Basic fibroblast growth factor and vascular endothelial growth factor serum levels in breast cancer patients and healthy women: useful as diagnostic tools?

Anna Maria Granato, Oriana Nanni, Fabio Falcini, Secondo Folli, Gabriella Mosconi, Franca De Paola, Laura Medri, Dino Amadori, Annalisa Volpi, Anna Maria Granato, Oriana Nanni, Fabio Falcini, Secondo Folli, Gabriella Mosconi, Franca De Paola, Laura Medri, Dino Amadori, Annalisa Volpi

Abstract

Introduction: The aim of the present study was to analyze the relationship between the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in breast cancer cells and the corresponding serum levels in individual patients. The study also evaluated the potential of serum levels of the two growth factors as diagnostic markers in a case-control study.

Methods: VEGF expression and bFGF expression were determined in 62 and 63 tumor samples, respectively. Serum VEGF and bFGF levels were determined in 54 and 65 healthy women and in 69 and 73 breast cancer patients, respectively, using a quantitative sandwich enzyme immunoassay technique.

Results: A direct correlation was observed between VEGF expression and bFGF expression in individual tumors (P = 0.001) and between serum levels (P = 0.038) in individual patients, but not between tumor cell expression and the corresponding serum level for either growth factor. Median values of serum levels in healthy women and breast cancer patients were not different for VEGF (P = 0.055), but were significantly different for bFGF (P < 0.001). The receiver operating characteristic curve identified a serum bFGF concentration of 1.0 pg/ml, with 84.9% sensitivity and 63.1% specificity, as the best cut-off value to discriminate between healthy women and breast cancer patients. An age-based subgroup analysis showed that serum values of patients older than 70 years of age mainly contributed to the high accuracy.

Conclusions: Our data repropose bFGF as a noninvasive diagnostic tool for breast cancer.

Figures

Figure 1
Figure 1
Box plots of (a) vascular endothelial growth factor (VEGF) and (b) basic fibroblast growth factor (bFGF) serum levels. The lower boundary of the box is the 25th percentile and the upper boundary is the 75th percentile. The bold line inside the box represents the median. * Cases with values more than 1.5 box lengths from the upper or lower edge of the box (extreme values). The largest and smallest observed values that are not extreme values are also shown (whiskers).
Figure 2
Figure 2
Receiver operating characteristic curve of (a) vascular endothelial growth factor and (b) basic fibroblast growth factor serum levels. CI, confidence interval.

