Skip to main content
SpringerLink
Log in

Positive VEGF Immunostaining Independently Predicts Poor Prognosis in Curatively Resected Gastric Cancer Patients: Results of a Study Assessing a Panel of Angiogenic Markers

  • Published:
Journal of Gastrointestinal Surgery Aims and scope

Abstract

Angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) contribute to gastric cancer aggressiveness by up-regulating the expression of proteases. We evaluated the expression and the prognostic significance of angiogenic factors and proteases in 148 patients with R0-resected gastric cancer. Expression of VEGF, Ang-2, cyclooxygenase-2 (COX-2), urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1, matrix metalloproteinases (MMP)-1 and -9 were assayed by immunohistochemistry. After a mean of 63 ± 4 months, 81 out of 148 patients had died due to disease. The probability of being free of recurrence was 62, 48, and 42% at 2, 5, and 10 years, respectively. Single bivariate analysis identified VEGF, Ang-2, COX-2, PAI-1, and MMP-9 expression, along with several clinicopathological parameters (grade of curability, lymph node ratio, pTNM, pT, pN), as variables associated with both decreased disease-specific survival and recurrence. On multivariate analysis, after adjusting for significant clinical covariables, positive VEGF immunostaining was the primary prognostic factor, and no other tumor marker variable could add any significant improvement for the prediction, for both disease-specific survival (p = 0.001; HR, 3.27; 95% CI, 1.76 to 6.10) and tumor recurrence (p = 0.002; HR, 2.81; 95% CI, 1.48 to 5.35). Our study suggests that VEGF alone may be clinically useful for establishing therapeutic decisions in gastric cancer patients.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics. 2002. CA Cancer J Clin 2005;55:74–108.

    Article  PubMed  Google Scholar 

  2. Dicken BJ, Bigam DL, Cass C, Mackey JR, Joy AA, Hamilton SM. Gastric adenocarcinoma: review and considerations for future directions. Ann Surg 2005;241:27–39.

    PubMed  Google Scholar 

  3. Maehara Y, Kakeji Y, Koga T, Emi Y, Baba H, Akazawa K, Sugimachi K. Therapeutic value of lymph node dissection and the clinical outcome for patients with gastric cancer. Surgery 2002;131:S85–S91.

    Article  PubMed  Google Scholar 

  4. Cunningham D, Allum W, Stenning S, Thompson JN, Van de Velde CJH, Nicolson M, Scarffe H, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley, BVerma M, Weeden S, Chua YJ. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11–20.

    Article  PubMed  CAS  Google Scholar 

  5. Riley RD, Abrams KR, Sutton AJ, Lambert PC, Jones DR, Heney D, Burchill SA. Reporting of prognostic markers: current problems and development of guidelines for evidence-based practice in the future. Br J Cancer 2003;88:1191–1198.

    Article  PubMed  CAS  Google Scholar 

  6. Folkman J. Angiogenesis in cancer, vascular rheumatoid and other diseases. Nature Med 1995;1:27–31.

    Article  PubMed  CAS  Google Scholar 

  7. Carmeliet P. Angiogenesis in life, disease and medicine. Nature 2005;438:932–936.

    Article  PubMed  CAS  Google Scholar 

  8. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005;23:1011–1027.

    Article  PubMed  CAS  Google Scholar 

  9. Tait CR, Jones PF. Angiopoietins in tumours: the angiogenic switch. J Pathol 2004;204:1–10.

    Article  PubMed  CAS  Google Scholar 

  10. Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993;362:841–844.

    Article  PubMed  CAS  Google Scholar 

  11. Oliner J, Min H, Leal J, Yu D, Rao S, You E, Tang X, Kim H, Meyer S, Han SJ, Hawkins N, Rosenfeld R, Davy E, Graham K, Jacobsen F, Stevenson S, Ho J, Chen Q, Hartmann T, Michaels M, Kelley M, Li L, Sitney K, Martin F, Sun JR, Zhang N, Lu J, Estrada J, Kumar R, Coxon A, Kaufman S, Pretorius J, Scully S, Cattley R, Payton M, Coats S, Nguyen L, Desilva B, Ndifor A, Hayward I, Radinsky R, Boone T, Kendall R. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 2004;6:507–516.

