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British Journal of Cancer logoLink to British Journal of Cancer
. 1999 May;80(5-6):892–897. doi: 10.1038/sj.bjc.6690437

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

R Salgado 1, P B Vermeulen 1,2, I Benoy 1, R Weytjens 1, P Huget 1, E Van Marck 1,2, L Y Dirix 1
PMCID: PMC2362300  PMID: 10360671

Abstract

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. © 1999 Cancer Research Campaign

Keywords: angiogenesis, interleukin-6, blood platelets, VEGF

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Selected References

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  1. Banks R. E., Forbes M. A., Kinsey S. E., Stanley A., Ingham E., Walters C., Selby P. J. Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br J Cancer. 1998 Mar;77(6):956–964. doi: 10.1038/bjc.1998.158. [DOI] [PMC free article] [PubMed] [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. Serum level of interleukin 6 as a prognosis factor in metastatic renal cell carcinoma. Cancer Res. 1992 Jun 15;52(12):3317–3322. [PubMed] [Google Scholar]
  3. Bousvaros A., Zurakowski D., Fishman S. J., Keough K., Law T., Sun C., Leichtner A. M. Serum basic fibroblast growth factor in pediatric Crohn's disease. Implications for wound healing. Dig Dis Sci. 1997 Feb;42(2):378–386. doi: 10.1023/a:1018882322566. [DOI] [PubMed] [Google Scholar]
  4. Brekken R. A., Huang X., King S. W., Thorpe P. E. Vascular endothelial growth factor as a marker of tumor endothelium. Cancer Res. 1998 May 1;58(9):1952–1959. [PubMed] [Google Scholar]
  5. Bross D. A., Leichtner A. M., Zurakowski D., Law T., Bousvaros A. Elevation of serum interleukin-6 but not serum-soluble interleukin-2 receptor in children with Crohn's disease. J Pediatr Gastroenterol Nutr. 1996 Aug;23(2):164–171. doi: 10.1097/00005176-199608000-00012. [DOI] [PubMed] [Google Scholar]
  6. Clarke D., Johnson P. W., Banks R. E., Storr M., Kinsey S. E., Johnson R., Morgan G., Gordon M. Y., Illingworth J. M., Perren T. J. Effects of interleukin 6 administration on platelets and haemopoietic progenitor cells in peripheral blood. Cytokine. 1996 Sep;8(9):717–723. doi: 10.1006/cyto.1996.0095. [DOI] [PubMed] [Google Scholar]
  7. Cohen T., Nahari D., Cerem L. W., Neufeld G., Levi B. Z. Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem. 1996 Jan 12;271(2):736–741. doi: 10.1074/jbc.271.2.736. [DOI] [PubMed] [Google Scholar]
  8. Degeorges A., Tatoud R., Fauvel-Lafeve F., Podgorniak M. P., Millot G., de Cremoux P., Calvo F. Stromal cells from human benign prostate hyperplasia produce a growth-inhibitory factor for LNCaP prostate cancer cells, identified as interleukin-6. Int J Cancer. 1996 Oct 9;68(2):207–214. doi: 10.1002/(SICI)1097-0215(19961009)68:2<207::AID-IJC12>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  9. Dirix L. Y., Vermeulen P. B., Hubens G., Benoy I., Martin M., De Pooter C., Van Oosterom A. T. Serum basic fibroblast growth factor and vascular endothelial growth factor and tumour growth kinetics in advanced colorectal cancer. Ann Oncol. 1996 Oct;7(8):843–848. doi: 10.1093/oxfordjournals.annonc.a010764. [DOI] [PubMed] [Google Scholar]
  10. Dirix L. Y., Vermeulen P. B., Pawinski A., Prové A., Benoy I., De Pooter C., Martin M., Van Oosterom A. T. 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(2):238–243. doi: 10.1038/bjc.1997.368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dosquet C., Coudert M. C., Lepage E., Cabane J., Richard F. Are angiogenic factors, cytokines, and soluble adhesion molecules prognostic factors in patients with renal cell carcinoma? Clin Cancer Res. 1997 Dec;3(12 Pt 1):2451–2458. [PubMed] [Google Scholar]
  12. Duensing S., Grosse J., Atzpodien J. Increased serum levels of basic fibroblast growth factor (bFGF) are associated with progressive lung metastases in advanced renal cell carcinoma patients. Anticancer Res. 1995 Sep-Oct;15(5B):2331–2333. [PubMed] [Google Scholar]
