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Co-determination of the angiogenic factors thymidine phosphorylase and vascular endothelial growth factor in node-negative breast cancer: prognostic implications

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Abstract

Experimental and clinical studies have shown that human breast cancer is an angiogenesis-dependent neoplasm. In fact, several authors have demonstrated that the determination in primary tumors of the degree of vascularization (microvessel counts) as well as of some angiogenic peptides is of prognostic value. However, which are the most important mediators of angiogenesis and their relationship with other relevant biological markers needs further investigation. In the series of 260 women with node-negative breast cancer (NNBC) on which we previously assessed vascular endothelial growth factor (VEGF), we have now also determined thymidine phosphorylase (TP) protein as well as p53 protein and Cathepsin-D cytosolic levels using immunometric methods. The median concentrations of TP, p53 and Cathepsin-D were 105.4U/mg (range 1.2–843.1), 0.22 ng/mg (range 0.0–41.65) and 33.80nmol/mg (range 4.20–216.0), respectively. We found that TP concentrations were associated with Cathepsin-D and p53, but not with VEGF. VEGF (p<0.0001) and p53 (p = 0.03 and p = 0.012, respectively) were found to be statistically significant prognostic variables for both relapse-free survival (RFS) and overall survival in univariate analysis. Conversely, TP and Cathepsin-D levels did not correlate with prognosis. In multivariate analysis for RFS, VEGF levels (p<0.0001), TP levels (p = 0.050) and their first-order interaction terms (p = 0.027) were statistically significant prognostic indicators. Cathepsin-D and p53 protein levels did not retain significance in the model inclusive of all the above variables. The predictive capability of the complete model was satisfactory (Harrell c statistic = 0.72). Moreover, these results suggest a possible potentiation of the capability of predicting the likelihood of recurrence by the co-determination of TP and VEGF. The probability of recurrence was particularly high in the patients with primary tumors characterized by elevated levels of both angiogenic factors. This is the first study showing in vivo that two different angiogenic peptides concur in the progression of human breast cancer. The biology and possible therapeutic implications of this observation are discussed.

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References

  1. Gasparini G. Clinical significance of the determination of angiogenesis in human breast cancer. Update of the biological background and overview of the Vicenza studies. Eur J Cancer 1996; 32A, 2485–93.

    Google Scholar 

  2. Ellis LM, Fidler IJ. Angiogenesis and metastasis. Eur J Cancer 1996; 32A, 2451–2460.

    Google Scholar 

  3. Toi M, Taniguchi T, Yamamoto Y, Kurisaki T, Suzuki H, Tominaga T. Clinical significance of the determination of angiogenic factors. Eur J Cancer 1996; 32A, 2513–2519.

    Google Scholar 

  4. Page DL, Jensen RA. Angiogenesis in human breast carcinoma: what is the question? Human Pathol 1995; 26, 1173–1174.

    Google Scholar 

  5. Simpson JF, Battifora H. Angiogenesis as a prognostic factor in breast cancer: can we count on it? Appl Immunohistochem 1995; 3, 73–74.

    Google Scholar 

  6. Walker RA. Angiogenesis and breast cancer prognosis—a continuous issue. J Pathol 1996; 180, 6–7.

    Google Scholar 

  7. Vermeulen PB, Gasparini G, Fox SB, et al. Quantification of angiogenesis in solid human tumours: an international consensus on the methodology and criteria of evaluation. Eur J Cancer 1996; 32A, 2474–2484.

    Google Scholar 

  8. Toi M, Kondo S, Suzuki H, et al. Quantitative analysis on vascular endothelial growth factor in primary breast cancer. Cancer 1996; 77, 1101–1106.

    Google Scholar 

  9. Gasparini G, Toi M, Gion M, et al. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst 1997; 89, 139–147.

    Google Scholar 

  10. Nguyen M, Watanabe H, Budson AE, Richie JP, Hayes DF, Folkman J. Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers. J Natl Cancer Inst 1994; 86, 356–361.

    Google Scholar 

  11. Taniguchi T, Toi M, Inada K, Imazawa T, Yamamoto Y, Tominaga T. Serum concentrations of hepatocyte growth factor in breast cancer patients. Clin Cancer Res 1995; 1, 1031–1034.

    Google Scholar 

  12. Yamamoto Y, Toi M, Kondo S, et al. Concentrations of vascular endothelial growth factor in sera of normal controls and cancer patients. Clin Cancer Res 1996; 2, 821–826.

    Google Scholar 

  13. Gasparini G. Angiogenesis research up to 1996. A commentary on the state of art and suggestions for future studies. Eur J Cancer 1996; 32A, 2379–2385.

    Google Scholar 

  14. Goto F, Goto K, Weindel K, Folkman J. Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels. Lab Invest 1993; 69, 508–517.

    Google Scholar 

  15. Koolwijk P, van Erck MGM, de Vree WJA, et al. Cooperative effect of TNFα, bFGF, and VEGF on the formation of tubular structures of human microvascular endothelial cells in a fibrin matrix. Role of urokinase activity. J Cell Biol 1996; 132, 1177–1188.

    Google Scholar 

  16. Bouck N. p53 and angiogenesis. Biochim Biophys Acta 1996; 1287, 63–66.

    Google Scholar 

  17. Gasparini G, Harris AL. p53 and angiogenesis in neoplasia. In: Klijn JGM (ed.), ESO Scientific Updates. Vol. 1. Prognostic and Predictive value of p53. Amsterdam: Elsevier 1997; 115–130.

