Advertisement

Journal of Neuro-Oncology

, Volume 102, Issue 1, pp 35–41 | Cite as

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

  • Gaspar ReynésEmail author
  • Virtudes Vila
  • María Martín
  • Antonio Parada
  • Tania Fleitas
  • Edelmiro Reganon
  • Vicenta Martínez-Sales
Laboratory Investigation - Human/Animal Tissue

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.

Keywords

Glioblastoma Inflammation Angiogenesis Coagulation Circulating markers 

Notes

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.

References

  1. 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 33–49Google Scholar
  2. 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 9:89–95CrossRefPubMedGoogle Scholar
  3. 3.
    Lu H, Ouyang W, Huang C (2006) Inflammation, a key event in cancer development. Mol Cancer Res 4:221–233CrossRefPubMedGoogle Scholar
  4. 4.
    Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444CrossRefPubMedGoogle Scholar
  5. 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 CrossRefPubMedGoogle Scholar
  6. 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 96:474–476CrossRefPubMedGoogle Scholar
  7. 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 19:38–45PubMedGoogle Scholar
  8. 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 53:347–351PubMedGoogle Scholar
  9. 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 32:169–175CrossRefPubMedGoogle Scholar
  10. 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 16:1155–1159CrossRefPubMedGoogle Scholar
  11. 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 84:10–18CrossRefPubMedGoogle Scholar
  12. 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 9:1399–1405PubMedGoogle Scholar
  13. 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 191:1789–1798CrossRefPubMedGoogle Scholar
  14. 14.
    Rege TA, Fears CY, Gladson CL (2005) Endogenous inhibitors of angiogenesis in malignant gliomas: nature’s antiangiogenic therapy. Neuro Oncol 7:106–121CrossRefPubMedGoogle Scholar
  15. 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 77:1877–1883CrossRefPubMedGoogle Scholar
  16. 16.
    Rickles FR, Patierno S, Fernandez PM (2003) Tissue factor, thrombin, and cancer. Chest 124(3 Suppl):58S–68SCrossRefPubMedGoogle Scholar
  17. 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 125:1054–1064CrossRefPubMedGoogle Scholar
  18. 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 352:987–996CrossRefPubMedGoogle Scholar
  19. 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 16:874–878Google Scholar
  20. 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 26:2466–2474PubMedGoogle Scholar
  21. 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 14:233–238PubMedGoogle Scholar
  22. 22.
    Reganon E, Vila V, Aznar J (1984) Gelification of fibrinogen in plasma. A kinetic study by turbidity measurement. Haemostasis 14:170–178PubMedGoogle Scholar
  23. 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 9:4653–4665PubMedGoogle Scholar
  24. 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 11:1639–1643PubMedGoogle Scholar
  25. 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 22:353–358CrossRefPubMedGoogle Scholar
  26. 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 68:388–394CrossRefPubMedGoogle Scholar
  27. 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 15:35–40PubMedGoogle Scholar
  28. 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 51:493–501CrossRefPubMedGoogle Scholar
  29. 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 55:1189–1193PubMedGoogle Scholar
  30. 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 56:2185–2190PubMedGoogle Scholar
  31. 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 100:101–105CrossRefPubMedGoogle Scholar
  32. 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 3:647–651PubMedGoogle Scholar
  33. 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 226:324–328CrossRefPubMedGoogle Scholar
  34. 34.
    Ahmad S, Ahmed A (2004) Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ Res 95:884–891CrossRefPubMedGoogle Scholar
  35. 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:e5108CrossRefPubMedGoogle Scholar
  36. 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 98:14–18CrossRefPubMedGoogle Scholar
  37. 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 25:322–327CrossRefPubMedGoogle Scholar
  38. 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 37:145–150CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Gaspar Reynés
    • 1
    Email author
  • Virtudes Vila
    • 2
  • María Martín
    • 1
  • Antonio Parada
    • 2
  • Tania Fleitas
    • 1
  • Edelmiro Reganon
    • 2
  • Vicenta Martínez-Sales
    • 2
  1. 1.Servicio de Oncología MédicaHospital Universitario La FeValenciaSpain
  2. 2.Centro de InvestigaciónHospital Universitario La FeValenciaSpain

Personalised recommendations