Gagnon, M. L., Corless, C., Soker, S., Niknejad, K., G. E., and Klagsbrun, M. 1995. Peripheral blood T lymphocytes and lymphocytes infiltrating human cancers express vascular endothelial growth factor: a potential role for T cells in angiogenesis. Cancer Res. 55:4140–4145.PubMedGoogle Scholar
  61. Fregene, T. A., Kellogg, C. M., and Pienta, K. J. 1994. Microvessel quantification as a measure of angiogenic activity in benign breast tissues lesions: a marker for precancerous disease? Int. J. Oncol. 4:1199–1202.PubMedGoogle Scholar
  62. Fukumura, D., Xavier, R., Sugiura, T., Chen, Y., Park, E. C., Lu, N., Selig, M., Nielsen, G., Taksir, T., Jain, R. K., and Seed, B. 1998. Tumor induction of VEGF promoter activity in stromal cells. Cell 94:715–725.PubMedCrossRefGoogle Scholar
  63. 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
  64. Gasparini, G., Toi, M., Miceli, R., Vermeulen, P. B., Dittadi, R., Biganzoli, E., Morabito, A., Fanelli, M., Gatti, C., Suzuki, H., Tominaga, T., Dirix, L. Y., and Gion, M. 1999. Clinical relevance of vascular endothelial growth factor and thymidine phosphorylase in patients with node-positive breast cancer treated with either adjuvant chemotherapy or hormone therapy. Cancer J. Sci. Am. 5:101–111.Google Scholar
  65. Gately, S., Twardowski, P., Stack, M. S., Patrick, M., Boggio, L., Cundiff, D. L., Schnaper, H. W, Madison, L., Volpert, O., Bouck, N., Enghild, J., Kwaan, H. C., and Soff, G. A. 1996. Human prostate carcinoma cells express enzymatic activity that converts human plasminogen to the angiogenesis inhibitor, angiostatin. Cancer Res. 56:4887–4890.PubMedGoogle Scholar
  66. Gately, S., Twardowski, P., Stack, M. S., Cundiff, D. L., Grella, D., Castellino, F. J., Enghild, J., Kwaan, H. C., Lee, F., Kramer, R. A., Volpert, O., Bouck, N., and Soff, G. A. 1997. The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin. Proc. Natl. Acad. Sci. USA 94:10868–10872.PubMedCrossRefGoogle Scholar
  67. Gimbrone, M., Leapman, S. B., Cotran, R. S., and Folkman, J. 1972. Tumor dormancy in vivo by prevention of neovascularization. J. Exp. Med. 136:261–276.PubMedCrossRefGoogle Scholar
  68. Gnarra, J. R., Zhou, S., Merrill, M. J., Wagner, J. R., Krumm, A., Papavassiliou, E., Oldfield, E. H., Klausner, R. D., and Linehan, W. M. 1996. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc. Natl. Acad. Sci. USA 93:10589–10594.PubMedCrossRefGoogle Scholar
  69. 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
  70. Gorski, D. H., Mauceri, H. J., Salloum, R. M., Gately, S., Hellman, S., Beckett, M. A., Sukhatme, V. P., Soff, G. A., Kufe, D. W., and Weichselbaum, R. R. 1998. Potentiation of the antitumor effect of ionizing radiation by brief concomitant exposures to angiostatin. Cancer Res. 58:5686–5689.PubMedGoogle Scholar
  71. Graff, J. R., Boghaert, E. R., de Benedetti, A., Tudor, D. L., Zimmer, C. C., Chan, S. K., and Zimmer, S. G. 1995. Reduction of translation initiation factor 4E decreases the malignancy of ras-transformed cloned rat embryo fibroblasts. Int. J. Cancer 60:255–263.PubMedCrossRefGoogle Scholar
  72. Griffiths, L., Dachs, G. U., Bicknell, R., Harris, A. L., and Stratford, I. J. 1997. The influence of oxygen tension and pH on the expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human breast tumor cells grown in vitro and in vivo. Cancer Res. 57:570–572.PubMedGoogle Scholar
  73. Griscelli, F., Li, H., Bennaceur-Griscelli, A., Soria, J., Opolon, P., Soria, C., Perricaudet, M., Yeh, P., and Lu, H. 1998. Angiostatin gene transfer: inhibition of tumor growth in vivo by blockage of endothelial cell proliferation associated with a mitosis arrest. Proc. Natl. Acad. Sci. USA 95:6367–6372.PubMedCrossRefGoogle Scholar
