Platelet number and interleukin-6 correlate with VEGF but not with bFGF serum levels of advanced cancer patients

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Summary

We have compared the platelet number and the serum concentration of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and interleukin-6 (IL-6) in 80 blood samples of 50 patients with advanced cancer. We have also measured the mitogenic effect of patient sera on endothelial cells in vitro in order to estimate the biological activity of serum VEGF. Serum VEGF concentration correlated with platelet number (r = 0.61; P < 10–4). Serum IL-6 levels correlated with platelet count (r = 0.36; P < 10–3), with serum VEGF levels (r = 0.55; P < 10–4) and with the calculated load of VEGF per platelet (r = 0.4; P = 3 × 10–4). Patients with thrombocytosis had a median VEGF serum concentration which was 3.2 times higher (P < 10–4) and a median IL-6 serum level which was 5.8 times higher (P = 0.03) than in other patients. Serum bFGF did not show an association with any of the other parameters. Patient sera with high VEGF and bFGF content stimulated endothelial cell proliferation significantly more than other sera (P = 4 × 10–3). These results support the role of platelets in the storage of biologically active VEGF. Platelets seem to prevent circulating VEGF from inducing the development of new blood vessels except at sites where coagulation takes place. IL-6, besides its thrombopoietic effect, also seems to affect the amount of VEGF stored in the platelets. This is in accordance with the indirect angiogenic action of IL-6 reported previously. The interaction of IL-6 with the angiogenic pathways in cancer might explain the stimulation of tumour growth occasionally observed during IL-6 administration. It also conforms to the worse outcome associated with high IL-6 levels and with thrombocytosis in several tumour types and benign angiogenic diseases.

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  • 16 November 2011

    This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication

References

  1. Banks, R. E., Forbes, M. A., Kinsey, S. E., Stanley, A., Ingham, E., Walters, C. & Selby, P. J. (1998). Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br J Cancer 77: 956–964.

    CAS  Article  Google Scholar 

  2. Blay, J. Y., Negrier, S., Combaret, V., Attali, S., Goillot, E., Merrouche, Y., Mercatello, A., Ravault, A., Tourani, J. M., Moskovtchenko, J. F. & Philip, T. (1992). Serum levels of interleukin 6 as a prognostic factor in metastatic renal cell carcinoma. Cancer Res 52: 3317–3322.

    CAS  PubMed  Google Scholar 

  3. Bousvaros, A., Zurakowski, D., Fishman, S. J., Keough, K., Law, T., Sun, C. & Leichter, A. M. (1997). Serum basic fibroblast growth factor in pediatric Crohn’s disease. Implications for wound healing. Dig Dis Sci 42: 378–386.

    CAS  Article  Google Scholar 

  4. Brekken, R. A., Huang, X., King, S. W. & Thorpe, P. E. (1998). Vascular endothelial growth factor as a marker of tumor endothelium. Cancer Res 58: 1952–1959.

    CAS  PubMed  Google Scholar 

  5. Bross, D. A., Leichtner, A. M., Zurakowski, D., Law, T. & Bousvaros, A. (1996). Elevation of serum interleukin-6 but not serum-soluble interleukin-2 receptor in children with Crohn’s disease. J Pediatr Gastroenterol Nutr 23: 164–171.

    CAS  Article  Google Scholar 

  6. Clarke, D., Johnson, P. W. M., Banks, R. E., Storr, M., Kinsey, S. E., Johnson, R., Morgan, G., Gordon, M. Y., lllingworth, J. M., Perren, T. J. & Selby, P. J. (1996). Cytokine 8: 717–723.

    CAS  Article  Google Scholar 

  7. Cohen, T., Nahari, D., Weiss Cerem, L., Neufeld, G. & Levi, B. (1996). Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem 271: 736–741.

    CAS  Article  Google Scholar 

  8. Degeorges, A., Tatoud, R., Fauvel-Lafeve, F., Podgorniak, M-P, Millot, G., De Cremoux, P. & Calvo, F. (1996). Stromal cells from human benign prostate hyperplasia produce a growth-inhibitory factor for LNCaP prostate cancer cells, identified as interleukin-6. Int J Cancer 68: 207–214.

    CAS  Article  Google Scholar 

  9. Duensig, S., Grosse, J. & Atzpodien, J. (1995). Increased serum levels of basic fibroblast growth factor (bFGF) are associated with progressive lung metastases in advanced renal cell carcinoma patients. Anticancer Res 15: 2331–2334.

    Google Scholar 

  10. Dvorak, H. F. (1986). Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315: 1650–1659.

    CAS  Article  Google Scholar 

  11. Dirix, L. Y., Vermeulen, P. B., Hubens, G., Benoy, I., Martin, M., De Pooter, C. & Van Oosterom, A. T. (1996). Serum basic fibroblast growth factor and vascular endothelial growth factor and tumour growth kinetics in advanced colorectal cancer. Ann Oncol 7: 843–848.