    Article  PubMed  CAS  Google Scholar 

  12. Bergers G, Coussens LM. Extrinsic regulators of epithelial tumor progression: metalloproteinases. Curr Opin Genet Dev 2000;10:120–127.

    Article  PubMed  CAS  Google Scholar 

  13. Baba M, Konno H, Maruo Y, Tanaka T, Kanai T, Matsumoto K, Matsura M, Nishino N, Maruyama K, Nakamura S, Baba S. Relationship of p53 and vascular endothelial growth factor expression of clinicopathological factors in human scirrhous gastric cancer. Eur Surg Res 1998;30:130–137.

    Article  PubMed  CAS  Google Scholar 

  14. Maeda K, Chung YS, Ogawa Y, Takatsuka S, Kang SM, Ogawa M, Sawada T, Sowa M. Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer 1996;77:858–863.

    Article  PubMed  CAS  Google Scholar 

  15. Maehara Y, Kabashima A, Koga T, Tokunaga E, Takeuchi H, Kakeji Y, Sugimachi K. Vascular invasion and potential for tumor angiogenesis and metastasis in gastric carcinoma. Surgery 2000;128:408–416.

    Article  PubMed  CAS  Google Scholar 

  16. Fondevila C, Metges JP, Fuster J, Grau JJ, Palacin A, Castells A, Volant A, Pera M. p53 and VEGF expression are independent predictors of tumour recurrence and survival following curative resection of gastric cancer. Br J Cancer 2004;90:206–215.

    Article  PubMed  CAS  Google Scholar 

  17. Etoh T, Inoue H, Tanaka S, Barnard GF, Kitano S, Mori M. Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases. Cancer Res 2001;61:2145–2153.

    PubMed  CAS  Google Scholar 

  18. Sun XD, Liu XE, Wu JM, Cai XJ, Mou YP, Li JD. Expression and significance of angiopoietin-2 in gastric cancer. World J Gastroenterol 2004;10:1382–1385.

    PubMed  CAS  Google Scholar 

  19. Heiss MM, Babic R, Allgayer H, Gruetzner KU, Jauch KW, Loehrs U, Schildberg FW. Tumor-associated proteolysis and prognosis: new functional risk factors in gastric cancer defined by the urokinase-type plasminogen activator system. J Clin Oncol 1995;13:2084–2093.

    PubMed  CAS  Google Scholar 

  20. Kaneko T, Konno H, Baba M, Tanaka T, Nakamura S. Urokinase-type plasminogen activator expression correlates with tumor angiogenesis and poor outcome in gastric cancer. Cancer Sci 2003;94:43–49.

    Article  PubMed  CAS  Google Scholar 

  21. Greene FL, Page DL, Fleming ID, Fritz A, Balch CH, Haller DG, Morrow M, eds. AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer-Verlag, 2002.

  22. Japanese Gastric Cancer Association. Japanese Classification of Gastric Carcinoma-2nd English Edition. Gastric Cancer 1998;1:10–24.

    Article  PubMed  Google Scholar 

  23. Grau JJ, Estape J, Fuster J, Filella X, Visa J, Teres J, Soler G, Albiol S, Garcia-Valdecasas JC, Grande L, Bombi JA, Bordas JM, Alcobendas F. Randomized trial of adjuvant chemotherapy with mitomycin plus ftorafur versus mitomycin alone in resected locally advanced gastric cancer. J Clin Oncol 1998;16:1036–1039.

    PubMed  CAS  Google Scholar 

  24. Inoue K, Ozeki Y, Suganuma T, Sugiura Y, Tanaka S. Vascular endothelial growth factor expression in primary esophageal squamous cell carcinoma. Association with angiogenesis and tumor progression. Cancer 1997;79:206–213.

    Article  PubMed  CAS  Google Scholar 

  25. Nakayama T, Yoshizaki A, Kawahara N, Ohtsuru A, Wen CY, Fukuda E, Nakashima M, Sekine I. Expression of Tie-1 and 2 receptors, and angiopoietin-1, 2 and 4 in gastric carcinoma; immunohistochemical analyses and correlation with clinicopathological factors. Histopathology 2004;44:232–239.