  74. Grunstein, J., Roberts, W. G., Mathieu-Costello, O., Hanahan, D., and Johnson, R. S. 1999. Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function. Cancer Res. 59:1592–1598.PubMedGoogle Scholar
  75. Guidi, A. J., Fischer, L., Harris, J. R., and Schnitt, S. J. 1994. Microvessel density and distribution in ductal carcinoma in situ of the breast. J. Natl. Cancer Inst. 86:614619.Google Scholar
  76. Guidi, A. J., Schnitt, S. J., Fischer, L., Tognazzi, K., Harris, J. R., Dvorak, H. F., and Brown, L. F. 1997. Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in patients with ductal carcinoma in situ of the breast. Cancer 80:1945–1953.PubMedCrossRefGoogle Scholar
  77. Hajitou, A., Deroanne, C. F., Noël, A., Colette, J., Nusgens, B. V., Foidart, J. M., and Calberg-Bacq, C.-M. 1998. FGF-3 increases tumorigenicity in MCF7 breast cancer cells but FGF-4 effect is more pronounced and associated with VEGF upregulation. Proc. Am. Assoc. Cancer Res. 39:34.Google Scholar
  78. Hlatky, L., Tsionou, C., Hahnfeldt, P., and Coleman, C. N. 1994. Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial growth factor up-regulation and protein expression. Cancer Res. 54:6083–6086.PubMedGoogle Scholar
  79. Hohenester, E., Sasaki, T., Olsen, B. R., and Timpl, R. 1998. Crystal structure of the angiogenesis inhibitor endostatin at 1.5 A resolution. EMBO J. 17:1656–1664.PubMedCrossRefGoogle Scholar
  80. Holmgren, L., Jackson, G., and Arbiser, J. 1998. p53 induces angiogenesis-restricted dormancy in a mouse fibrosarcoma. Oncogene 17:819–824.PubMedCrossRefGoogle Scholar
  81. Iliopoulos, O., Levy, A. P., Jiang, C., Kaelin Jr., W. G., and Goldberg, M. A. 1996. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc. Natl. Acad. Sci. USA 93:10595–10599.PubMedCrossRefGoogle Scholar
  82. Incardona, F., Lewalle, J. M., Morandi, V., Lambert, S., Legrand, Y., Foidart, J. M., and Legrand, C. 1995. Thrombospondin modulates human breast adenocarcinoma cell adhesion in human vascular endothelial cells. Cancer Res. 55:166–173.PubMedGoogle Scholar
  83. Iruela-Arispe, M. L., Bornstein, P., and Sage, H. 1991. Thrombospondin exerts an antiangiogenic effect on cord formation by endothelial cells in vitro. Proc. Natl. Acad. Sci. USA 88:5026–5030.PubMedCrossRefGoogle Scholar
  84. Ji, W R., Castellino, F. J., Chang, Y., Deford, M. E., Gray, H., Villarreal, X., Kondri, M. E., Marti, D. N., Llinas, M., Schaller, J., Kramer, R. A., and Trail, P. A. 1998. Characterization of kringle domains of angiostatin as antagonists of endothelial cell migration, an important process in angiogenesis. FASEB J. 12:1731–1738.PubMedGoogle Scholar
  85. Jiang, B.-H., Agani, F., Passaniti, A., and Semenza, G. L. 1997. V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res. 57:5328–5335.PubMedGoogle Scholar
  86. Jiang, B.-H., Rue, E., Wang, G. L., Roe, R., and Semenza, G. L. 1996. Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J. Biol. Chem. 271:17771–17778.PubMedCrossRefGoogle Scholar
  87. Jones, R. M., Branda, J., Johnston, K. A., Polymenis, M., Gadd, M., Rustgi, A., Callanan, L., and Schmidt, E. V. 1996. An essential E box in the promoter of the gene encoding the mRNA cap-binding protein (eukaryotic initiation factor 4E) is a target for activation by c-myc. Mol. Cell. Biol. 16:4754–4764.PubMedGoogle Scholar
  88. Jouanneau, J., Gavrilovic, J., Caruelle, D., Jaye, M., Moens, G., Caruelle, J. P., and Thiery, J. P. 1991. Secreted or nonsecreted forms of acidic fibroblast growth factor produced by transfected epithelial cells influence cell morphology, motility, and invasive potential. Proc. Natl. Acad. Sci. USA 88:2893–2897.PubMedCrossRefGoogle Scholar
