Abstract
Angiogenesis is an independent prognostic indicator in breast cancer. In this report, the relationship between expression of vascular endothclial growth factor (VEGF; a selective mitogen for endothelial cells) and the microvessel density was examined in 103 primary breast cancers. The expression of VEGF was evaluated by immunocytochemical staining using anti‐VEGF antibody. The microvessel density, which was determined by immunostaining for factor VIII antigen, in VEGF‐rich tumors was clearly higher than that in VEGF‐poor tumors (P<0.01). There was a good correlation between VEGF expression and the increment of microvessel density. Furthermore, postoperative survey demonstrated that the relapse‐free survival rate of VEGF‐rich tumors was significantly worse than that of VEGF‐poor tumors. It was suggested that the expression of VEGF is closely associated with the promotion of angiogenesis and with early relapse in primary breast cancer.
Keywords: Angiogenesis, Vascular endothelial growth factor, Breast cancer
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REFERENCES
- 1. ) Folkman , J. , Watson , K. , Ingber , D. and Hanahan , D.Induction of angiogenesis during the transition from hyperplasia to neoplasia . Nature , 339 , 58 – 61 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 2. ) Bicknell , R. and Harris , A. L.Novel growth regulatory factors and tumor angiogenesis . Eur. J. Cancer , 27 , 781 – 784 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 3. ) Weidner , N. , Folkman , J. , Pozza , F. , Bevilacqua , P. , Allied , E. N. , Moore , D. H. , Meli , S. and Gasparini , G.Tumor angiogenesis: a new significant and independent prognostic indicator in early‐stage breast carcinoma . J. Natl. Cancer Inst. , 84 , 1875 – 1887 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 4. ) Horak , E. R. , Leek , R. , Klenk , N. , Lejeune , S. , Smith , K. , Stuart , N. , Greenall , M. , Stepniewska , K. and Harris , A. L.Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer . Lancet , 340 , 1120 – 1124 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 5. ) Bosari , S. , Lee , A. K. C. , DeLellis , R. A. , Wiley , B. D. , Heatley , G. J. and Silverman , M. L.Microvessel quantitation and prognosis in invasive breast carcinoma . Hum. Pathol. , 23 , 755 – 761 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 6. ) Toi , M. , Kashitani , J. and Tominaga , T.Tumor angiogenesis is an independent prognostic indicator in primary breast carcinoma . Int. J. Cancer , 55 , 371 – 374 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 7. ) Ferrara , N. , Houck , K. , Jakeman , L. and Leung , D. W.Molecular and biological properties of the vascular en‐dothelial growth factor family of proteins . Endocr. Rev. , 13 , 18 – 32 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 8. ) Peto , R. , and Peto , J.Asymptotically efficient rank invariant test procedures . J. R. Stat. Soc. (A) , 135 , 185 – 207 ( 1972. ). [Google Scholar]
- 9. ) Cox , D. R.Regression models and life tables . J R. Stat. Soc. Ser. B , 34 , 187 – 220 ( 1972. ). [Google Scholar]
- 10. ) Vries , C. , Escobedo , J. A. , Ueno , H. , Houck , K. , Ferrara , N. and Williams , L. T.The fins‐like tyrosine kinase, a receptor for vascular endothelial growth factor . Science , 255 , 989 – 991 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 11. ) Millauer , B. , Wizigmann‐Voos , S. , Schnurch , H. , Martinez , R. , Moller , N. P. H. , Risau , W. and Ullrich , A.High affinity VEGF binding and developmental expression suggest FLK‐1 as a major regulator of vasculogenesis and angiogenesis . Cell , 12 , 835 – 846 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 12. ) Leung , D. W. , Cachianes , G. , Kuang , W. J. , Goeddel , D. V. and Ferrara , N.Vascular endothelial growth factor is a secreted angiogenic mitogen . Science , 246 , 1306 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 13. ) Claffey , K. P. , Wilkison , W. O. and Spiegelman , B. M.Vascular endothelial growth factor . J. Biol. Chem. , 267 , 16317 – 16322 ( 1992. ). [PubMed] [Google Scholar]
- 14. ) Brown , F. B. , Berse , B. , Jackman , R. W. , Tognazzi , K. , Manseau , E. J. , Dvorak , H. F. and Senger , D. R.Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas . Am. J. Pathol. , 143 , 1255 – 1262 ( 1993. ). [PMC free article] [PubMed] [Google Scholar]
- 15. ) Berkman , R. , Merrill , M. J. , Reinhold , W. C. , Monacci , W. T. , Saxena , A. , Clark , W. C. , Robertson , J. T. , Ali , I. U. and Oldfleld , E. H.Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasmas . J. Clin. Invest. , 91 , 153 – 159 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. ) Cullinan , B. K. and Koos , R. D.Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: rapid stimulation by estrogen correlates with estrogen‐induced increases in uterine capillary permeability and growth . Endocrinology , 133 , 829 – 837 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Goldman , C. K. , Kim , J. , Wong , W. L. , King , V. , Brock , T. and Gillespie , G. Y.Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology . Mol Biol. Cell , 4 , 121 – 133 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. ) Wright , C. , Angus , B. , Nicholson , S. , Sainsbury , J. R. , Cairns , J. , Gullick , W. J. , Kelly , P. , Harris , A. L. and Home , C. H. W.Expression of c‐erbB‐2 oncoprotein: a prognostic indicator in human breast cancer . Cancer Res. , 49 , 2087 – 2090 ( 1989. ). [PubMed] [Google Scholar]
- 19. ) Osaki , A. , Toi , M. , Yamada , H. , Kawami , H. , Kuroi , K. and Toge , T.Prognostic significance of co‐expression of c‐erbB‐2 oncoprotein and epidermal growth factor receptor in breast cancer patients . Am. J. Surg. , 164 , 323 – 326 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 20. ) Kim , K. J. , Li , B. , Winer , J. , Armanini , M. , Illett , N. , Phillips , H. S. and Ferrara , N.Inhibition of vascular endothelial growth factor‐induced angiogenesis suppresses tumor growth in vivo . Nature , 362 , 841 – 844 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 21. ) Kondo , S. , Asano , M. and Suzuki , H.Significance of vascular endothelial growth factor/vascular permeability factor for solid tumor growth, and its inhibition by the antibody , Biochem. Biophys. Res. Commun. , 194 , 1234 – 1241 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 22. ) Toi , M. , Yamamoto , Y. , Imazawa , T. , Takayanagi , T. , Akutsu , K. and Tominaga , T.Antitumor effect of the angiogenesis inhibitor AGM‐1470 and its combination effect with tamoxifen in DMBA induced mammary tumors in rats . Int. J. Clin. Oncol. , 3 , 525 – 528 ( 1993. ). [DOI] [PubMed] [Google Scholar]