Abstract
High microvessel density, an indirect measure of angiogenesis, has been shown to correlate with increased tumour size, lymph node involvement and poor prognosis in non-small-cell lung cancer (NSCLC). Tumour cell vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) expression correlate with angiogenesis and a poor outcome in this disease. In a retrospective study VEGF and PD-ECGF expression and microvessel density were evaluated immunohistochemically in surgically resected specimens (T1–3, N0–2) from 223 patients with operable NSCLC using the VG1, P-GF.44C and JC70 monoclonal antibodies respectively. High VEGF immunoreactivity was seen in 104 (46.6%) and PD-ECGF in 72 (32.3%) cases and both were associated with high vascular grade tumours (P = 0.009 and P = 0.05 respectively). Linear regression analysis revealed a weak positive correlation between VEGF and PD-ECGF expression in cancer cells (r = 0.21;P = 0.002). Co-expression of VEGF and PD-ECGF was not associated with a higher microvessel density than VEGF or PD-ECGF only expressing tumours. Furthermore a proportion of high vascular grade tumours expressed neither growth factor. Univariate analysis revealed tumour size, nodal status, microvessel density and VEGF and PD-ECGF expression as significant prognostic factors. Tumour size (P< 0.02) and microvessel density (P< 0.04) remained significant on multivariate analysis. In conclusion, VEGF and PD-ECGF are important angiogenic growth factors and have prognostic significance in NSCLC. Furthermore the study underlines the prognostic significance of microvessel density in operable NSCLC. © 2000 Cancer Research Campaign
Keywords: vascular endothelial growth factor, platelet-derived endothelial cell growth factor, angiogenesis, non-small cell lung cancer
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- Amaya H., Tanigawa N., Lu C., Matsumura M., Shimomatsuya T., Horiuchi T., Muraoka R. Association of vascular endothelial growth factor expression with tumor angiogenesis, survival and thymidine phosphorylase/platelet-derived endothelial cell growth factor expression in human colorectal cancer. Cancer Lett. 1997 Nov 11;119(2):227–235. doi: 10.1016/s0304-3835(97)00280-2. [DOI] [PubMed] [Google Scholar]
- Apolinario R. M., van der Valk P., de Jong J. S., Deville W., van Ark-Otte J., Dingemans A. M., van Mourik J. C., Postmus P. E., Pinedo H. M., Giaccone G. Prognostic value of the expression of p53, bcl-2, and bax oncoproteins, and neovascularization in patients with radically resected non-small-cell lung cancer. J Clin Oncol. 1997 Jun;15(6):2456–2466. doi: 10.1200/JCO.1997.15.6.2456. [DOI] [PubMed] [Google Scholar]
- Arenberg D. A., Polverini P. J., Kunkel S. L., Shanafelt A., Hesselgesser J., Horuk R., Strieter R. M. The role of CXC chemokines in the regulation of angiogenesis in non-small cell lung cancer. J Leukoc Biol. 1997 Nov;62(5):554–562. doi: 10.1002/jlb.62.5.554. [DOI] [PubMed] [Google Scholar]
- Budman D. R., Meropol N. J., Reigner B., Creaven P. J., Lichtman S. M., Berghorn E., Behr J., Gordon R. J., Osterwalder B., Griffin T. Preliminary studies of a novel oral fluoropyrimidine carbamate: capecitabine. J Clin Oncol. 1998 May;16(5):1795–1802. doi: 10.1200/JCO.1998.16.5.1795. [DOI] [PubMed] [Google Scholar]
- Chandrachud L. M., Pendleton N., Chisholm D. M., Horan M. A., Schor A. M. Relationship between vascularity, age and survival in non-small-cell lung cancer. Br J Cancer. 1997;76(10):1367–1375. doi: 10.1038/bjc.1997.562. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ferrara N., Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997 Feb;18(1):4–25. doi: 10.1210/edrv.18.1.0287. [DOI] [PubMed] [Google Scholar]
