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British Journal of Cancer logoLink to British Journal of Cancer
. 1997;76(6):689–693. doi: 10.1038/bjc.1997.447

Platelet-derived endothelial cell growth factor thymidine phosphorylase in tumour growth and response to therapy.

L Griffiths 1, I J Stratford 1
PMCID: PMC2228052  PMID: 9310231

Abstract

Angiogenesis plays an important role in the growth and metastasis of solid tumours. Platelet-derived endothelial cell growth factor (PD-ECGF) is known to be chemotactic for endothelial cells in vitro and angiogenic in vivo. It is also known as gliostatin, a factor promoting neuronal survival, and thymidine phosphorylase (dThdPase), which catalyses the reversible phosphorylation of thymidine to thymine and 2-deoxyribose-1-phosphate. This enzymatic activity is critical for angiogenic activity. PD-ECGF protein is highly expressed in tumours compared with most normal tissues and has been correlated with tumour growth, invasion and metastasis in clinical studies. In addition, dThdPase activity (by inference PD-ECGF) has been found to be a major determinant of the toxicity of 5-fluorouracil and its prodrugs, which are extensively studied clinically as anti-cancer agents. This review attempts to summarize recent gains in understanding the nature, location and action of PD-ECGF and its specific relevance to tumour biology.

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Selected References

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  1. Asai K., Hirano T., Kaneko S., Moriyama A., Nakanishi K., Isobe I., Eksioglu Y. Z., Kato T. A novel glial growth inhibitory factor, gliostatin, derived from neurofibroma. J Neurochem. 1992 Jul;59(1):307–317. doi: 10.1111/j.1471-4159.1992.tb08905.x. [DOI] [PubMed] [Google Scholar]
  2. Asai K., Hirano T., Matsukawa K., Kusada J., Takeuchi M., Otsuka T., Matsui N., Kato T. High concentrations of immunoreactive gliostatin/platelet-derived endothelial cell growth factor in synovial fluid and serum of rheumatoid arthritis. Clin Chim Acta. 1993 Sep 17;218(1):1–4. doi: 10.1016/0009-8981(93)90216-q. [DOI] [PubMed] [Google Scholar]
  3. Asai K., Nakanishi K., Isobe I., Eksioglu Y. Z., Hirano A., Hama K., Miyamoto T., Kato T. Neurotrophic action of gliostatin on cortical neurons. Identity of gliostatin and platelet-derived endothelial cell growth factor. J Biol Chem. 1992 Oct 5;267(28):20311–20316. [PubMed] [Google Scholar]
  4. Barton G. J., Ponting C. P., Spraggon G., Finnis C., Sleep D. Human platelet-derived endothelial cell growth factor is homologous to Escherichia coli thymidine phosphorylase. Protein Sci. 1992 May;1(5):688–690. doi: 10.1002/pro.5560010514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Claffey K. P., Robinson G. S. Regulation of VEGF/VPF expression in tumor cells: consequences for tumor growth and metastasis. Cancer Metastasis Rev. 1996 Jun;15(2):165–176. doi: 10.1007/BF00437469. [DOI] [PubMed] [Google Scholar]
  6. Desgranges C., Razaka G., Rabaud M., Bricaud H., Balzarini J., De Clercq E. Phosphorolysis of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and other 5-substituted-2'-deoxyuridines by purified human thymidine phosphorylase and intact blood platelets. Biochem Pharmacol. 1983 Dec 1;32(23):3583–3590. doi: 10.1016/0006-2952(83)90307-6. [DOI] [PubMed] [Google Scholar]
  7. Desgranges C., Razaka G., Rabaud M., Picard P., Dupuch F., Bricaud H. The human blood platelet: a cellular model to study the degradation of thymidine and its inhibition. Biochem Pharmacol. 1982 Sep 1;31(17):2755–2759. doi: 10.1016/0006-2952(82)90129-0. [DOI] [PubMed] [Google Scholar]
  8. Eda H., Fujimoto K., Watanabe S., Ishikawa T., Ohiwa T., Tatsuno K., Tanaka Y., Ishitsuka H. Cytokines induce uridine phosphorylase in mouse colon 26 carcinoma cells and make the cells more susceptible to 5'-deoxy-5-fluorouridine. Jpn J Cancer Res. 1993 Mar;84(3):341–347. doi: 10.1111/j.1349-7006.1993.tb02876.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Eda H., Fujimoto K., Watanabe S., Ura M., Hino A., Tanaka Y., Wada K., Ishitsuka H. Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 5'-deoxy-5-fluorouridine. Cancer Chemother Pharmacol. 1993;32(5):333–338. doi: 10.1007/BF00735915. [DOI] [PubMed] [Google Scholar]