  13. Dvorak H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986 Dec 25;315(26):1650–1659. doi: 10.1056/NEJM198612253152606. [DOI] [PubMed] [Google Scholar]
  14. Ferriere J. P., Bernard D., Legros M., Chassagne J., Chollet P., Gaillard G., Plagne R. beta-Thromboglobulin in patients with breast cancer. Am J Hematol. 1985 May;19(1):47–53. doi: 10.1002/ajh.2830190107. [DOI] [PubMed] [Google Scholar]
  15. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990 Jan 3;82(1):4–6. doi: 10.1093/jnci/82.1.4. [DOI] [PubMed] [Google Scholar]
  16. Gasparini G. Angiogenesis research up to 1996. A commentary on the state of art and suggestions for future studies. Eur J Cancer. 1996 Dec;32A(14):2379–2385. doi: 10.1016/s0959-8049(96)00424-8. [DOI] [PubMed] [Google Scholar]
  17. Handagama P. J., Shuman M. A., Bainton D. F. Incorporation of intravenously injected albumin, immunoglobulin G, and fibrinogen in guinea pig megakaryocyte granules. J Clin Invest. 1989 Jul;84(1):73–82. doi: 10.1172/JCI114173. [DOI] [PMC free article] [PubMed] [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. Uptake of plasma fibrinogen into the alpha granules of human megakaryocytes and platelets. J Clin Invest. 1989 Oct;84(4):1320–1324. doi: 10.1172/JCI114300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ishibashi T., Kimura H., Shikama Y., Uchida T., Kariyone S., Hirano T., Kishimoto T., Takatsuki F., Akiyama Y. Interleukin-6 is a potent thrombopoietic factor in vivo in mice. Blood. 1989 Sep;74(4):1241–1244. [PubMed] [Google Scholar]
  20. Jaffe E. A., Nachman R. L., Becker C. G., Minick C. R. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest. 1973 Nov;52(11):2745–2756. doi: 10.1172/JCI107470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kaushansky K. Thrombopoietin: platelets on demand? Ann Intern Med. 1997 May 1;126(9):731–733. doi: 10.7326/0003-4819-126-9-199705010-00009. [DOI] [PubMed] [Google Scholar]
  22. Kaushansky K. Thrombopoietin: the primary regulator of platelet production. Blood. 1995 Jul 15;86(2):419–431. [PubMed] [Google Scholar]
  23. Kumar H., Heer K., Lee P. W., Duthie G. S., MacDonald A. W., Greenman J., Kerin M. J., Monson J. R. Preoperative serum vascular endothelial growth factor can predict stage in colorectal cancer. Clin Cancer Res. 1998 May;4(5):1279–1285. [PubMed] [Google Scholar]
  24. Lake A. M., Stauffer J. Q., Stuart M. J. Hemostatic alterations in inflammatory bowel disease: response to therapy. Am J Dig Dis. 1978 Oct;23(10):897–902. doi: 10.1007/BF01072463. [DOI] [PubMed] [Google Scholar]
  25. Liotta L. A., Kleinerman J., Saidel G. M. Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res. 1974 May;34(5):997–1004. [PubMed] [Google Scholar]
  26. Mateo R. B., Reichner J. S., Albina J. E. Interleukin-6 activity in wounds. Am J Physiol. 1994 Jun;266(6 Pt 2):R1840–R1844. doi: 10.1152/ajpregu.1994.266.6.R1840. [DOI] [PubMed] [Google Scholar]
  27. Milroy R., Douglas J. T., Campbell J., Carter R., Lowe G. D., Banham S. W. Abnormal haemostasis in small cell lung cancer. Thorax. 1988 Dec;43(12):978–981. doi: 10.1136/thx.43.12.978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Motro B., Itin A., Sachs L., Keshet E. Pattern of interleukin 6 gene expression in vivo suggests a role for this cytokine in angiogenesis. Proc Natl Acad Sci U S A. 1990 Apr;87(8):3092–3096. doi: 10.1073/pnas.87.8.3092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Möhle R., Green D., Moore M. A., Nachman R. L., Rafii S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):663–668. doi: 10.1073/pnas.94.2.663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nakano T., Chahinian A. P., Shinjo M., Tonomura A., Miyake M., Togawa N., Ninomiya K., Higashino K. Interleukin 6 and its relationship to clinical parameters in patients with malignant pleural mesothelioma. Br J Cancer. 1998 Mar;77(6):907–912. doi: 10.1038/bjc.1998.150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pedersen L. M., Milman N. Prognostic significance of thrombocytosis in patients with primary lung cancer. Eur Respir J. 1996 Sep;9(9):1826–1830. doi: 10.1183/09031936.96.09091826. [DOI] [PubMed] [Google Scholar]