  89. Kaelin, W. G., Iliopoulos, O., Lonergan, M., and Ohh, M. 1998. Functions of the von Hippel-Lindau tumor suppressor protein. J. Intern. Med. 243:535–539.PubMedCrossRefGoogle Scholar
  90. Kandel, J., Bossy-Wetzel, E., Radvanyi, F., Klagsbrun, M., Folkman, J., and Hanahan, D. 1991. Neovascularization is associated with a switch to the export of bFGF in the multistep development of fibrosarcoma. Cell 66:1095–1104.PubMedCrossRefGoogle Scholar
  91. Kevil, C. G., de Benedetti, A., Payne, D. K., Coe, L. L., Laroux, F. S., and Alexander, J. S. 1996. Translational regulation of vascular permeability factor by eukaryotic intitiation factor 4E: implications for tumor angiogenesis. Int. J. Cancer 65:785–790.PubMedCrossRefGoogle Scholar
  92. Kevil, C., Carter, P., Hu, B., and de Benedetti, A. 1995. Translational enhancement of FGF2 by eIF-4 factors, and alternate utilization of CUG and AUG codons for translation initiation. Oncogene 11:2339–2348.PubMedGoogle Scholar
  93. Kraggerud, S. M., Sandvik, J. A., and Pettersen, E. O. 1995. Regulation of protein synthesis in human cells exposed to extreme hypoxia. Anticancer Res. 15:683–686.PubMedGoogle Scholar
  94. Kurebayashi, J., McLeskey, S. W, Johnson, M. D., Lippman, M. E., Dickson, R. B., and Kern, F. G. 1993. Quantitative demonstration of spontaneous metastasis by MCF-7 human breast cancer cells cotransfected with fibroblast growth factor 4 and LacZ. Cancer Res. 53:2178–2187.Google Scholar
  95. Lannutti, B. J., Gately, S. T., Quevedo, M. E., Soff, G. A., and Faller, A. S. 1997. Human angiostatin inhibits murine hemangioendothelioma tumor growth in vivo. Cancer Res. 57:5277–5280.PubMedGoogle Scholar
  96. Larcher, F., Robles, A. I., Duran, H., Murillas, R., Quintanilla, M., Cano, A., Conti, C. J., and Jorcano, J. L. 1996. Up-regulation of vascular endothelial growth factor/vascular permeability factor in mouse skin carcinogenesis correlates with malignant progression state and activated H-ras expression levels. Cancer Res. 56:5391–5396.PubMedGoogle Scholar
  97. Lee, Y. J., Galoforo, S. S., Berns, C. M., Erdos, G., Gupta, A. K., Ways, D. K., and Corry, P. M. 1995. Effect of ionizing radiation on AP-1 binding activity and basic fibroblast growth factor gene expression in drug-sensitive human breast carcinoma MCF-7 and multidrug-resistant MCF-7/ADR cells. J. Biol. Chem. 270:28790–28796.PubMedCrossRefGoogle Scholar
  98. Leek, R. D., Lewis, C. E., Whitehouse, R., Greenall, M., Clarke, J., and Harris, A. L. 1996. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res. 56:4625–4629.PubMedGoogle Scholar
  99. Levy, A. P., Levy, N. S., and Goldberg, M. A. 1996a. Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J. Biol. Chem. 271:2746–2753.PubMedCrossRefGoogle Scholar
  100. Levy, A. P., Levy, N. S., and Goldberg, M. A. 1996b. Hypoxia-inducible protein binding to vascular endothelial growth factor mRNA and its modulation by the von HippelLindau protein. J. Biol. Chem. 271:25492–25497.PubMedCrossRefGoogle Scholar
  101. Levy, A. P., Levy, N. S., Iliopoulos, O., Jiang, C., Kaelin Jr., W. G., and Goldberg, M. A. 1997. Regulation of vascular endothelial growth factor by hypoxia and its modulation by the von Hippel-Lindau tumor suppressor gene. Kidney Int. 51:575–578.PubMedCrossRefGoogle Scholar
  102. Levy, A. P., Levy, N. S., Wegner, S., and Goldberg, M. A. 1995. Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J. Biol. Chem. 270:1333–1340.Google Scholar