    Google Scholar 

  18. Gasparini G. Angiogenesis in endocrine-related tumours. Endocr-Rel Cancer 1997; 4, in press.

  19. Moghaddam A, Zhang H-T, Fan T-PD, et al. Thymidine phosphorylase is angiogenic and promotes tumor growth. Proc Natl Acad Sci USA 1995; 92, 998–1002.

    Google Scholar 

  20. Harris CC. Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies. J Natl Cancer Inst 1996; 88, 1442–1445.

    Google Scholar 

  21. Ravdin PM, Tandon AK, Allred DC, et al. Cathepsin-D by western blotting and immunohistochemistry: failure to confirm correlations with prognosis in node-negative breast cancer. J Clin Oncol 1994; 12, 467–474.

    Google Scholar 

  22. Gion M, Mione R, Dittadi R, et al. Relationship between Cathepsin-D and other pathological and biological parameters in 1752 patients with primary breast cancer. Eur J Cancer 1995; 31, 671–677.

    Google Scholar 

  23. Revision of the standards for the assessment of hormone receptors in human breast cancer. Report of the second EORTC Workshop, held on 16–17 March, 1979 at The Netherlands Cancer Institute. Eur J Cancer 1980; 16, 1513–1515.

    Google Scholar 

  24. Nishida M, Hino A, Mori K, et al. Preparation of anti-human thymidine phosphorylase monoclonal antibodies useful for detecting the enzyme levels in tumor tissues. Biol Pharm Bull 1996; 11, 1407–1411.

    Google Scholar 

  25. Borg A, Lennerstrand J, Stenmark-Askmalm M, et al. Prognostic significance of p53 overexpression in primary breast cancer; a novel luminometric immunoassay applicable on steroid receptor cytosols. Br J Cancer 1995; 71, 1013–1017.

    Google Scholar 

  26. Marubini E, Valsecchi MG (Eds). Analysing Survival Data from Clinical Trials and Observational Studies. Chichester: John Wiley: 1995.

    Google Scholar 

  27. Durrleman S and Simon R. Flexible regression models with cubic splines. Stat Med 1989; 8, 551–561.

    Google Scholar 

  28. Harrell FE, Lee KL, Mark DB. Tutorial in biostatistics. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med 1996; 15, 361–387.

    Google Scholar 

  29. Akaike H. Information theory and an extension of the Maximum Likelihood Principle. In: Patrov BN, Csaki F (eds), Proc 2nd Int Symp on Information Theory. Budapest: Akademia Kiedo 1973.

    Google Scholar 

  30. Gasparini G, Bonoldi E, Viale G, et al. Prognostic and predictive value of tumor angiogenesis in ovarian carcinomas. Int J Cancer (Pred Oncol) 1996; 69, 205–211.

    Google Scholar 

  31. Folkman J. Clinical applications of research on angiogenesis. N Engl J Med 1995; 333, 1757–1763.

    Google Scholar 

  32. Hanahan D, Folkman J. Patterns of emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86, 353–364.

    Google Scholar 

  33. Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK. Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc Natl Acad Sci USA 1996; 93, 14765–14770.

    Google Scholar 

  34. Gabrilovich DI, Chen HL, Girgis KR, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 1996; 2, 1096–1103.

    Google Scholar 

  35. Ishikawa F, Miyazono K, Hellman U, et al. Identification of angiogenic acitivity and the cloning and expression of platelet-derived endothelial cell growth factor. Nature 1989; 338, 557–562.

    Google Scholar 

  36. Furukawa T, Yoshimura A, Sumizawa T, Haraguchi M, Akiyama S-I. Angiogenic factor. Nature 1992; 356, 668.

    Google Scholar 

  37. Haraguchi M, Kazutaka M, Uemura K, et al. Angiogenic activity of enzymes. Nature 1994; 368, 198.

    Google Scholar 

  38. Gruber BL, Marchese MJ, Kew R. Angiogenic factors stimulate mast-cell migration. Blood 1995; 86, 2488–2493.

    Google Scholar 

  39. Patterson A, Zhang H, Moghaddam A, et al. 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; 72, 669–675.

    Google Scholar 

  40. Gasparini G, Presta M. Clinical studies with angiogenesis inhibitors: biological rationale and challenges for their evaluation. Ann Oncol 1996; 7, 441–444.

    Google Scholar 

  41. O'Reilly MS, Holmgren L, Chen C, Folkman J. Angiostatin induces and sustains dormancy of human primary tumors. Nat Med 1996; 2, 689–692.

    Google Scholar 

  42. Ferrara N. Vascular endothelial growth factor. Eur J Cancer 1996; 32A, 2413–2422.

    Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan

    Masakazu Toi & Takeshi Tominaga

  2. Tumoral Biomarkers Laboratory, Regional Medical Centre, Venice, Italy

    Massimo Gion & Ruggero Dittadi

  3. Division of Medical Statistics and Biometry, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy

    Elia Biganzoli, Patrizia Boracchi & Rosalba Miceli

  4. St Bortolo Regional Medical Centre, Vicenza, Italy

    Salvatore Meli

  5. Nippon Roche Research Centre, Kamakura, Kanagawa, Japan

    Kazushige Mori

  6. Azienda Ospedali Riuniti, Reggio Calabria, Italy

    Giampietro Gasparini

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  1. Masakazu Toi
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  2. Massimo Gion
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Toi, M., Gion, M., Biganzoli, E. et al. Co-determination of the angiogenic factors thymidine phosphorylase and vascular endothelial growth factor in node-negative breast cancer: prognostic implications. Angiogenesis 1, 71–83 (1997). https://doi.org/10.1023/A:1018305132489

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  • DOI: https://doi.org/10.1023/A:1018305132489

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