References

    1. Folkman J. Clinical application of research on angiogenesis. N Engl J Med. 1995;333:1757–1763. doi: 10.1056/NEJM199512283332608.
    1. D'Amore PA. Heparin–endothelial cell interactions. Haemostasis. 1990;Suppl 1:159–165.
    1. Vlodavsky I, Korner G, Ishai-Michaeli R, Bashkin P, Bar-Shavit R, Fuks Z. Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis. Cancer Metastasis Rev. 1990;9:203–226.
    1. 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.
    1. Yamamoto Y, Toi M, Kondo S, Matsumoto T, Suzuki H, Kitamura M, Tsuruta K, Taniguchi T, Okamoto A, Mori T, Yoshida M, Ikeda T, Tominaga T. Concentrations of vascular endothelial growth factor in the sera of normal controls and cancer patients. Clin Cancer Res. 1996;2:821–826.
    1. Takei Y, M Kurobe, A Uchida, K Hayash. Serum concentrations of basic fibroblast growth factor in breast cancer [letter to the editor] Clin Chem. 1994;40:1980–1981.
    1. Heer K, Kumar H, Read JR, Fox JN, Monson JR, Kerin MJ. Serum vascular endothelial growth factor in breast cancer: its relation with cancer type and estrogen receptor status. Clin Cancer Res. 2001;7:3491–3494.
    1. Kraft A, Weindel K, Ochs A, Marth C, Zmija J, Schumacher P, Unger C, Marme D, Gastl G. Vascular endothelial growth factor in the sera and effusions of patients with malignant and non-malignant disease. Cancer. 1999;85:178–187. doi: 10.1002/(SICI)1097-0142(19990101)85:1<178::AID-CNCR25>;2-Z.
    1. Salven P, Perhoniemi V, Tykka H, Maenpaa H, Joensuu H. Serum VEGF levels in women with a benign breast tumor or breast cancer. Breast Cancer Res Treat. 1999;53:161–166. doi: 10.1023/A:1006178517505.
    1. Salven P, Manpaa H, Orpana A, Alitalo K, Joensuu H. Serum vascular endothelial growth factor is often elevated in disseminated cancer. Clin Cancer Res. 1997;3:647–651.
    1. Pichon MF, Moulin G, Pallud C, Pecking A, Floiras JL. Serum bFGF (basic fibroblast growth factor) and CA 15.3 in the monitoring of breast cancer patients. Anticancer Res. 2000;20:1189–1194.
    1. Dirix LY, Vermeulen PB, Pawinski A, Prove A, Benoy I, De Pooter C, Martin M, Van Oosterom AT. Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients. Br J Cancer. 1997;76:238–243.
    1. Sliutz G, Tempfer C, Obermair A, Dadak C, Kainz C. Serum evaluation of basic FGF in breast cancer patients. Anticancer Res. 1995;15:2675–2677.
    1. Findeisen R, Albrecht S, Richter B, Deutschmann K, Zimmermann T, Distler W. Chemiluminometric determination of tissue polypeptide antigen (TPA), cancer antigen 15-3 (CA 15-3), carcinoembryonic antigen (CEA) in comparison with vascular endothelial growth factor (VEGF) in follow-up of breast cancer. Luminescence. 2000;15:283–289. doi: 10.1002/1522-7243(200009/10)15:5<283::AID-BIO593>;2-6.
    1. Adams J, Carder PJ, Downey S, Forbes MA, MacLennan K, Allgar V, Kaufman S, Hallam S, Bicknell R, Walker JJ, Cairnduff F, Selby PJ, Perren TJ, Lansdown M, Banks RE. Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen. Cancer Res. 2000;60:2898–2905.
    1. Emilio A, Aranega A, Sevilla M, Parra G, Villarreal V, Viñas J, Alonso L, Ruiz I, Ribelles N, Gonzalez F. Evolution of serum angiogenic growth factor levels after breast cancer surgery [abstract] ASCO Proc. 2000;19:601.
    1. Verheul HM, Hoekman K, Luykx-de Bakker S, Eekman CA, Folman CC, Broxterman HJ, Pinedo HM. Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res. 1997;3:2187–2190.
    1. Webb NJ, Bottomley MJ, Watson CJ, Brenchley PE. Vascular endothelial growth factor (VEGF) is released from platelets during blood clotting: implications for measurement of circulating VEGF levels in clinical disease. Clin Sci (Lond) 1998;94:395–404.
    1. Banks RE, Forbes MA, Kinsey SE, Stanley A, Ingham E, Walters C, Selby PJ. Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br J Cancer. 1998;77:956–964.
    1. Salgado R, Vermeulen PB, Benoy I, Weytjens R, Huget P, Van Marck E, Dirix LY. Platelet number and interleukin-6 correlate with VEGF but not with bFGF serum levels of advanced cancer patients. Br J Cancer. 1999;80:892–897. doi: 10.1038/sj.bjc.6690437.
    1. Brunner G, Nguyen H, Gabrilove J, Rifkin DB, Wilson EL. Basic fibroblast growth factor expression in human bone marrow and peripheral blood cells. Blood. 1993;81:631–638.
    1. Toi M, Inada K, Suzuki H, Tominaga T. Tumor angiogenesis in breast cancer: its importance as a prognostic indicator and the association with vascular endothelial growth factor expression. Breast Cancer Res Treat. 1995;36:193–204.
    1. Faridi A, Rudlowski C, Biesterfeld S, Schuh S, Rath W, Schroder W. Long-term follow-up and prognostic significance of angiogenic basic fibroblast growth factor (bFGF) expression in patients with breast cancer. Pathol Res Pract. 2002;198:1–5.
    1. Visscher DW, DeMattia F, Ottosen S, Sarkar FH, Crissman JD. Biologic and clinical significance of basic fibroblast growth factor immunostaining in breast carcinoma. Mod Pathol. 1995;8:665–670.
    1. Smith K, Fox SB, Whitehouse R, Taylor M, Greenall M, Clarke J, Harris AL. Upregulation of basic fibroblast growth factor in breast carcinoma and its relationship to vascular density, oestrogen receptor, epidermal growth factor receptor and survival. Ann Oncol. 1999;10:707–713. doi: 10.1023/A:1008303614441.
    1. De Paola F, Granato AM, Scarpi E, Monti F, Medri L, Bianchi S, Amadori D, Volpi A. Vascular endothelial growth factor and prognosis in patients with node-negative breast cancer. Int J Cancer. 2002;98:228–233. doi: 10.1002/ijc.10118.
    1. Hsiung R, Zhu W, Klein G, Qin W, Rosenberg A, Park P, Rosato E, Sauter E. High basic fibroblast growth factor levels in nipple aspirate fluid are correlated with breast cancer. Cancer J. 2002;8:303–310.
    1. Dreisbach L, Cowgill A, Brunn E, Vahedian M, Villar H, Reichlin S, Stopeck A. Random pre-operative VEGF levels are not diagnostic of the presence of breast cancer [abstract] ASCO Proc. 2000;19:2587.
    1. Liu Y, Wang JL, Chang H, Barsky SH, Nguyen M. Breast-cancer diagnosis with nipple fluid bFGF [letter] Lancet. 2000;356:567. doi: 10.1016/S0140-6736(00)02587-3.
    1. Chung HC, Rha SY, Ahn JB, Shim KY, Yoo NC, Kim JH, Roh JK, Lee KS, Min JS, Kim BS, Kim JJ. Menstrual state should be considered in determining sero-positivity of soluble angiogenic factors in breast cancer. Int J Mol Med. 1998;2:465–470.
    1. Wartiovaara U, Salven P, Mikkola H, Lassila R, Kaukonen J, Joukov V, Orpana A, Ristimaki A, Heikinheimo M, Joensuu H, Alitalo K, Palotie A. Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation. Thromb Haemost. 1998;80:171–175.
    1. Mohle R, Green D, Moore MA, Nachman RL, Rafii S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci USA. 1997;94:663–668. doi: 10.1073/pnas.94.2.663.
    1. Dittadi R, Meo S, Fabris F, Gasparini G, Contri D, Medici M, Gion M. Validation of blood collection procedures for the determination of circulating vascular endothelial growth factor (VEGF) in different blood compartments. Int J Biol Markers. 2001;16:87–96.
    1. Bast RC, Jr, Ravdin P, Hayes DF, Bates S, Fritsche H, Jr, Jessup JM, Kemeny N, Locker GY, Mennel RG, Somerfield MR, for the American Society of Clinical Oncology Tumor Markers Expert Panel 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001;19:1865–1878.

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