  103. Levy, N. S., Chung, S., Furneaux, H., and Levy, A. P. 1998. Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. J. Biol. Chem. 273:6417–6423.PubMedCrossRefGoogle Scholar
  104. Lewis, C. E., Leek, R., Harris, A., and McGee, J. O. 1995. Cytokine regulation of angiogenesis in breast cancer: the role of tumor-associated macrophages. J. Leukoc. Biol. 57:747–751.PubMedGoogle Scholar
  105. Li, B. D. L., Liu, L., Dawson, M., and de Benedetti, A. 1997. Overexpression of eukaryotic initiation factor 4E (eIF4E) in breast carcinoma. Cancer 79:2385–2390.PubMedCrossRefGoogle Scholar
  106. Li, B. D., McDonald, J. C., Nassar, R., and de Benedetti, A. 1998. Clinical outcome in stage I to III breast carcinoma and eIF4E overexpression. Ann. Surg. 227:756–761; discussion 761–763.PubMedCrossRefGoogle Scholar
  107. Lucas, R., Holmgren, L., Garcia, I., Jimenez, B., Mandriota, S. J., Borlat, F., Sim, B. K., Wu, Z., Grau, G. E., Shing, Y., Soff, G. A., Bouck, N., and Pepper, M. S. 1998. Multiple forms of angiostatin induce apoptosis in endothelial cells. Blood 92:4730–4741.PubMedGoogle Scholar
  108. Malkin, D., Li, F. P., Strong, L. C., Fraumeni, J. F., Jr., Nelson, C. E., Kim, D. H., Kassel, J., Gryka, M. A., Bischoff, E Z., and Tainsky, M. A. 1990. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:12331238.Google Scholar
  109. Mauceri, H. J., Hanna, N. N., Beckett, M. A., Gorski, D. H., Staba, M. J., Stellato, K. A., Bigelow, K., Heimann, R., Gately, S., Dhanabal, M., Soff, G. A., Sukhatme, V. P., Kufe, D. W., and Weichselbaum, R. R. 1998. Combined effects of angiostatin and ionizing radiation in antitumour therapy. Nature 394:287–291.PubMedCrossRefGoogle Scholar
  110. Mazure, N. M., Chen, E. Y., Laderoute, K. R., and Giaccia, A. J. 1997. Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element. Blood 90:3322–3331.PubMedGoogle Scholar
  111. McLeskey, S. W., Kurebayashi, J., Honig, S. E, Zwiebel, J., Lippman, M. E., Dickson, R. B., and Kern, F. G. 1993. Fibroblast growth factor 4 transfection of MCF-7 cells produces cell lines that are tumorigenic and metastatic in ovariectomized or tamoxifentreated athymic nude mice. Cancer Res. 53:2168–2177.PubMedGoogle Scholar
  112. Milanini, J., Vinals, E, Pouyssegur, J., and Pages, G. 1998. p42/p44 MAP kinase module plays a key role in the transcriptional regulation of the vascular endothelial growth factor gene in fibroblasts. J. Biol. Chem. 273:18165–18172.PubMedCrossRefGoogle Scholar
  113. Miyakis, S., Sourvinos, G., and Spandidos, D. A. 1998. Differential expression and mutation of the ras family genes in human breast cancer. Biochem. Biophys. Res. Commun. 251:609–612.PubMedCrossRefGoogle Scholar
  114. Moghaddam, A., Zhang, H.-T., Fan, T.-P. D., Hu, D.-E., Lees, V. C., Turley, H., Fox, S. B., Gatter, K. C., Harris, A. L., and Bicknell, R. 1995. Thymidine phosphorylase is angiogenic and promotes tumor growth. Proc. Natl. Acad. Sci. USA 92:998–1002.PubMedCrossRefGoogle Scholar
  115. Morelli, D., Lazzerini, D., Cazzaniga, S., Squicciarini, P., Bignami, P., Maier, J. A. M., Sfondrini, L., Ménard, S., Colnaghi, M. I., and Balsari, A. 1998. Evaluation of the balance between angiogenic and antiangiogenic circulating factors in patients with breast and gastrointestinal cancers. Clin. Cancer Res. 4:1221–1225.PubMedGoogle Scholar
  116. Moser, T. L., Stack, M. S., Asplin, I., Enghild, J. J., Hojrup, P., Everitt, L., Hubchak, S., Schnaper, H. W., and Pizzo, S. V. 1999. Angiostatin binds ATP synthase on the surface of human endothelial cells. Proc. Natl. Acad. Sci. USA 96:2811–2816.PubMedCrossRefGoogle Scholar
