Abstract
Angiogenesis is a recently described prognostic factor in non-small-cell lung cancer. Platelet-derived endothelial cell growth factor (PD-ECGF), shown to be the enzyme thymidine phosphorylase (TP), induces angiogenesis in vitro and in vivo. High intracellular levels of the enzyme are associated with increased chemosensitivity to pyrimidine antimetabolites. PD-ECGF/TP expression was evaluated immunohistochemically in surgically resected specimens from 107 patients with operable non-small-cell lung cancer using the P-GF,44C monoclonal antibody. High expression of PD-ECGF/TP was found in 25% of cases and was associated with high vascular grade (P = 0.01). Fourteen of 32 (44%) high vascular grade tumours showed a positive reactivity for PD-ECGF/TP vs 13/75 (17%) of low/medium vascular grade. Positive expression was observed more frequently in T2-staged cases than in T1 (P = 0.04). While overall survival was not affected (P = 0.09), subset analysis revealed that node-negative patients with positive PD-ECGF/TP expression had a worse prognosis (P = 0.04). The results suggest that PD-ECGF/TP may be an important molecule involved in angiogenesis in non-small-cell lung cancer. Up-regulation of the enzyme defines a more aggressive tumour phenotype in patients with node-negative disease. Assessment of vascular grade and PD-ECGF/TP expression should be taken into account in the design of randomized trials assessing the role of adjuvant chemotherapy in non-small-cell lung cancer.
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- 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]
- 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]
- 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]
- 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]
- Furukawa T., Yoshimura A., Sumizawa T., Haraguchi M., Akiyama S., Fukui K., Ishizawa M., Yamada Y. Angiogenic factor. Nature. 1992 Apr 23;356(6371):668–668. doi: 10.1038/356668a0. [DOI] [PubMed] [Google Scholar]
- Giatromanolaki A., Koukourakis M., O'Byrne K., Fox S., Whitehouse R., Talbot D. C., Harris A. L., Gatter K. C. Prognostic value of angiogenesis in operable non-small cell lung cancer. J Pathol. 1996 May;179(1):80–88. doi: 10.1002/(SICI)1096-9896(199605)179:1<80::AID-PATH547>3.0.CO;2-X. [DOI] [PubMed] [Google Scholar]
- Haraguchi M., Furukawa T., Sumizawa T., Akiyama S. Sensitivity of human KB cells expressing platelet-derived endothelial cell growth factor to pyrimidine antimetabolites. Cancer Res. 1993 Dec 1;53(23):5680–5682. [PubMed] [Google Scholar]
- 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]
- 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]
- Horak E. R., Leek R., Klenk N., LeJeune S., Smith K., Stuart N., Greenall M., Stepniewska K., Harris A. L. Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet. 1992 Nov 7;340(8828):1120–1124. doi: 10.1016/0140-6736(92)93150-l. [DOI] [PubMed] [Google Scholar]
- 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]
- Koch A. E., Harlow L. A., Haines G. K., Amento E. P., Unemori E. N., Wong W. L., Pope R. M., Ferrara N. Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol. 1994 Apr 15;152(8):4149–4156. [PubMed] [Google Scholar]
- Kono A., Hara Y., Sugata S., Matsushima Y., Ueda T. Substrate specificity of a thymidine phosphorylase in human liver tumor. Chem Pharm Bull (Tokyo) 1984 May;32(5):1919–1921. doi: 10.1248/cpb.32.1919. [DOI] [PubMed] [Google Scholar]
- Maeda K., Chung Y. S., Ogawa Y., Takatsuka S., Sawada T., Onoda N., Nitta A., Arimoto Y., Sowa M. [Malignancy of gastric cancer analyzed by the expression of thymidine phosphorylase]. Gan To Kagaku Ryoho. 1995 Apr;22(5):679–682. [PubMed] [Google Scholar]
- Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966 Mar;50(3):163–170. [PubMed] [Google Scholar]
- McLaren R., Kuzu I., Dunnill M., Harris A., Lane D., Gatter K. C. The relationship of p53 immunostaining to survival in carcinoma of the lung. Br J Cancer. 1992 Oct;66(4):735–738. doi: 10.1038/bjc.1992.348. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- Parums D. V., Cordell J. L., Micklem K., Heryet A. R., Gatter K. C., Mason D. Y. JC70: a new monoclonal antibody that detects vascular endothelium associated antigen on routinely processed tissue sections. J Clin Pathol. 1990 Sep;43(9):752–757. doi: 10.1136/jcp.43.9.752. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- 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]
- Schwartz E. L., Baptiste N., O'Connor C. J., Wadler S., Otter B. A. Potentiation of the antitumor activity of 5-fluorouracil in colon carcinoma cells by the combination of interferon and deoxyribonucleosides results from complementary effects on thymidine phosphorylase. Cancer Res. 1994 Mar 15;54(6):1472–1478. [PubMed] [Google Scholar]
- Sotos G. A., Grogan L., Allegra C. J. Preclinical and clinical aspects of biomodulation of 5-fluorouracil. Cancer Treat Rev. 1994 Jan;20(1):11–49. doi: 10.1016/0305-7372(94)90009-4. [DOI] [PubMed] [Google Scholar]
- 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]
- Tungekar M. F., Gatter K. C., Dunnill M. S., Mason D. Y. Ki-67 immunostaining and survival in operable lung cancer. Histopathology. 1991 Dec;19(6):545–550. doi: 10.1111/j.1365-2559.1991.tb01503.x. [DOI] [PubMed] [Google Scholar]
- 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]
- Veale D., Ashcroft T., Marsh C., Gibson G. J., Harris A. L. Epidermal growth factor receptors in non-small cell lung cancer. Br J Cancer. 1987 May;55(5):513–516. doi: 10.1038/bjc.1987.104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vertongen F., Fondu P., van den Heule B., Cauchie C., Mandelbaum I. M. Thymidine kinase and thymidine phosphorylase activities in various types of leukaemia and lymphoma. Tumour Biol. 1984;5(6):303–311. [PubMed] [Google Scholar]
- 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]