  10. Fan T. P., Jaggar R., Bicknell R. Controlling the vasculature: angiogenesis, anti-angiogenesis and vascular targeting of gene therapy. Trends Pharmacol Sci. 1995 Feb;16(2):57–66. doi: 10.1016/s0165-6147(00)88979-8. [DOI] [PubMed] [Google Scholar]
  11. Finnis C., Dodsworth N., Pollitt C. E., Carr G., Sleep D. Thymidine phosphorylase activity of platelet-derived endothelial cell growth factor is responsible for endothelial cell mitogenicity. Eur J Biochem. 1993 Feb 15;212(1):201–210. doi: 10.1111/j.1432-1033.1993.tb17651.x. [DOI] [PubMed] [Google Scholar]
  12. Folkman J. How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes memorial Award lecture. Cancer Res. 1986 Feb;46(2):467–473. [PubMed] [Google Scholar]
  13. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990 Jan 3;82(1):4–6. doi: 10.1093/jnci/82.1.4. [DOI] [PubMed] [Google Scholar]
  14. Fox S. B., Moghaddam A., Westwood M., Turley H., Bicknell R., Gatter K. C., Harris A. L. Platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in normal tissues: an immunohistochemical study. J Pathol. 1995 Jun;176(2):183–190. doi: 10.1002/path.1711760212. [DOI] [PubMed] [Google Scholar]
  15. Fox S. B., Westwood M., Moghaddam A., Comley M., Turley H., Whitehouse R. M., Bicknell R., Gatter K. C., Harris A. L. The angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase is up-regulated in breast cancer epithelium and endothelium. Br J Cancer. 1996 Feb;73(3):275–280. doi: 10.1038/bjc.1996.49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fujimoto S., Wang Y., Inoue K., Ogawa M. Antitumor activity of a new fluoropyrimidine derivative, 5'-deoxy-5-fluorouridine, against murine and human experimental tumors. Jpn J Cancer Res. 1985 Jul;76(7):644–650. [PubMed] [Google Scholar]
  17. Griffiths L., Dachs G. U., Bicknell R., Harris A. L., Stratford I. J. 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. 1997 Feb 15;57(4):570–572. [PubMed] [Google Scholar]
  18. Hagiwara K., Stenman G., Honda H., Sahlin P., Andersson A., Miyazono K., Heldin C. H., Ishikawa F., Takaku F. Organization and chromosomal localization of the human platelet-derived endothelial cell growth factor gene. Mol Cell Biol. 1991 Apr;11(4):2125–2132. doi: 10.1128/mcb.11.4.2125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Haraguchi M., Miyadera K., Uemura K., Sumizawa T., Furukawa T., Yamada K., Akiyama S., Yamada Y. Angiogenic activity of enzymes. Nature. 1994 Mar 17;368(6468):198–198. doi: 10.1038/368198a0. [DOI] [PubMed] [Google Scholar]
  20. Heldin N. E., Usuki K., Bergh J., Westermark B., Heldin C. H. Differential expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human lung carcinoma cell lines. Br J Cancer. 1993 Oct;68(4):708–711. doi: 10.1038/bjc.1993.414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Iltzsch M. H., el Kouni M. H., Cha S. Kinetic studies of thymidine phosphorylase from mouse liver. Biochemistry. 1985 Nov 19;24(24):6799–6807. doi: 10.1021/bi00345a011. [DOI] [PubMed] [Google Scholar]
  22. Ishikawa F., Miyazono K., Hellman U., Drexler H., Wernstedt C., Hagiwara K., Usuki K., Takaku F., Risau W., Heldin C. H. Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor. Nature. 1989 Apr 13;338(6216):557–562. doi: 10.1038/338557a0. [DOI] [PubMed] [Google Scholar]
  23. Leyva A., Kraal I., Lankelma J., Delemarre J. F., Pinedo H. M. High uridine phosphorylase activity in human melanoma tumor. Anticancer Res. 1983 Jul-Aug;3(4):227–231. [PubMed] [Google Scholar]
  24. Luccioni C., Beaumatin J., Bardot V., Lefrançois D. Pyrimidine nucleotide metabolism in human colon carcinomas: comparison of normal tissues, primary tumors and xenografts. Int J Cancer. 1994 Aug 15;58(4):517–522. doi: 10.1002/ijc.2910580411. [DOI] [PubMed] [Google Scholar]