    CAS  Article  Google Scholar 

  12. Dirix, L. Y., Vermeulen, P. B., Pawinski, A., Prové, A., Benoy, I., De Pooter, C., Martin, M. & Van Oosterom, A. T. (1997). Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients. Br J Cancer 76: 238–243.

    CAS  Article  Google Scholar 

  13. Dosquet, C., Coudert, M-C, Lepage, E., Cabane, J. & Richard, F. (1997). Are angiogenic factors, cytokines, and soluble adhesion molecules prognostic factors in patients with renal cell carcinoma?. Clin Cancer Res 3: 2451–2458.

    CAS  PubMed  Google Scholar 

  14. Ferriere, J. P., Bernard, D., Legros, M., Chassagne, J., Chollet, P., Gaillard, G. & Plagne, R. (1985). β-Thromboglobulin in patients with breast cancer. Am J Hematol 19: 47–53.

    CAS  Article  Google Scholar 

  15. Folkman, J. (1990). What is the evidence that tumors are angiogenesis dependent?. J Natl Cancer Inst 82: 4–6.

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  17. Handagama, P. J., Shuman, M. A. & Bainston, D. F. (1987). Incorporation of intravenously injected albumin, immunoglobulin G, and fibrinogen in guinea pig megakaryocyte granules. J Clin Invest 84: 73–82.

    Article  Google Scholar 

  18. Harrison, P., Wilbourn, B., Debili, N., Vainchenker, W., Breton-Gorius, J., Lawrie, A. S., Masse, J-M, Savidge, G. F. & Cramer, E. M. (1989). Uptake of plasma fibrogen into the alpha granules of human megakaryocytes and platelets. J Clin Invest 84: 1320–1324.

    CAS  Article  Google Scholar 

  19. Ishibashi, T., Kimura, H., Shikama, Y., Uchida, T., Kariyone, S., Hirano, T., Kishimoto, T., Takatsuki, F. & Akiyama, Y. (1989). Interleukin-6 is a potent thrombopoietic factor in vivo in mice. Blood 74: 1241–1244.

    CAS  PubMed  Google Scholar 

  20. Jaffe, E. A., Nachman, R. L., Becker, C. G. & Minick, C. R. (1973). Culture of human endothelial cells derived from umbilical veins. J Clin Invest 52: 2745–2756.

    CAS  Article  Google Scholar 

  21. Kaushansky, K. (1995). Thrombopoietin: the primary regulator of platelet production. Blood 86: 419–431.

    CAS  PubMed  Google Scholar 

  22. Kumar, H., Heer, K., Lee, P. W. R., Duthie, G. S., MacDonald, A. W., Greenman, J., Kerin, M. J. & Monson, J. R. T. (1998). Preoperative serum vascular endothelial growth factor can predict stage in colorectal cancer. Clin Cancer Res 4: 1279–1285.

    CAS  PubMed  Google Scholar 

  23. Lake, A. M., Stauffer, J. Q. & Stuart, M. J. (1978). Hemostatic alterations in inflammatory bowel disease: response to therapy. Am J Dig Dis 23: 897–902.

    CAS  Article  Google Scholar 

  24. Liotta, L. A. & Saidel, G. M. (1974). Quantitative relationship of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res 34: 997–1004.

    CAS  PubMed  Google Scholar 

  25. Mateo, R. B., Reichner, J. S. & Albina, J. E. (1994). Interleukin-6 activity in wounds. Am J Physiol 266: R1840–1844.

    CAS  PubMed  Google Scholar 

  26. Milroy, R., Douglas, J. T., Campbell, J., Carter, R., Lowe, G. D. & Banham, S. W. (1988). Abnormal haemostasis in small cell lung cancer. Thorax 43: 978–981.

    CAS  Article  Google Scholar 

  27. Möhle, R., Green, D., Moore, M. A. S., Nachman, R. L. & Rafii, S. (1997). Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci USA 94: 663–668.

    Article  Google Scholar 

  28. Møller Pedersen, L. M. & Milman, N. (1996). Prognostic significance of thrombocytosis in patients with primary lung cancer. Eur Respir J 9: 1826–1830.

    Article  Google Scholar 

  29. Motro, B., Itin, A., Sachs, L. & Keshet, E. (1990). Pattern of interleukin 6 gene expression in vivo suggests a role for this cytokine in angiogenesis. Proc Natl Acad Sci USA 87: 3092–3096.

    CAS  Article  Google Scholar 

  30. Nakano, T., Chaninian, A. P., Shinjo, M., Tonomura, A., Miyake, M., Togawa, N., Ninomiya, K. & Higashino, K. (1998). Interleukin 6 and its relationship to clinical parameters in patients with malignant pleural mesothelioma. Br J Cancer 77: 907–912.

    CAS  Article  Google Scholar 

  31. Rak, J. W., Hegmann, E. J., Lu, C. & Kerbel, R. S. (1994). Progressive loss of sensitivity to endothelium-derived growth inhibitors expressed by human melanoma cells during disease progression. J Cell Physiol 159: 245–255.

