Advertisement

Serum Levels of Angiogenic Factors and their Prognostic Relevance in Bladder Cancer

  • Tibor SzarvasEmail author
  • Tobias Jäger
  • Falk Droste
  • Markus Becker
  • Ilona Kovalszky
  • Imre Romics
  • Süleyman Ergün
  • Herbert Rübben
Original Paper

Abstract

Angiogenesis plays a critical role in tumor growth. VEGF, angiopoietins (Ang-1, Ang-2) and their tyrosine kinase receptor Tie2 are major regulators of angiogenesis. The aim of this study was to evaluate the prognostic value of the serum levels of these factors in bladder cancer. We analyzed the serum samples of 117 bladder cancer patients and 64 healthy volunteers by enzyme linked immunosorbent assay (ELISA) for Ang-1, Ang-2, VEGF and the extracellular domain of Tie2. The statistical evaluation of the obtained data was performed via Kaplan–Meier log-rank test, univariate Cox analyses as well as Cox proportional hazards regression model. Serum Ang-1 levels of bladder cancer patients were significantly higher (p < 0.001), while soluble Ang-2 and Tie2 levels were significantly lower (p = 0.016 and p = 0.001 respectively) in patients than those in controls. Cox univariate analysis revealed high sTie2 serum level as a risk factor for metastasis and as a borderline significant risk factor for disease related death (p = 0.022 and p = 0.081 respectively). These correlations were independent from tumor stage and grade in a Cox multivariate model (p = 0.016 and p = 0.069). These data indicate that the serum levels of analyzed angiogenic factors do change characteristically in bladder cancer. The soluble extracellular serum level of Tie2 may provide a stage and grade independent diagnostic tool to select a high risk group of bladder cancer patients.

Keywords

Bladder cancer Serum Angiopoietin Tie2 VEGF Prognosis 

Abbreviations

HR

hazard ratio

CI

confidence interval

TEM

Tie2-expressing monocyte

TCC

transitional cell carcinoma

Notes

Acknowledgement

We thank Jacqueline Wittschier for excellent technical assistance. Grant support from the German National Federal Ministry of Education and Research (0313659B) is also acknowledged.