  25. Maeda K., Chung Y. S., Ogawa Y., Takatsuka S., Kang S. M., Ogawa M., Sawada T., Onoda N., Kato Y., Sowa M. Thymidine phosphorylase/platelet-derived endothelial cell growth factor expression associated with hepatic metastasis in gastric carcinoma. Br J Cancer. 1996 Apr;73(8):884–888. doi: 10.1038/bjc.1996.177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Miyadera K., Sumizawa T., Haraguchi M., Yoshida H., Konstanty W., Yamada Y., Akiyama S. Role of thymidine phosphorylase activity in the angiogenic effect of platelet derived endothelial cell growth factor/thymidine phosphorylase. Cancer Res. 1995 Apr 15;55(8):1687–1690. [PubMed] [Google Scholar]
  27. Miyazono K., Okabe T., Urabe A., Takaku F., Heldin C. H. Purification and properties of an endothelial cell growth factor from human platelets. J Biol Chem. 1987 Mar 25;262(9):4098–4103. [PubMed] [Google Scholar]
  28. Moghaddam A., Bicknell R. Expression of platelet-derived endothelial cell growth factor in Escherichia coli and confirmation of its thymidine phosphorylase activity. Biochemistry. 1992 Dec 8;31(48):12141–12146. doi: 10.1021/bi00163a024. [DOI] [PubMed] [Google Scholar]
  29. Moghaddam A., Zhang H. T., Fan T. P., Hu D. E., Lees V. C., Turley H., Fox S. B., Gatter K. C., Harris A. L., Bicknell R. Thymidine phosphorylase is angiogenic and promotes tumor growth. Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):998–1002. doi: 10.1073/pnas.92.4.998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Naguib F. N., Levesque D. L., Wang E. C., Panzica R. P., el Kouni M. H. 5-Benzylbarbituric acid derivatives, potent and specific inhibitors of uridine phosphorylase. Biochem Pharmacol. 1993 Oct 5;46(7):1273–1283. doi: 10.1016/0006-2952(93)90477-e. [DOI] [PubMed] [Google Scholar]
  31. O'Brien T., Cranston D., Fuggle S., Bicknell R., Harris A. L. Different angiogenic pathways characterize superficial and invasive bladder cancer. Cancer Res. 1995 Feb 1;55(3):510–513. [PubMed] [Google Scholar]
  32. Patterson A. V., Zhang H., Moghaddam A., Bicknell R., Talbot D. C., Stratford I. J., Harris A. L. Increased sensitivity to the prodrug 5'-deoxy-5-fluorouridine and modulation of 5-fluoro-2'-deoxyuridine sensitivity in MCF-7 cells transfected with thymidine phosphorylase. Br J Cancer. 1995 Sep;72(3):669–675. doi: 10.1038/bjc.1995.392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Pauly J. L., Paolini N. S., Ebarb R. L., Germain M. J. Elevated thymidine phosphorylase activity in the plasma and ascitis fluids of tumor-bearing animals. Proc Soc Exp Biol Med. 1978 Feb;157(2):262–267. doi: 10.3181/00379727-157-40034. [DOI] [PubMed] [Google Scholar]
  34. Pauly J. L., Schuller M. G., Zelcer A. A., Kirss T. A., Gore S. S., Germain M. J. Identification and comparative analysis of thymidine phosphorylase in the plasma of healthy subjects and cancer patients. J Natl Cancer Inst. 1977 Jun;58(6):1587–1590. doi: 10.1093/jnci/58.6.1587. [DOI] [PubMed] [Google Scholar]
  35. Reynolds K., Farzaneh F., Collins W. P., Campbell S., Bourne T. H., Lawton F., Moghaddam A., Harris A. L., Bicknell R. Association of ovarian malignancy with expression of platelet-derived endothelial cell growth factor. J Natl Cancer Inst. 1994 Aug 17;86(16):1234–1238. doi: 10.1093/jnci/86.16.1234. [DOI] [PubMed] [Google Scholar]
  36. Sanfilippo O., Camici M., Tozzi M. G., Turriani M., Faranda A., Ipata P. L., Silvestrini R. Relationship between the levels of purine salvage pathway enzymes and clinical/biological aggressiveness of human colon carcinoma. Cancer Biochem Biophys. 1994 Apr;14(1):57–66. [PubMed] [Google Scholar]
  37. Schwartz E. L., Baptiste N., Wadler S., Makower D. Thymidine phosphorylase mediates the sensitivity of human colon carcinoma cells to 5-fluorouracil. J Biol Chem. 1995 Aug 11;270(32):19073–19077. doi: 10.1074/jbc.270.32.19073. [DOI] [PubMed] [Google Scholar]