    CAS  Article  Google Scholar 

  32. Rak, J., Filmus, J. & Kerbel, R. S. (1996). Reciprocal paracrine interactions between tumour cells and endothelial cells: ‘angiogenesis progression’ hypothesis. Eur J Cancer 32A: 2438–2450.

    CAS  Article  Google Scholar 

  33. Ravoet, C., De Grève, J., Vandewoude, K., Kerger, J., Sculier, J-P, Lacor, P., Stryckmans, P. & Piccart, M. (1994). Tumour stimulating effects of recombinant human interleukin-6. Lancet 344: 1576–1577.

    CAS  Article  Google Scholar 

  34. Salven, P., Teerenhovi, L. & Joensuu, H. (1997). A high pretreatment serum vascular endothelial growth factor concentration is associated with poor outcome in non-Hodgkin’s lymphoma. Blood 90: 3167–3172.

    CAS  PubMed  Google Scholar 

  35. Salven, P., Ruotsalainen, Mattson, K. & Joensuu, H. (1998). High pretreatment serum level of vascular endothelial growth factor (VEGF) is associated with poor outcome in small cell lung cancer. Int J Cancer 79: 144–146.

    CAS  Article  Google Scholar 

  36. Skobe, M., Rockwell, P., Goldstein, N., Vosseler, S. & Fusenig, N. E. (1997). Halting angiogenesis suppresses carcinoma cell invasion. Nat Med 11: 1222–1227.

    Article  Google Scholar 

  37. Vadhan-Raj, S., Murray, L. J., Bueso-Ramos, C., Patel, S., Reddy, S. P., Hoots, W. K., Johnston, T., Papadopoulos, N. E., Hittelman, W. N., Johnston, D. A., Yang, T. A., Paton, V. E., Cohen, R. L., Hellmann, S. D., Benjamin, R. S. & Broxmeyer, H. E. (1997). Stimulation of megakaryocyte and platelet production by a single dose of recombinant human thrombopoietin in patients with cancer. Ann Intern Med 126: 731–3.

    Article  Google Scholar 

  38. Verheul, H. M. W., Hoekman, K., Luykx-de Bakker, S., Eekman, C. A., Folman, C. C., Broxterman, H. J. & Pinedo, H. M. (1997). Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 3: 2187–2190.

    CAS  PubMed  Google Scholar 

  39. Vermeulen, P. B., Gasparini, G., Fox, S. B., Toi, M., Martin, L., McCulloch, P., Pezzella, F., Viale, G., Weidner, N., Harris, A. L. & Dirix, L. Y. (1996). Quantification of angiogenesis in solid human tumours: an international consensus on the methodology and criteria of evaluation. Eur J Cancer 32A: 2474–2484.

    CAS  Article  Google Scholar 

  40. Vermeulen, P. B., Dirix, L. Y., Martin, M., Lemmens, J. & Van Oosterom, A. T. (1997). The predictive value of serum bFGF and VEGF in patients with metastatic renal cell carcinoma treated with interferon α-2b. J Natl Cancer Inst 89: 1317

    Article  Google Scholar 

  41. Wartiovaara, U., Salven, P., Mikkola, H., Lassila, R., Kaukonen, J., Joukov, V., Orpana, A., Ristimäki, A., Heikinheimo, M., Joensuu, H., Alitalo, K. & Palotie, A. (1998). Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation. Thromb Haemost 80: 171–175.

    CAS  Article  Google Scholar 

  42. Weber, J., Yang, J. C., Topalian, S. L., Parkinson, D. R., Schwartzentruber, D. S., Ettinghausen, S. E., Gunn, H., Mixon, A., Kim, H. & Cole, D. (1993). Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies. J Clin Oncol 11: 499–506.

    CAS  Article  Google Scholar 

  43. Yazaki, T., Inage, H., Iizumi, T., Koyama, A., Kanoh, S., Koiso, K., Narita, M. & Tojo, S. (1987). Studies on platelet function in patients with prostatic cancer. Preliminary report. Urology 30: 60–63.

    CAS  Article  Google Scholar 

  44. Yan, S. F., Tritto, I., Pinsky, D., Liao, H., Huang J Fuller, G., Brett, J., May, L. & Stern, D. (1995). Induction of interleukin 6 (IL-6) by hypoxia in vascular cells. J Biol Chem 270: 11463–11471.

    CAS  Article  Google Scholar 

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Correspondence to L Y Dirix.

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Salgado, R., Vermeulen, P., Benoy, I. et al. Platelet number and interleukin-6 correlate with VEGF but not with bFGF serum levels of advanced cancer patients. Br J Cancer 80, 892–897 (1999). https://doi.org/10.1038/sj.bjc.6690437

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Keywords

  • angiogenesis
  • interleukin-6
  • blood platelets
  • VEGF

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