- Fontanini G., Boldrini L., Chinè S., Pisaturo F., Basolo F., Calcinai A., Lucchi M., Mussi A., Angeletti C. A., Bevilacqua G. Expression of vascular endothelial growth factor mRNA in non-small-cell lung carcinomas. Br J Cancer. 1999 Jan;79(2):363–369. doi: 10.1038/sj.bjc.6690058. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fontanini G., Lucchi M., Vignati S., Mussi A., Ciardiello F., De Laurentiis M., De Placido S., Basolo F., Angeletti C. A., Bevilacqua G. Angiogenesis as a prognostic indicator of survival in non-small-cell lung carcinoma: a prospective study. J Natl Cancer Inst. 1997 Jun 18;89(12):881–886. doi: 10.1093/jnci/89.12.881. [DOI] [PubMed] [Google Scholar]
- Fox S. B., Engels K., Comley M., Whitehouse R. M., Turley H., Gatter K. C., Harris A. L. Relationship of elevated tumour thymidine phosphorylase in node-positive breast carcinomas to the effects of adjuvant CMF. Ann Oncol. 1997 Mar;8(3):271–275. doi: 10.1023/a:1008280110558. [DOI] [PubMed] [Google Scholar]
- Fox S. B., Leek R. D., Weekes M. P., Whitehouse R. M., Gatter K. C., Harris A. L. Quantitation and prognostic value of breast cancer angiogenesis: comparison of microvessel density, Chalkley count, and computer image analysis. J Pathol. 1995 Nov;177(3):275–283. doi: 10.1002/path.1711770310. [DOI] [PubMed] [Google Scholar]
- Giatromanolaki A., Koukourakis M. I., Comley M., Kaklamanis L., Turley H., O'Byrne K., Harris A. L., Gatter K. C. Platelet-derived endothelial cell growth factor (thymidine phosphorylase) expression in lung cancer. J Pathol. 1997 Feb;181(2):196–199. doi: 10.1002/(SICI)1096-9896(199702)181:2<196::AID-PATH763>3.0.CO;2-U. [DOI] [PubMed] [Google Scholar]
- Giatromanolaki A., Koukourakis M. I., Kakolyris S., Turley H., O'Byrne K., Scott P. A., Pezzella F., Georgoulias V., Harris A. L., Gatter K. C. Vascular endothelial growth factor, wild-type p53, and angiogenesis in early operable non-small cell lung cancer. Clin Cancer Res. 1998 Dec;4(12):3017–3024. [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]
- Harris A. L. Are angiostatin and endostatin cures for cancer? Lancet. 1998 May 30;351(9116):1598–1599. doi: 10.1016/S0140-6736(98)22022-8. [DOI] [PubMed] [Google Scholar]
- Igarashi M., Dhar D. K., Kubota H., Yamamoto A., El-Assal O., Nagasue N. The prognostic significance of microvessel density and thymidine phosphorylase expression in squamous cell carcinoma of the esophagus. Cancer. 1998 Apr 1;82(7):1225–1232. doi: 10.1002/(sici)1097-0142(19980401)82:7<1225::aid-cncr3>3.0.co;2-e. [DOI] [PubMed] [Google Scholar]
- Ikeda N., Adachi M., Taki T., Huang C., Hashida H., Takabayashi A., Sho M., Nakajima Y., Kanehiro H., Hisanaga M. Prognostic significance of angiogenesis in human pancreatic cancer. Br J Cancer. 1999 Mar;79(9-10):1553–1563. doi: 10.1038/sj.bjc.6690248. [DOI] [PMC free article] [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]
- Jäger R., Noll K., Havemann K., Pflüger K. H., Knabbe C., Rauvala H., Zugmaier G. Differential expression and biological activity of the heparin-binding growth-associated molecule (HB-GAM) in lung cancer cell lines. Int J Cancer. 1997 Nov 14;73(4):537–543. doi: 10.1002/(sici)1097-0215(19971114)73:4<537::aid-ijc14>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
- Kim K. J., Li B., Winer J., Armanini M., Gillett N., Phillips H. S., Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993 Apr 29;362(6423):841–844. doi: 10.1038/362841a0. [DOI] [PubMed] [Google Scholar]
- Koomägi R., Volm M. Tissue-factor expression in human non-small-cell lung carcinoma measured by immunohistochemistry: correlation between tissue factor and angiogenesis. Int J Cancer. 1998 Feb 20;79(1):19–22. doi: 10.1002/(sici)1097-0215(19980220)79:1<19::aid-ijc4>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
- Koukourakis M. I., Giatromanolaki A., Kakolyris S., O'Byrne K. J., Apostolikas N., Skarlatos J., Gatter K. C., Harris A. L. Different patterns of stromal and cancer cell thymidine phosphorylase reactivity in non-small-cell lung cancer: impact on tumour neoangiogenesis and survival. Br J Cancer. 1998 May;77(10):1696–1703. doi: 10.1038/bjc.1998.280. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lin P., Sankar S., Shan S., Dewhirst M. W., Polverini P. J., Quinn T. Q., Peters K. G. Inhibition of tumor growth by targeting tumor endothelium using a soluble vascular endothelial growth factor receptor. Cell Growth Differ. 1998 Jan;9(1):49–58. [PubMed] [Google Scholar]