  117. Mukhopadhyay, D., Knebelmann, B., Cohen, H. T., Ananth, S., and Sukhatme, V. P. 1997. The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. Mol. Cell. Biol. 17:5629–5639.PubMedGoogle Scholar
  118. 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
  119. 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
  120. Nagaoka, H., Iino, Y., Takei, H., and Morishita, Y. 1998. Platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in macrophages correlates with tumor angiogenesis and prognosis in invasive breast cancer. Int. J. Oncol. 13:449–454.PubMedGoogle Scholar
  121. Nass, S. J., and Dickson, R. B. 1997. Defining a role for c-Myc in breast tumorigenesis. Breast Cancer Res. Treat. 44:1–22.PubMedCrossRefGoogle Scholar
  122. Nathan, C.-A., Carter, P., Liu, L., Li, B. D. L., Abreo, F., Tudor, A., Zimmer, S. G., and de Benedetti, A. 1997. Elevated expression of eIF4E and FGF-2 isoforms during vascularization of breast carcinomas. Oncogene 15:1087–1094.PubMedCrossRefGoogle Scholar
  123. Neufeld, G., Cohen, T., Gengrinovitch, S., and Poltorak, Z. 1999. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 13:9–22.PubMedGoogle Scholar
  124. O’Mahony, C. A., Albo, D., Tuszynski, G. P., and Berger, D. H. 1998a. Transforming growth factor-beta 1 inhibits generation of angiostatin by human pancreatic cancer cells. Surgery 124:388–393.PubMedCrossRefGoogle Scholar
  125. O’Mahony, C. A., Seidel, A., Albo, D., Chang, H., Tuszynski, G. P., and Berger, D. H. 1998b. Angiostatin generation by human pancreatic cancer. J. Surg. Res. 77:55–58.PubMedCrossRefGoogle Scholar
  126. O’Reilly, M. S., Boehm, T., Shing, Y., Fukai, N, Vasios, G., Lane, W. S., Flynn, E., Birkhead, J. R., Olsen, B. R., and Folkman, J. 1997. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277–285.PubMedCrossRefGoogle Scholar
  127. O’Reilly, M. S., Holmgren, L., Chen, C., and Folkman, J. 1996. Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat. Med. 2:689–692.PubMedCrossRefGoogle Scholar
  128. 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
  129. Okada, F., Rak, J. W., St. Croix, B., Lieubeau, B., Kaya, M., Roncari, L., Shirasawa, S., Sasazuki, T., and Kerbel, R. S. 1998. Impact of oncogenes in tumor angiogenesis: mutant K-ras up-regulation of vascular endothelial growth factor/vascular permeability factor is necessary, but not sufficient for tumorigenicity of human colorectal carcinoma cells. Proc. Natl. Acad. Sci. USA 95:3609–3614.PubMedCrossRefGoogle Scholar
  130. Ozbun, M. A., and Butel, J. S. 1995. Tumor suppressor p53 mutations and breast cancer: a critical analysis. Adv. Cancer Res. 66:71–141.PubMedCrossRefGoogle Scholar
  131. Patterson, B. C., and Sang, Q. A. 1997. Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9). J. Biol. Chem. 272: 28823–28825.PubMedCrossRefGoogle Scholar
  132. Pluda, J. M. 1997. Tumor-associated angiogenesis: mechanisms, clinical implications, and therapeutic strategies. Semin. Oncol. 24:203–218.PubMedGoogle Scholar
  133. Qian, X., Wang, T. N., Rothman, V. L., Nicosia, R. F., and Tuszynski, G. P. 1997. Thrombospondin-1 modulates angiogenesis in vitro by up-regulation of matrix metalloproteinase-9 in endothelial cells. Exp. Cell Res. 235:403–412.PubMedCrossRefGoogle Scholar
  134. Rak, J., Mitsuhashi, Y., Bayko, L., Filmus, J., Shirasawa, S., Sasazuki, T., and Kerbel, R.S. 1995. Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res. 55:4575–4580.PubMedGoogle Scholar
  135. Rastinejad, F., Polverini, P. J., and Bouck, N. P. 1989. Regulation of the activity of a new inhibitor of angiogenesis by a cancer suppressor gene. Cell 56:345–355.PubMedCrossRefGoogle Scholar
