Skip to main content

Advertisement

Log in

Circulating markers of angiogenesis, inflammation, and coagulation in patients with glioblastoma

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Inflammation, angiogenesis, and coagulation are linked to the development of cancer. In glioblastoma, microvascular proliferation is a hallmark, and lymphocytic infiltration is a common finding. Thromboses are frequent in patients with glioblastoma. The objective of this study was to assess presurgical levels of circulating markers of inflammation, angiogenesis, and coagulation in a prospective series of patients with glioblastoma, and to explore their correlations and possible associations with clinical findings. Angiogenesis markers included were vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor-receptor 1 (sVEGFR-1), and thrombospondin-1 (TSP-1). Inflammatory markers included were C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and sialic acid (SA). Coagulation markers included were fibrinogen (Fg), endogen thrombin generation (ETG), prothrombin fragments 1 + 2 (F1 + 2), and tissue factor (TF). Forty-seven patients and 60 healthy subjects were included in the study. Signs of tumor necrosis in presurgical MRI were associated with shorter survival (P < 0.01). All inflammation markers, F1 + 2, ETG, VEGF and sVEGFR-1, were significantly elevated in glioblastoma patients. Correlations were found between ETG and Fg (r = 0.44, P < 0.01). Sialic acid correlated with Fg (r = 0.63, P < 0,001); CPR correlated with SA (r = 0.60, P < 0.001), Fg (r = 0.76, P < 0.001), TNFα (r = 0.56, P < 0.001), and IL-6 (r = 0.65, P < 0.001); and IL-6 also correlated positively with TNFα (r = 0.40, P < 0.02) and Fg (r = 0.45, P < 0.01). Vascular endothelial growth factor inversely correlated with sVEGFR-1 (r = −0.35, P < 0.02). No associations were found between marker levels and survival or progression-free survival.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Kleihues P, Burger PC, Aldape KD, Brat DJ, Biernat W, Bigner DD (2007) Glioblastoma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK et al (eds) WHO classification of tumors of the Central Nervous System, 4th edn. IARC, Lyon, pp 33–49

    Google Scholar 

  2. Simanek R, Vormittag R, Hassler M, Roessler K, Schwarz M, Zielinski C, Pabinger I, Marosi C (2007) Venous thromboembolism and survival in patients with high-grade glioma. Neuro-oncol 9:89–95

    Article  PubMed  Google Scholar 

  3. Lu H, Ouyang W, Huang C (2006) Inflammation, a key event in cancer development. Mol Cancer Res 4:221–233

    Article  PubMed  Google Scholar 

  4. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444

    Article  CAS  PubMed  Google Scholar 

  5. Anderson JC, McFarland BC, Gladson CL (2008) New molecular targets in angiogenic vessels of glioblastoma tumours. Expert Rev Mol Med 10:e23. doi:10.1017/S1462399408000768

    Article  PubMed  Google Scholar 

  6. Tchirkov A, Khalil T, Chautard E, Mokhtari K, Véronèse L, Irthum B, Vago P, Kémény JL, Verrelle P (2007) Interleukin-6 gene amplification and shortened survival in glioblastoma patients. Br J Cancer 96:474–476

    Article  CAS  PubMed  Google Scholar 

  7. Feijoo-Carnero C, Rodríguez-Berrocal FJ, Páez de la Cadena M, Ayude D, de Carlos A, Martínez-Zorzano VS (2004) Clinical significance of preoperative serum sialic acid levels in colorectal cancer: utility in the detection of patients at high risk of tumor recurrence. Int J Biol Markers 19:38–45

    CAS  PubMed  Google Scholar 

  8. Celen O, Yildirim E, Ozen N, Sonmez C (2006) Predictive value of relative changes in serum total sialic acid level for response to neoadjuvant chemotherapy in patients with locally advanced breast carcinoma. Neoplasma 53:347–351

    CAS  PubMed  Google Scholar 

  9. Koukourakis MI, Kambouromiti G, Pitsiava D, Tsousou P, Tsiarkatsi M, Kartalis G (2009) Serum C-reactive protein (CRP) levels in cancer patients are linked with tumor burden and are reduced by anti-hypertensive medication. Inflammation 32:169–175