    Article  PubMed  CAS  Google Scholar 

  26. Tatsuguchi A, Matsui K, Shinji Y, Gudis K, Tsukui T, Kishida T, Fukuda Y, Sugisaki Y, Tokunaga A, Tajiri T, Sakamoto C. Cyclooxygenase-2 expression correlates with angiogenesis and apoptosis in gastric cancer tissue. Hum Pathol 2004;35:488–495.

    Article  PubMed  CAS  Google Scholar 

  27. Zhang S, Li L, Lin JY, Lin H. Imbalance between expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in invasiveness and metastasis of human gastric carcinoma. World J Gastroenterol 2003;9:899–904.

    PubMed  CAS  Google Scholar 

  28. Vermeulen PB, Gasparini G, Fox SB, Colpaert C, Marson LP, Gion M, Belien JA, de Waal RM, Van Marck E, Magnani E, Weidner N, Harris AL, Dirix LY. Second international consensus on the methodology and criteria of evaluation of angiogenesis quantification in solid human tumours. Eur J Cancer 2002;38:1564–1579.

    Article  PubMed  CAS  Google Scholar 

  29. Poon RT, Fan ST, Wong J. Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 2001;19:1207–1225.

    PubMed  CAS  Google Scholar 

  30. Maeda K, Kang SM, Onoda N, Ogawa M, Kato Y, Sawada T, Chung KH. Vascular endothelial growth factor expression in preoperative biopsy specimens correlates with disease recurrence in patients with early gastric carcinoma. Cancer 1999;86:566–571.

    Article  PubMed  CAS  Google Scholar 

  31. Saito H, Tsujitani S, Kondo A, Ikegushi M, Maeta M, Kaibara N. Expression of vascular endothelial growth factor correlates with hematogenous recurrence in gastric carcinoma. Surgery 1999;125:195–201.

    PubMed  CAS  Google Scholar 

  32. Ichikura T, Tomimatsu S, Ohkura E, Mochizuki H. Prognostic significance of the expression of vascular endothelial growth factor (VEGF) and VEGF-C in gastric carcinoma. J Surg Oncol 2001;78:132–137.

    Article  PubMed  CAS  Google Scholar 

  33. McCarty MF, Wey J, Stoeltzing O, Liu W, Fan F, Bucana C, Mansfield PF, Ryan AJ, Ellis LM. ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor with additional activity against epidermal growth factor receptor tyrosine kinase, inhibits orthotopic growth and angiogenesis of gastric cancer. Mol Cancer Ther 2004;3:1041–1048.

    PubMed  CAS  Google Scholar 

  34. Shah MA, Ramanathan RK, Ilson D, Randazzo J, Schwartz GK, Tse A, Tse A, D’Adamo D, Levner A, Capanu M, Kelsen DP. Final results of a multicenter phase II study of irinotecan (CPT), cisplatin (CIS), and bevacizumab (BEV) in patients with metastatic gastric or gastroesophageal (GEJ) adenocarcinoma (NCI #6447). J Clin Oncol 2006;24:183s.

    Article  CAS  Google Scholar 

  35. Wang J, Wu K, Zhang D, Tang H, Xie H, Hong L, Pan Y, Lan M, Hu S, Ning X, Fan D. Expressions and clinical significances of angiopoietin-1, -2 and Tie2 in human gastric cancer. Biochem Biophys Res Commun 2005;337:386–393.

    Article  PubMed  CAS  Google Scholar 

  36. Chen CN, Sung CT, Lin MT, Lee PH, Chang KJ. Clinicopathologic association of cyclooxygenase 1 and cyclooxygenase 2 expression in gastric adenocarcinoma. Ann Surg 2001;233:183–188.

    Article  PubMed  CAS  Google Scholar 

  37. Joo YE, Rew JS, Seo YH, Choi SK, Kim YJ, Park CS, Kim SJ. Cyclooxygenase-2 overexpression correlates with vascular endothelial growth factor expression and tumor angiogenesis in gastric cancer. J Clin Gastroenterol 2003;37:28–33.