  136. Relf, M., LeJeune, S., Scott, P. A. E., Fox, S., Smith, K., Leek, R., Moghaddam, A., Whitehouse, R., Bicknell, R., and Harris, A. L. 1997. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor 13–1, platelet-derived endothelial cell growth factor, placenta growth factor and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 57:963–969.PubMedGoogle Scholar
  137. Rhoads, R. E. 1991. Protein synthesis, cell growth and oncogenesis. Curr. Opin. Cell Biol. 3:1019–1024.PubMedCrossRefGoogle Scholar
  138. Rhoads, R. E. 1993. Regulation of eukaryotic protein synthesis by initiation factors. J. Biol. Chem. 268:3017–3020.PubMedGoogle Scholar
  139. Rinker-Schaeffer, C. W., Graff, J. R., de Benedetti, A., Zimmer, S. G., and Rhoads, R. E. 1993. Decreasing the level of translation initiation factor 4E with antisense RNA causes reversal of ras-mediated transformation and tumorigenesis of cloned rat embryo fibroblasts. Int. J. Cancer 55:841–847.PubMedCrossRefGoogle Scholar
  140. Roberts, D. D. 1996. Regulation of tumor growth and metastasis by thrombospondin-1. FASEB J. 10:1183–1191.PubMedGoogle Scholar
  141. Rogelj, S., Weinberg, A., Fanning, P., and Klagsbrun, M. 1988. Basic fibroblast growth factor fused to a signal peptide transforms cells. Nature 331:173–175.PubMedCrossRefGoogle Scholar
  142. 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
  143. Scandurro, A. B., and Beckman, B. S. 1998. Common proteins bind mRNAs encoding erythropoietin, tyrosine hydroxylase, and vascular endothelial growth factor. Biochem. Biophys. Res. Commun. 246:436–440.PubMedCrossRefGoogle Scholar
  144. Scott, P. A. E., Smith, K., Poulsom, R., de Benedetti, A., Bicknell, R., and Harris, A. L. 1998. Differential expression of vascular endothelial growth factor mRNA vs protein isoform expression in human breast cancer and relationship to eIF-4E. Br. J. Cancer 77:2120–2128.PubMedCrossRefGoogle Scholar
  145. Semenza, G. L., Agani, F., Iyer, N., Jiang, B.-H., Leung, S., Wiener, C., and Yu, A. 1998. Hypoxia-inducible factor 1: from molecular biology to cardiopulmonary physiology. Chest 114:40S–45S.PubMedCrossRefGoogle Scholar
  146. Semenza, G. L., and Wang, G. L. 1992. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol. Cell. Biol. 12:5447–5454.PubMedGoogle Scholar
  147. Shoji, M., Hancock, W. W., Abe, K., et al. 1998. Activation of coagulation and angiogenesis in cancer. Am. J. Pathol. 152:399–411.PubMedGoogle Scholar
  148. Shweiki, D., Itin, A., Soffer, D., and Keshet, E. 1992. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–848.Google Scholar
  149. Siemeister, G., Weindel, K., Mohrs, K., Barleon, B., Mariny-Baron, G., and Marmé, D. 1996. Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein. Cancer Res. 56:2299–2301.PubMedGoogle Scholar
  150. Sim, B. K. L., O’Reilly, M. S., Liang, H., Fortier, A. H., He, W., Madsen, J. W., Lapcevich, R., and Nacy, C. A. 1997. A recombinant human angiostatin protein inhibits experimental primary and metastatic cancer. Cancer Res. 57:1329–1334.PubMedGoogle Scholar
  151. Smith, L. M., Birrer, M. J., Stampfer, M. R., and Brown, P. H. 1997. Breast cancer cells have lower activating protein 1 transcription factor activity than normal mammary epithelial cells. Cancer Res. 57:3046–3054.PubMedGoogle Scholar
  152. Soutou, B., Gamby, C., Crepin, M., and Hamelin, R. 1996. Tumoral progression of human breast epithelial cells secreting FGF2 and FGF4. Int. J. Cancer 68:675–681.CrossRefGoogle Scholar
  153. Stathakis, P., Fitzgerald, M., Matthias, L. J., Chesterman, C. N., and Hogg, R J. 1997. Generation of angiostatin by reduction and proteolysis of plasmin. Catalysis by a plasmin reductase secreted by cultured cells. J. Biol. Chem. 272:20641–20645.PubMedCrossRefGoogle Scholar