    Article  CAS  PubMed  Google Scholar 

  10. Heikkilä K, Ebrahim S, Rumley A, Lowe G, Lawlor DA (2007) Associations of circulating C-reactive protein and interleukin-6 with survival in women with and without cancer: findings from the British Women’s Heart and Health Study. Cancer Epidemiol Biomarkers Prev 16:1155–1159

    Article  PubMed  Google Scholar 

  11. Schmidt NO, Westphal M, Hagel C, Ergün S, Stavrou D, Rosen EM, Lamszus K (1999) Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int J Cancer 84:10–18

    Article  CAS  PubMed  Google Scholar 

  12. Lamszus K, Ulbricht U, Matschke J, Brockmann MA, Fillbrandt R, Westphal M (2003) Levels of soluble vascular endothelial growth factor (VEGF) receptor 1 in astrocytic tumors and its relation to malignancy, vascularity, and VEGF-A. Clin Cancer Res 9:1399–1405

    CAS  PubMed  Google Scholar 

  13. Tenan M, Fulci G, Albertoni M, Diserens AC, Hamou MF, El Atifi-Borel M, Feige JJ, Pepper MS, Van Meir EG (2000) Thrombospondin-1 is downregulated by anoxia and suppresses tumorigenicity of human glioblastoma cells. J Exp Med 191:1789–1798

    Article  CAS  PubMed  Google Scholar 

  14. Rege TA, Fears CY, Gladson CL (2005) Endogenous inhibitors of angiogenesis in malignant gliomas: nature’s antiangiogenic therapy. Neuro Oncol 7:106–121

    Article  CAS  PubMed  Google Scholar 

  15. Hamada K, Kuratsu J, Saitoh Y, Takeshima H, Nishi T, Ushio Y (1996) Expression of tissue factor correlates with grade of malignancy in human glioma. Cancer 77:1877–1883

    Article  CAS  PubMed  Google Scholar 

  16. Rickles FR, Patierno S, Fernandez PM (2003) Tissue factor, thrombin, and cancer. Chest 124(3 Suppl):58S–68S

    Article  CAS  PubMed  Google Scholar 

  17. Saidi A, Hagedorn M, Allain N, Verpelli C, Sala C, Bello L, Bikfalvi A, Javerzat S (2009) Combined targeting of interleukin-6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness. Int J Cancer 125:1054–1064

    Article  CAS  PubMed  Google Scholar 

  18. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  CAS  PubMed  Google Scholar 

  19. Schoenegger K, Oberndorfer S, Wuschitz B, Struhal W, Hainfellner J et al. (2009) Peritumoral edema on MRI at initial diagnosis: an independent prognostic factor for glioblastoma? Eur J Neurol 16:874–878

    Google Scholar 

  20. Pope WB, Sayre J, Perlina A, Villablanca JP, Mischel PS, Cloughesy TF (2005) MR imaging correlates of survival in patients with high-grade gliomas. AJNR Am J Neuroradiol 26:2466–2474

    PubMed  Google Scholar 

  21. Martínez-Sales V, Vila V, Ferrando M, Reganon E (2007) Atorvastatin neutralizes the up-regulation of thrombospondin induced by thrombin in human umbilical vein endothelial cells. Endothelium 14:233–238

    PubMed  Google Scholar 

  22. Reganon E, Vila V, Aznar J (1984) Gelification of fibrinogen in plasma. A kinetic study by turbidity measurement. Haemostasis 14:170–178

    CAS  PubMed  Google Scholar 

  23. Trikha M, Corringham R, Klein B, Rossi JF (2003) Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res 9:4653–4665

    CAS  PubMed  Google Scholar 

  24. Nikiteas NI, Tzanakis N, Gazouli M, Rallis G, Daniilidis K, Theodoropoulos G, Kostakis A, Peros G (2005) Serum IL-6, TNFalpha and CRP levels in Greek colorectal cancer patients: prognostic implications. World J Gastroenterol 11:1639–1643

    CAS  PubMed  Google Scholar 

  25. Tas F, Duranyildiz D, Argon A, Oğuz H, Camlica H, Yasasever V, Topuz E (2005) Serum levels of leptin and proinflammatory cytokines in advanced-stage non-small cell lung cancer. Med Oncol 22:353–358