References

  1. 1.
    Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesisand metastasis correlation in invasive breast carcinoma. N Engl J Med 324:1–8PubMedGoogle Scholar
  2. 2.
    Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC, Yancopoulos GD (1996) Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87:1161–1169CrossRefPubMedGoogle Scholar
  3. 3.
    Papapetropoulos A, Garcia-Cardena G, Dengler TJ, Maisonpierre PC, Yancopoulos GD, Sessa WC (1999) Direct actions of angiopoietin-1 on human endothelium: evidence for network stabilization, cell survival, and interaction with other angiogenic growth factors. Lab Invest 79:213–223PubMedGoogle Scholar
  4. 4.
    Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60CrossRefPubMedGoogle Scholar
  5. 5.
    Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284:1994–1998CrossRefPubMedGoogle Scholar
  6. 6.
    Volm M, Koomagi R, Mattern J (1997) Prognostic value of vascular endothelial growth factor and its receptor flt-1 in squamous cell lung cancer. Int J Cancer 74:64–68CrossRefPubMedGoogle Scholar
  7. 7.
    Inoue K, Ozeki Y, Suganuma T, Sugiura Y, Tanaka S (1997) Vascular endothelial growth factor expression in primary esophageal squamous cell carcinoma. Cancer 79:206–213CrossRefPubMedGoogle Scholar
  8. 8.
    Maeda K, Chung Y, Takatsuka S, Ogawa Y, Sawada T, Yamashita Y et al (1995) Tumor angiogenesis as a predictor of recurrence in gastric carcinoma. J Clin Oncol 13:477–481PubMedGoogle Scholar
  9. 9.
    Dosquet C, Coudert MC, 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 3:2451–2458PubMedGoogle Scholar
  10. 10.
    Tas F, Duranyildiz D, Oguz H, Camlica H, Yasasever V, Topuz E (2006) Circulating serum levels of angiogenic factors and vascular endothelial growth factor receptors 1 and 2 in melanoma patients. Melanoma Res 16:405–411CrossRefPubMedGoogle Scholar
  11. 11.
    Bernardini S, Fauconnet S, Chabannes E, Henry PC, Adessi G, Bittard H (2001) Serum levels of vascular endothelial growth factor as a prognostic factor in bladder cancer. J Urol 166:1275–1279CrossRefPubMedGoogle Scholar
  12. 12.
    Sfiligoi C, de Luca A, Cascone I, Sorbello V, Fuso L, Ponzone R, Biglia N, Audero E, Arisio R, Bussolino F, Sismondi P, De Bortoli M (2003) Angiopoietin-2 expression in breast cancer correlates with lymph node invasion and short survival. Int J Cancer 103:466–474CrossRefPubMedGoogle Scholar
  13. 13.
    Wurmbach JH, Hammerer P, Sevinc S, Huland H, Ergun S (2000) The expression of angiopoietins and their receptor Tie-2 in human prostate carcinoma. Anticancer Res 20:5217–5220PubMedGoogle Scholar
  14. 14.
    Wong MP, Chan SY, Fu KH, Leung SY, Cheung N, Yuen ST, Chung LP (2000) The angiopoietins, tie2 and vascular endothelial growth factor are differentially expressed in the transformation of normal lung to non-small cell lung carcinomas. Lung Cancer 29:11–22CrossRefPubMedGoogle Scholar
  15. 15.
    Hata K, Nakayama K, Fujiwaki R, Katabuchi H, Okamura H, Miyazaki K (2004) Expression of the angopoietin-1, angopoietin-2, Tie2, and vascular endothelial growth factor gene in epithelial ovarian cancer. Gynecol Oncol 93:215–222CrossRefPubMedGoogle Scholar
  16. 16.
    Szarvas T, Jäger T, Tötsch M, vom Dorp F, Kempkensteffen C, Kovalszky I, Romics I, Ergün S, Rübben H (2008) Angiogenic switch of angiopietins-Tie2-system and its prognostic value in bladder cancer. Clin Cancer Res (in press)CrossRefPubMedGoogle Scholar
  17. 17.
    Liersch R, Schliemann C, Bieker R, Hintelmann H, Buechner T, Berdel WE, Mesters RM (2008) Expression of VEGF-C and its receptor VEGFR-3 in the bone marrow of patients with acute myeloid leukaemia. Leuk Res 32:954–961CrossRefPubMedGoogle Scholar
  18. 18.
    Park JH, Park KJ, Kim YS, Sheen SS, Lee KS, Lee HN, Oh YJ, Hwang SC (2007) Serum angiopoietin-2 as a clinical marker for lung cancer. Chest 132:200–206CrossRefPubMedGoogle Scholar
  19. 19.
    Lewis CE, De Palma M, Naldini L (2007) Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res 67:8429–8432CrossRefPubMedGoogle Scholar
  20. 20.
    Reusch P, Barleon B, Weindel K, Martiny-Baron G, Gödde A, Siemeister G, Marmé D (2001) Identification of a soluble form of the angiopoietin receptor TIE-2 released from endothelial cells and present in human blood. Angiogenesis 4:123–131CrossRefPubMedGoogle Scholar
  21. 21.
    Eble JN, Epstein JI, Sesterhenn I, World Health Organization classification of tumors (2004) Pathology and genetics of tumors of the urinary system and male genital organs. IARCC, Lyon, pp 89–158Google Scholar