  154. Stein, I., Itin, A., Einat, R, Skaliter, R., Grossman, Z., and Keshet, E. 1998. Translation of vascular endothelial growth factor mRNA by internal ribosome entry: Implications for translation under hypoxia. Mol. Cell. Biol. 18:3112–3149.PubMedGoogle Scholar
  155. Stein, I., Neeman, M., Shweiki, D., Itin, A., and Keshet, E. 1995. Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation witih other ischemia-induced genes. Mol. Cell. Biol. 15:5363–5368.PubMedGoogle Scholar
  156. 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
  157. Stratmann, R., Krieg, M., Haas, R., and Plate, K. H. 1997. Putative control of angiogenesis in hemangioblastomas by the von Hippie-Lindau tumor suppressor gene. J. Neuropathol. Exp. Neurol. 56:1242–1252.PubMedCrossRefGoogle Scholar
  158. Surmacz, E., Guvakova, M. A., Nolan, M. K., Nicosia, R. F., and Sciacca, L. 1998. Type I insulin-like growth factor receptor function in breast cancer. Breast Cancer Res. Treat. 47:255–267.PubMedCrossRefGoogle Scholar
  159. 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
  160. Takahashi, Y., Cleary, K. R., Mai, M., Kitadai, Y., Bucana, C. D., and Ellis, L. M. 1996. Significance of vessel count and vascular endothelial growth factor and its receptor (KDR) in intestinal-type gastric cancer. Clin. Cancer Res. 2:1679–1684.PubMedGoogle Scholar
  161. Tanaka, T., Cao, Y., Folkman, J., and Fine, H. A. 1998. Viral vector-targeted antiangiogenic gene therapy utilizing an angiostatin complementary DNA. Cancer Res. 58:3362–3369.PubMedGoogle Scholar
  162. Taraboletti, G., Roberts, D., Liotta, L. A., and Giavazzi, R. 1990. Platelet thrombospondin modulates endothelial cell adhesion, motility, and growth: a potential angiogenesis regulatory factor. J. Cell Biol. 111:765–772.PubMedCrossRefGoogle Scholar
  163. Toi, M., Hoshina, S., Taniguchi, T., Yamamoto, Y., Ishitsuka, H., and Tominaga, T. 1995b. Expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human breast cancer. Int. J. Cancer 64:79–82.PubMedCrossRefGoogle Scholar
  164. Toi, M., Inada, K., Suzuki, H., and Tominaga, T. 1995a. Tumor angiogenesis in breast cancer: its importance as a prognostic indicator and the association with vascular endothelial growth factor expression. Breast Cancer Res. Treat. 36:193–204.PubMedCrossRefGoogle Scholar
  165. Toi, M., Ueno, T., Matsumoto, H., Saji, H., Funata, N., Koike, M., and Tominaga, T. 1999. Significance of thymidine phosphorylase as a marker of protumor monocytes in breast cancer. Clin. Cancer Res. 5:1131–1137.PubMedGoogle Scholar
  166. 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.PubMedCrossRefGoogle Scholar
  167. Tuszynski, G. R, and Nicosia, R. F. 1994. Localization of thrombospondin and its cysteineserine-valine-threonine-cysteine-glycine-specific receptor in human breast carcinoma. Lab. Invest. 70:228–233.PubMedGoogle Scholar
  168. Vagner, S., Gensac, M.-C., Maret, A., Bayard, F., Amalric, F., Prats, H., and Prats, A.-C. 1995. Alternative translation of human fibroblast growth factor 2 mRNA occurs by internal entry of ribosomes. Mol. Cell. Biol. 15:35–44.PubMedGoogle Scholar
  169. Vazquez, F., Hastings, G., Ortega, M. A., Lane, T. F., Oikemus, S., Lombardo, M., and Iruela-Arispe, M. L. 1999. METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-inhibitory activity. J. Biol. Chem. 274:23349–23357.PubMedCrossRefGoogle Scholar
  170. Vlodaysky, I., Miao, H.-Q., Medalion, B., Danagher, P., and Ron, D. 1996. Involvement of heparan sulfate and related molecules in sequestration and growth promoting activity of fibroblast growth factor. Cancer Metastasis Rev. 15:177–186.CrossRefGoogle Scholar