  32. Rak J. W., Hegmann E. J., Lu C., Kerbel R. S. Progressive loss of sensitivity to endothelium-derived growth inhibitors expressed by human melanoma cells during disease progression. J Cell Physiol. 1994 May;159(2):245–255. doi: 10.1002/jcp.1041590208. [DOI] [PubMed] [Google Scholar]
  33. Rak J., Filmus J., Kerbel R. S. Reciprocal paracrine interactions between tumour cells and endothelial cells: the 'angiogenesis progression' hypothesis. Eur J Cancer. 1996 Dec;32A(14):2438–2450. doi: 10.1016/s0959-8049(96)00396-6. [DOI] [PubMed] [Google Scholar]
  34. Ravoet C., DeGrève J., Vandewoude K., Kerger J., Sculier J. P., Lacor P., Stryckmans P., Piccart M. Tumour stimulating effects of recombinant human interleukin-6. Lancet. 1994 Dec 3;344(8936):1576–1577. doi: 10.1016/s0140-6736(94)90387-5. [DOI] [PubMed] [Google Scholar]
  35. Salven P., Ruotsalainen T., Mattson K., Joensuu H. High pre-treatment serum level of vascular endothelial growth factor (VEGF) is associated with poor outcome in small-cell lung cancer. Int J Cancer. 1998 Apr 17;79(2):144–146. doi: 10.1002/(sici)1097-0215(19980417)79:2<144::aid-ijc8>3.0.co;2-t. [DOI] [PubMed] [Google Scholar]
  36. Salven P., Teerenhovi L., Joensuu H. A high pretreatment serum vascular endothelial growth factor concentration is associated with poor outcome in non-Hodgkin's lymphoma. Blood. 1997 Oct 15;90(8):3167–3172. [PubMed] [Google Scholar]
  37. 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]
  38. Verheul H. M., Hoekman K., Luykx-de Bakker S., Eekman C. A., Folman C. C., Broxterman H. J., Pinedo H. M. Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res. 1997 Dec;3(12 Pt 1):2187–2190. [PubMed] [Google Scholar]
  39. Vermeulen P. B., Dirix L. Y., Martin M., Lemmens J., Van Oosterom A. T. Serum basic fibroblast growth factor and vascular endothelial growth factor in metastatic renal cell carcinoma treated with interferon alfa-2b. J Natl Cancer Inst. 1997 Sep 3;89(17):1316–1317. doi: 10.1093/jnci/89.17.1316. [DOI] [PubMed] [Google Scholar]
  40. Vermeulen P. B., Gasparini G., Fox S. B., Toi M., Martin L., McCulloch P., Pezzella F., Viale G., Weidner N., Harris A. L. Quantification of angiogenesis in solid human tumours: an international consensus on the methodology and criteria of evaluation. Eur J Cancer. 1996 Dec;32A(14):2474–2484. doi: 10.1016/s0959-8049(96)00379-6. [DOI] [PubMed] [Google Scholar]
  41. Wartiovaara U., Salven P., Mikkola H., Lassila R., Kaukonen J., Joukov V., Orpana A., Ristimäki A., Heikinheimo M., Joensuu H. Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation. Thromb Haemost. 1998 Jul;80(1):171–175. [PubMed] [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. Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies. J Clin Oncol. 1993 Mar;11(3):499–506. doi: 10.1200/JCO.1993.11.3.499. [DOI] [PubMed] [Google Scholar]
  43. Yan S. F., Tritto I., Pinsky D., Liao H., Huang J., Fuller G., Brett J., May L., Stern D. Induction of interleukin 6 (IL-6) by hypoxia in vascular cells. Central role of the binding site for nuclear factor-IL-6. J Biol Chem. 1995 May 12;270(19):11463–11471. doi: 10.1074/jbc.270.19.11463. [DOI] [PubMed] [Google Scholar]
  44. Yazaki T., Inage H., Iizumi T., Koyama A., Kanoh S., Koiso K., Narita M., Tojo S. Studies on platelet function in patients with prostatic cancer. Preliminary report. Urology. 1987 Jul;30(1):60–63. doi: 10.1016/0090-4295(87)90574-7. [DOI] [PubMed] [Google Scholar]

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