  22. 22.
    Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD (1996) Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87:1171–1180CrossRefPubMedGoogle Scholar
  23. 23.
    Holash J, Wiegand SJ, Yancopoulos GD (1999) New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene 18:5356–5362CrossRefPubMedGoogle Scholar
  24. 24.
    Crew JP, Fuggle S, Bicknell R, Cranston DW, de Benedetti A, Harris AL (2000) Eukaryotic initiation factor-4E in superficial and muscle invasive bladder cancer and its correlation with vascular endothelial growth factor expression and tumour progression. Br J Cancer 82:161–166CrossRefPubMedGoogle Scholar
  25. 25.
    O'Brien T, Cranston D, Fuggle S, Bicknell R, Harris AL (1995) Different angiogenic pathways characterize superficial and invasive bladder cancer. Cancer Res 55:510–513PubMedGoogle Scholar
  26. 26.
    Quentin T, Schlott T, Korabiowska M, Kathei N, Zoller G, Glaser F, Kunze E (2004) Alteration of the vascular endothelial growth factor and angiopoietins-1 and -2 pathways in transitional cell carcinomas of the urinary bladder associated with tumor progression. Anticancer Res 24:2745–2756PubMedGoogle Scholar
  27. 27.
    Oliveira-Ferrer L, Tilki D, Ziegeler G, Hauschild J, Loges S, Irmak S, Kilic E, Huland H, Friedrich M, Ergün S (2004) Dual role of carcinoembryonic antigen-related cell adhesion molecule 1 in angiogenesis and invasion of human urinary bladder cancer. Cancer Res 64:8932–8938CrossRefPubMedGoogle Scholar
  28. 28.
    Beecken WD, Engl T, Hofmann J, Jonas D, Blaheta R (2005) Clinical relevance of serum angiogenic activity in patients with transitional cell carcinoma of the bladder. J Cell Mol Med 9:655–661CrossRefPubMedGoogle Scholar
  29. 29.
    Tait CR, Jones PF (2004) Angiopoietins in tumours: the angiogenic switch. J Pathol 204:1–10CrossRefPubMedGoogle Scholar
  30. 30.
    Oka N, Yamamoto Y, Takahashi M, Nishitani M, Kanayama HO, Kagawa S (2005) Expression of angiopoietin-1 and -2, and its clinical significance in human bladder cancer. BJU Int 95:660–663CrossRefPubMedGoogle Scholar
  31. 31.
    Schliemann C, Bieker R, Thoennissen N, Gerss J, Liersch R, Kessler T, Büchner T, Berdel WE, Mesters RM (2007) Circulating angiopoietin-2 is a strong prognostic factor in acute myeloid leukemia. Leukemia 21:1901–1906CrossRefPubMedGoogle Scholar
  32. 32.
    Park JH, Park KJ, Kim YS, Sheen SS, Lee KS, Lee HN, Oh YJ, Hwang SC (2007) Serum angiopoietin-2 as a clinical marker for lung cancer. Chest 132:200–206CrossRefPubMedGoogle Scholar
  33. 33.
    Lewis CE, De Palma M, Naldini L (2007) Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res 67:8429–8432CrossRefPubMedGoogle Scholar
  34. 34.
    Reusch P, Barleon B, Weindel K, Martiny-Baron G, Gödde A, Siemeister G, Marmé D (2001) Identification of a soluble form of the angiopoietin receptor TIE-2 released from endothelial cells and present in human blood. Angiogenesis 4:123–131CrossRefPubMedGoogle Scholar
  35. 35.
    Harris AL, Reusch P, Barleon B, Hang C, Dobbs N, Marme D (2001) Soluble Tie2 and Flt1 extracellular domains in serum of patients with renal cancer and response to antiangiogenic therapy. Clin Cancer Res 7:1992–1997PubMedGoogle Scholar
  36. 36.
    Findley CM, Cudmore MJ, Ahmed A, Kontos CD (2007) VEGF induces Tie2 shedding via a phosphoinositide 3-kinase/Akt dependent pathway to modulate Tie2 signaling. Arterioscler Thromb Vasc Biol 27:2619–2626CrossRefPubMedGoogle Scholar
  37. 37.
    Lin P, Polverini P, Dewhirst M, Shan S, Rao PS, Peters K (1997) Inhibition of tumor angiogenesis using a soluble receptor establishes a role for Tie2 in pathologic vascular growth. J Clin Invest 100:2072–2078CrossRefPubMedGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2008

Authors and Affiliations

  • Tibor Szarvas
    • 1
    Email author
  • Tobias Jäger
    • 1
  • Falk Droste
    • 1
  • Markus Becker
    • 1
  • Ilona Kovalszky
    • 2
  • Imre Romics
    • 3
  • Süleyman Ergün
    • 4
  • Herbert Rübben
    • 1
  1. 1.Experimental Urology, Department of UrologyUniversity of Duisburg-EssenEssenGermany
  2. 2.1st Institute of Pathology and Experimental Cancer ResearchSemmelweis UniversityBudapestHungary
  3. 3.Department of UrologySemmelweis UniversityBudapestHungary
  4. 4.Institute of AnatomyUniversity Hospital of EssenEssenGermany

Personalised recommendations