  171. 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
  172. Wang, G. L., Jiang, B.-H., Rue, E. A., and Semenza, G. L. 1995. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular 02 tension. Proc. Natl. Acad. Sci. USA 92:5510–5514.PubMedCrossRefGoogle Scholar
  173. Wang, G. L., and Semenza, G. L. 1993. Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J. Biol. Chem. 268:21513–21518.PubMedGoogle Scholar
  174. Wang, T. N., Qian, X.-H., Granick, M. S., Solomon, M. P., Rothman, V. L., Berger, D. H., and Tuszynski, G. P. 1996a. Thrombospondin-1 (TSP-1) promotes in the invasive properties of human breast cancer. J. Surg. Res. 63:39–43.PubMedCrossRefGoogle Scholar
  175. Wang, T. N., Qian, X.-H., Granick, M. S., Solomon, M. P., Rothman, V. L., Berger, D. H., and Tuszynski, G. P. 1996b. Inhibition of breast cancer progression by an antibody to a thrombospondin-1 receptor. Surgery 120:449–454.PubMedCrossRefGoogle Scholar
  176. Weidner, N., Semple, J. P., Welch, W. R., and Folkman, J. 1991. Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. N. Engl. J. Med. 324:1–8.PubMedCrossRefGoogle Scholar
  177. Weinstat-Saslow, D., Zabrenetzky, 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
  178. Wizigmann-Voos, S., Breier, G., Risau, W., and Plate, K. H. 1995. Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res. 55:1358–1364.PubMedGoogle Scholar
  179. Wu, Z., O’Reilly, M. S., Folkman, J., and Shing, Y. 1997. Suppression of tumor growth with recombinant murine angiostatin. Biochem. Biophys. Res. Commun. 236:651–654.PubMedCrossRefGoogle Scholar
  180. Yamaguchi, N., Anand-Apte, B., Lee, M., Sasaki, T., Fukai, N., Shapiro, R., Que, I., Lowik, C., Timpl, R., and Olsen, B. R. 1999. Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding. EMBO J. 18:4414–4423.Google Scholar
  181. Yoshiji, H., Harris, S. R., and Thorgeirsson, U. P. 1997. Vascular endothelial growth factor is essential for initial but not continued in vivo growth of human breast carcinoma cells. Cancer Res. 57:3924–3928.PubMedGoogle Scholar
  182. Zhan, X., Bates, B., Hu, X., and Goldfarb, M. 1988. The human FGF-5 oncogene encodes a novel protein related to fibroblast growth factor. Mol. Cell. Biol. 8:3487–3495.Google Scholar
  183. Zhang, H.-T., Craft, P., Scott, P. A. E., Ziche, M., Weich, H. A., Harris, A. L., and Bicknell, R. 1995. Enhancement of tumor growth and vascular density by transfection of vascular endothelial cell growth factor into MCF-7 human breast carcinoma cells. J. Natl. Cancer Inst. 87:213–219.PubMedCrossRefGoogle Scholar
  184. Zhang, L., Kharbanda, S., Chen, D., Bullocks, J., Miller, D. L., Ding, I. Y. F., Hanfelt, J., McLeskey, S. W., and Kern, F. G. 1997. MCF-7 breast carcinoma cells overexpressing FGF-1 form vascularized metastatic tumors in ovariectomized or tamoxifen-treated nude mice. Oncogene 15:2093–2108.PubMedCrossRefGoogle Scholar
  185. Zhang, L., Kharbanda, S., Hanfelt, J., and Kern, F. G. 1998. Both autocrine and paracrine effects of transfected acidic fibroblast growth factor are involved in the estrogen-independent and antiestrogen-resistant growth of MCF-7 breast cancer cells. Cancer Res. 58:352–361. PubMedGoogle Scholar
  186. Zhong, H., Agani, F., Baccala, A. A., Laughner, E., Rioseco-Camacho, N., Isaacs, W. B., Simons, J. W., and Semenza, G. L. 1998. Increased expression of hypoxia inducible factorlalpha in rat and human prostate cancer. Cancer Res. 58:5280–5284. PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Sandra W. McLeskey
  • Robert B. Dickson

There are no affiliations available

Personalised recommendations