    Article  PubMed  CAS  Google Scholar 

  38. Mrena J, Wiksten JP, Thiel A, Kokkola A, Pohjola L, Lundin J, Ristimaki A, Haglund C. Cyclooxygenase-2 is an independent prognostic factor in gastric cancer and its expression is regulated by the messenger RNA stability factor HuR. Clin Cancer Res 2005;11:7362–7368.

    Article  PubMed  CAS  Google Scholar 

  39. Andreasen PA, Kjoller L, Christensen L, Duffy MJ. The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 1997;72:1–22.

    Article  PubMed  CAS  Google Scholar 

  40. Duffy MJ, Maguire TM, McDermott EW, O’Higgins N. Urokinase plasminogen activator: a prognostic marker in multiple types of cancer. J Surg Oncol 1999;71:130–135.

    Article  PubMed  CAS  Google Scholar 

  41. Nekarda H, Schmitt M, Ulm K, Wenninger A, Vogelsang H, Becker K, Roder JD, Fink U, Siewert JR. Prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in completely resected gastric cancer. Cancer Res 1994;54:2900–2907.

    PubMed  CAS  Google Scholar 

  42. Okusa Y, Ichikura T, Mochizuki H. Prognostic impact of stromal cell-derived urokinase-type plasminogen activator in gastric carcinoma. Cancer 1999;85:1033–1038.

    Article  PubMed  CAS  Google Scholar 

  43. Okusa Y, Ichikura T, Mochizuki H, Shinomiya N. Urokinase type plasminogen activator and its receptor regulate the invasive potential of gastric cancer cell lines. Int J Oncol 2000;17:1001–1005.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Llorenç Badiella from the Department of Statistics, Universitat Autonoma de Barcelona, for expert help in the statistical analysis and Dr. Alan Cameron and Dr. Joaquim Bellmunt for editorial comments.

This work was supported in part by research grants from the Fundació “la Caixa” (LC 02/126-00, from the Instituto de Salud Carlos III (RC03/02 and RC03/10), and from Fundación Científica de la Asociación Española Contra el Cáncer (Junta Provincial de Albacete).

Author information

Authors and Affiliations

  1. Department of Surgery, Institut de Malalties Digestives i Metabolisme, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona Medical School, Barcelona, Spain

    Óscar Vidal & Manuel Pera

  2. Department of Gastroenterology, Institut de Malalties Digestives i Metabolisme, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERehd, University of Barcelona Medical School, Barcelona, Spain

    Antonio Soriano-Izquierdo, José I. Elizalde, Antoni Castells & Josep M. Piqué

  3. Department of Pathology, Hospital Clínic, University of Barcelona Medical School, Barcelona, Spain

    Antonio Palacín

  4. Department of Pathology, Centre Hospitalier Universitaire Cavale Blanche et Morvan, Brest, France

    Alain Volant

  5. Department of Medical Oncology, Centre Hospitalier Universitaire Cavale Blanche et Morvan, Brest, France

    Jean P. Metges

  6. Section of Gastrointestinal Surgery, Hospital Universitario del Mar, IMIM, Passeig Marítim 25-29, 08003, Barcelona, Spain

    Manuel Pera

Authors
  1. Óscar Vidal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antonio Soriano-Izquierdo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manuel Pera
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. José I. Elizalde
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Antonio Palacín
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antoni Castells
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Josep M. Piqué
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alain Volant
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jean P. Metges
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Manuel Pera.

Additional information

Óscar Vidal, Antonio Soriano-Izquierdo, contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vidal, Ó., Soriano-Izquierdo, A., Pera, M. et al. Positive VEGF Immunostaining Independently Predicts Poor Prognosis in Curatively Resected Gastric Cancer Patients: Results of a Study Assessing a Panel of Angiogenic Markers. J Gastrointest Surg 12, 1005–1014 (2008). https://doi.org/10.1007/s11605-007-0336-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11605-007-0336-3

Keywords

Search

Navigation