  38. Schwartz E. L., Hoffman M., O'Connor C. J., Wadler S. Stimulation of 5-fluorouracil metabolic activation by interferon-alpha in human colon carcinoma cells. Biochem Biophys Res Commun. 1992 Feb 14;182(3):1232–1239. doi: 10.1016/0006-291x(92)91863-l. [DOI] [PubMed] [Google Scholar]
  39. Shapiro R., Vallee B. L. Site-directed mutagenesis of histidine-13 and histidine-114 of human angiogenin. Alanine derivatives inhibit angiogenin-induced angiogenesis. Biochemistry. 1989 Sep 5;28(18):7401–7408. doi: 10.1021/bi00444a038. [DOI] [PubMed] [Google Scholar]
  40. Takahashi Y., Bucana C. D., Liu W., Yoneda J., Kitadai Y., Cleary K. R., Ellis L. M. Platelet-derived endothelial cell growth factor in human colon cancer angiogenesis: role of infiltrating cells. J Natl Cancer Inst. 1996 Aug 21;88(16):1146–1151. doi: 10.1093/jnci/88.16.1146. [DOI] [PubMed] [Google Scholar]
  41. Takebayashi Y., Miyadera K., Akiyama S., Hokita S., Yamada K., Akiba S., Yamada Y., Sumizawa T., Aikou T. Expression of thymidine phosphorylase in human gastric carcinoma. Jpn J Cancer Res. 1996 Mar;87(3):288–295. doi: 10.1111/j.1349-7006.1996.tb00219.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Tevaearai H. T., Laurent P. L., Suardet L., Eliason J. F., Givel J. C., Odartchenko N. Interactions of interferon-alpha 2a with 5'-deoxy-5-fluorouridine in colorectal cancer cells in vitro. Eur J Cancer. 1992;28(2-3):368–372. doi: 10.1016/s0959-8049(05)80055-3. [DOI] [PubMed] [Google Scholar]
  43. Toi M., Hoshina S., Taniguchi T., Yamamoto Y., Ishitsuka H., Tominaga T. Expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human breast cancer. Int J Cancer. 1995 Apr 21;64(2):79–82. doi: 10.1002/ijc.2910640202. [DOI] [PubMed] [Google Scholar]
  44. Usuki K., Miyazono K., Heldin C. H. Covalent linkage between nucleotides and platelet-derived endothelial cell growth factor. J Biol Chem. 1991 Oct 25;266(30):20525–20531. [PubMed] [Google Scholar]
  45. Usuki K., Norberg L., Larsson E., Miyazono K., Hellman U., Wernstedt C., Rubin K., Heldin C. H. Localization of platelet-derived endothelial cell growth factor in human placenta and purification of an alternatively processed form. Cell Regul. 1990 Jul;1(8):577–584. doi: 10.1091/mbc.1.8.577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Usuki K., Saras J., Waltenberger J., Miyazono K., Pierce G., Thomason A., Heldin C. H. Platelet-derived endothelial cell growth factor has thymidine phosphorylase activity. Biochem Biophys Res Commun. 1992 May 15;184(3):1311–1316. doi: 10.1016/s0006-291x(05)80025-7. [DOI] [PubMed] [Google Scholar]
  47. Wadler S., Schwartz E. L., Goldman M., Lyver A., Rader M., Zimmerman M., Itri L., Weinberg V., Wiernik P. H. Fluorouracil and recombinant alfa-2a-interferon: an active regimen against advanced colorectal carcinoma. J Clin Oncol. 1989 Dec;7(12):1769–1775. doi: 10.1200/JCO.1989.7.12.1769. [DOI] [PubMed] [Google Scholar]
  48. Woodman P. W., Sarrif A. M., Heidelberger C. Inhibition of nucleoside phosphorylase cleavage of 5-fluoro-2'-deoxyuridine by 2,4-pyrimidinedione derivatives. Biochem Pharmacol. 1980 Apr 1;29(7):1059–1063. doi: 10.1016/0006-2952(80)90170-7. [DOI] [PubMed] [Google Scholar]
  49. Yoshimura A., Kuwazuru Y., Furukawa T., Yoshida H., Yamada K., Akiyama S. Purification and tissue distribution of human thymidine phosphorylase; high expression in lymphocytes, reticulocytes and tumors. Biochim Biophys Acta. 1990 Apr 23;1034(1):107–113. doi: 10.1016/0304-4165(90)90160-x. [DOI] [PubMed] [Google Scholar]
  50. ZIMMERMAN M., SEIDENBERG J. DEOXYRIBOSYL TRANSFER. I. THYMIDINE PHOSPHORYLASE AND NUCLEOSIDE DEOXYRIBOSYLTRANSFERASE IN NORMAL AND MALIGNANT TISSUES. J Biol Chem. 1964 Aug;239:2618–2621. [PubMed] [Google Scholar]
  51. el Kouni M. H., el Kouni M. M., Naguib F. N. Differences in activities and substrate specificity of human and murine pyrimidine nucleoside phosphorylases: implications for chemotherapy with 5-fluoropyrimidines. Cancer Res. 1993 Aug 15;53(16):3687–3693. [PubMed] [Google Scholar]

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