- Macaulay V. M., O'Byrne K. J., Saunders M. P., Braybrooke J. P., Long L., Gleeson F., Mason C. S., Harris A. L., Brown P., Talbot D. C. Phase I study of intrapleural batimastat (BB-94), a matrix metalloproteinase inhibitor, in the treatment of malignant pleural effusions. Clin Cancer Res. 1999 Mar;5(3):513–520. [PubMed] [Google Scholar]
- Maeda K., Kang S. M., Ogawa M., Onoda N., Sawada T., Nakata B., Kato Y., Chung Y. S., Sowa M. Combined analysis of vascular endothelial growth factor and platelet-derived endothelial cell growth factor expression in gastric carcinoma. Int J Cancer. 1997 Oct 21;74(5):545–550. doi: 10.1002/(sici)1097-0215(19971021)74:5<545::aid-ijc12>3.0.co;2-5. [DOI] [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]
- Oshika Y., Nakamura M., Tokunaga T., Ozeki Y., Fukushima Y., Hatanaka H., Abe Y., Yamazaki H., Kijima H., Tamaoki N. Expression of cell-associated isoform of vascular endothelial growth factor 189 and its prognostic relevance in non-small cell lung cancer. Int J Oncol. 1998 Mar;12(3):541–544. doi: 10.3892/ijo.12.3.541. [DOI] [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]
- Pezzella F., Pastorino U., Tagliabue E., Andreola S., Sozzi G., Gasparini G., Menard S., Gatter K. C., Harris A. L., Fox S. Non-small-cell lung carcinoma tumor growth without morphological evidence of neo-angiogenesis. Am J Pathol. 1997 Nov;151(5):1417–1423. [PMC free article] [PubMed] [Google Scholar]
- Schor A. M., Pazouki S., Morris J., Smither R. L., Chandrachud L. M., Pendleton N. Heterogeneity in microvascular density in lung tumours: comparison with normal bronchus. Br J Cancer. 1998 Mar;77(6):946–951. doi: 10.1038/bjc.1998.156. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Skobe M., Rockwell P., Goldstein N., Vosseler S., Fusenig N. E. Halting angiogenesis suppresses carcinoma cell invasion. Nat Med. 1997 Nov;3(11):1222–1227. doi: 10.1038/nm1197-1222. [DOI] [PubMed] [Google Scholar]
- Takahashi Y., Bucana C. D., Akagi Y., Liu W., Cleary K. R., Mai M., Ellis L. M. Significance of platelet-derived endothelial cell growth factor in the angiogenesis of human gastric cancer. Clin Cancer Res. 1998 Feb;4(2):429–434. [PubMed] [Google Scholar]
- Takebayashi Y., Akiyama S., Akiba S., Yamada K., Miyadera K., Sumizawa T., Yamada Y., Murata F., Aikou T. Clinicopathologic and prognostic significance of an angiogenic factor, thymidine phosphorylase, in human colorectal carcinoma. J Natl Cancer Inst. 1996 Aug 21;88(16):1110–1117. doi: 10.1093/jnci/88.16.1110. [DOI] [PubMed] [Google Scholar]
- Toi M., Inada K., Hoshina S., Suzuki H., Kondo S., Tominaga T. Vascular endothelial growth factor and platelet-derived endothelial cell growth factor are frequently coexpressed in highly vascularized human breast cancer. Clin Cancer Res. 1995 Sep;1(9):961–964. [PubMed] [Google Scholar]
- Turley H., Scott P. A., Watts V. M., Bicknell R., Harris A. L., Gatter K. C. Expression of VEGF in routinely fixed material using a new monoclonal antibody VG1. J Pathol. 1998 Nov;186(3):313–318. doi: 10.1002/(SICI)1096-9896(1998110)186:3<313::AID-PATH188>3.0.CO;2-X. [DOI] [PubMed] [Google Scholar]
- Volm M., Koomägi R., Mattern J. Interrelationships between microvessel density, expression of VEGF and resistance to doxorubicin of non-small lung cell carcinoma. Anticancer Res. 1996 Jan-Feb;16(1):213–217. [PubMed] [Google Scholar]
- Whittle C., Gillespie K., Harrison R., Mathieson P. W., Harper S. J. Heterogeneous vascular endothelial growth factor (VEGF) isoform mRNA and receptor mRNA expression in human glomeruli, and the identification of VEGF148 mRNA, a novel truncated splice variant. Clin Sci (Lond) 1999 Sep;97(3):303–312. [PubMed] [Google Scholar]
- van Zandwijk N., Giaccone G. Treatment of metastatic non-small cell lung cancer. Curr Opin Oncol. 1996 Mar;8(2):120–125. doi: 10.1097/00001622-199603000-00008. [DOI] [PubMed] [Google Scholar]