    Article  CAS  PubMed  Google Scholar 

  26. Hedlund M, Ng E, Varki A, Varki NM (2008) alpha 2–6-Linked sialic acids on N-glycans modulate carcinoma differentiation in vivo. Cancer Res 68:388–394

    Article  CAS  PubMed  Google Scholar 

  27. Kökoğlu E, Süer S, Ozyurt E, Siyahhan A, Sönmez H (1995) Plasma fibronectin and sialic acid levels in various types of human brain tumors. Cancer Biochem Biophys 15:35–40

    PubMed  Google Scholar 

  28. Soedamah-Muthu SS, Chaturvedi N, Pickup JC, Fuller JH, the EURODIAB Prospective Complications Study Group (2008) Relationship between plasma sialic acid and fibrinogen concentration and incident micro- and macrovascular complications in type 1 diabetes. The EURODIAB Prospective Complications Study (PCS). Diabetologia 51:493–501

    Article  CAS  PubMed  Google Scholar 

  29. Samoto K, Ikezaki K, Ono M, Shono T, Kohno K, Kuwano M, Fukui M (1995) Expression of vascular endothelial growth factor and its possible relation with neovascularization in human brain tumors. Cancer Res 55:1189–1193

    CAS  PubMed  Google Scholar 

  30. Takano S, Yoshii Y, Kondo S, Suzuki H, Maruno T, Shirai S, Nose T (1996) Concentration of vascular endothelial growth factor in the serum and tumor tissue of brain tumor patients. Cancer Res 56:2185–2190

    CAS  PubMed  Google Scholar 

  31. Stockhammer G, Obwegeser A, Kostron H, Schumacher P, Muigg A et al (2000) Vascular endothelial growth factor (VEGF) is elevated in brain tumor cysts and correlates with tumor progression. Acta Neuropathol 100:101–105

    Article  CAS  PubMed  Google Scholar 

  32. Salven P, Mänpää H, Orpana A, Alitalo K, Joensuu H (1997) Serum vascular endothelial growth factor is often elevated in disseminated cancer. Clin Cancer Res 3:647–651

    CAS  PubMed  Google Scholar 

  33. Kendall RL, Wang G, Thomas KA (1996) Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR. Biochem Biophys Res Commun 226:324–328

    Article  CAS  PubMed  Google Scholar 

  34. Ahmad S, Ahmed A (2004) Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ Res 95:884–891

    Article  CAS  PubMed  Google Scholar 

  35. Wu FT, Stefanini MO, Mac Gabhann F, Popel AS (2009) A compartment model of VEGF distribution in humans in the presence of soluble VEGF receptor-1 acting as a ligand trap. PLoS One 4:e5108

    Article  PubMed  Google Scholar 

  36. Toi M, Bando H, Ogawa T, Muta M, Hornig C, Weich HA (2002) Significance of vascular endothelial growth factor (VEGF)/soluble VEGF receptor-1 relationship in breast cancer. Int J Cancer 98:14–18

    Article  CAS  PubMed  Google Scholar 

  37. Yilmaztepe A, Ulukaya E, Zik B, Yagci A, Sevimli A, Yilmaz M, Erdogan BB, Koc M, Akgoz S, Karadag M, Tokullugil A (2007) Soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) is decreased in lung cancer patients showing progression: a pilot study. Cancer Invest 25:322–327

    Article  CAS  PubMed  Google Scholar 

  38. Chang YT, Chang MC, Wei SC, Tien YW, Hsu C, Liang PC, Tsao PN, Jan IS, Wong JM (2008) Serum vascular endothelial growth factor/soluble vascular endothelial growth factor receptor 1 ratio is an independent prognostic marker in pancreatic cancer. Pancreas 37:145–150

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported in part by a grant of the Sociedad Española de Oncología Médica (SEOM), 2004, and by funds from Schering Plough España and Roche Pharma S.A. The authors thank Josefa Llorens and Ursula Salinas for their technical assistance. They also thank Dolores Pascual and Adela Máñez for their assistance in blood sample collection.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gaspar Reynés.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reynés, G., Vila, V., Martín, M. et al. Circulating markers of angiogenesis, inflammation, and coagulation in patients with glioblastoma. J Neurooncol 102, 35–41 (2011). https://doi.org/10.1007/s11060-010-0290-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-010-0290-x

Keywords

Navigation