Skip to main content

Advertisement

SpringerLink
Log in

Effect of heat shock protein-90 (HSP90) and vascular endothelial growth factor (VEGF) on survival in acute lymphoblastic leukemia: an immunohistochemical study

  • Original paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Background The significance of vascular endothelial growth factor (VEGF) and heat shock protein-90 (HSP90) has received only limited attention especially in acute lymphoblastic leukemia (ALL). In this study, we assessed expressions of HSP90 and VEGF in bone marrow samples of patients with ALL and effect of these expression quantities on the mean overall survival. Patients and methods Using immunohistochemical methods, we assessed expression of HSP90 and VEGF in 22 cases of ALL. Results Expression of HSP90 was detected in 19/22 (86.4%) and 3/22 (13.6%) of patients with ALL, for strongly positive and moderate-weakly positive, respectively. Negative HSP90 expression was not detected in patients with ALL. Expression of HSP90 in patients with ALL and in control group were statistically significant (P < 0.001), however, did not reflect the mean overall survival (P = 0.910). Mean OS was evaluated 992 ± 181 and 724.8 ± 88.2 days for moderate-weak and high HSP90 expression, respectively. VEGF expressions were not significantly different between ALL and control groups (P < 0.087). We did not find any relationship between HSP90 and VEGF expressions in bone marrow specimens of patients with ALL. Conclusion This study demonstrated that HSP90 expression grades in patients with ALL were significantly higher than that in controls and presence of strong HSP90 expression was associated with worse overall survival. VEGF expression in patients with ALL was not different from that in control samples. Determination HSP90 with immunohistochemical method in bone marrow can provide information about prognosis.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Hartl FU, Hayer-Hartl M. Molecular chaperones in the cytosol: from nascent chain to folded protein. Science. 2002;295:1852–8.

    Article  PubMed  CAS  Google Scholar 

  2. Burrows F, Zhang H, Kamal A. Hsp90 activation and cell cycle regulation. Cell Cycle. 2004;3:1530–6.

    Article  PubMed  CAS  Google Scholar 

  3. Sreedhar AS, Nardai G, Csermely P. Enhancement of complement-induced cell lysis: a novel mechanism for the anticancer effects of HSP90 inhibitors. Immunol Lett. 2004;92:157–61.

    Article  PubMed  CAS  Google Scholar 

  4. Kamal A, et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature. 2003;25:407–10.

    Article  Google Scholar 

  5. Isaacs JS, Xu W, Neckers L. Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell. 2003;3:213–7.

    Article  PubMed  CAS  Google Scholar 

  6. Kojika S, et al. Mechanisms of glucocorticoid resistance in human leukemic cells: Implication of abnormal 90 and 70 kDa heat shock proteins. Leukemia. 1996;10:994–9.

    PubMed  CAS  Google Scholar 

  7. Garrido C, et al. HSP27 as a mediator of influence- dependent resistance to cell death induced by anticancer drugs. Cancer Res. 1997;57:2661–7.

    PubMed  CAS  Google Scholar 

  8. Jolly C, Morimoto RI. Role of the heat shock response and molecular chaperones in oncogenesis and cell death. J Natl Cancer Res Inst. 2000;92:1564–72.

    Article  CAS  Google Scholar 

  9. Brozovic A, Simaga S, Osmak M. Induction of heat shock protein 70 in drug-resistant cells by anticancer drugs and hyperthermia. Neoplasma. 2001;48:99–103.

    PubMed  CAS  Google Scholar 

  10. Santos SC, Dias S. Internal and external autocrine VEGF/KDR loops regulate survival of subsets of acute leukemia through distinct signaling pathways. Blood. 2004;103:3883–9.

    Article  PubMed  CAS  Google Scholar 

  11. Gerber HP, et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature. 2002;417:954–8.

    Article  PubMed  CAS  Google Scholar 

  12. Dias S, Shmelkov SV, Lam G, Rafii S. VEGF promotes survival of leukemic cells by Hsp90-mediated induction of Bcl–2 expression and apoptosis inhibition. Blood. 2002;99:2532–40.

    Article  PubMed  CAS  Google Scholar 

  13. Aguayo A, Giles F, Albitar M. Vascularity, angiogenesis and angiogenic factors in leukemias and myelodysplastic syndromes. Leuk Lymphoma. 2003;44:213–22.

    Article  PubMed  CAS  Google Scholar 

  14. Zhang Y, et al. Expression and cellular localization of vascular endothelial growth factor A and its receptors in acute and chronic leukemias: an immuno- histochemical study. Hum Pathol. 2005;36:797–805.

    Article  PubMed  CAS  Google Scholar 

  15. Kalmanti L, et al. A morphometric approach for the evaluation of angiogenesis in acute lymphoblastic leukemia of childhood. Leuk Res. 2005;29:673–7.

    Article  PubMed  Google Scholar 

  16. Perez-Atayde A, et al. Spectrum of tumor angiogenesis in the bore marrow of children with acute lymphoblastic leukemia. Am J Pathol. 1997;150:815–25.

    PubMed  CAS  Google Scholar 

  17. Kuzu I, et al. Bone marrow microvessel density (MVD) in adult acute myeloid leukemia (AML): therapy induced changes and effects on survival. Leuk Lymphoma. 2004;45:1185–90.

    Article  PubMed  CAS  Google Scholar 

  18. de Bont ES, et al. Increased bone marrow vascularization in patients with acute myeloid leukaemia: a possible role for vascular endothelial growth factor. Br J Haematol. 2001;113:296–304.

    Article  PubMed  Google Scholar 

  19. Rabitsch W, et al. Bone marrow microvessel density and its prognostic significance in AML. Leuk Lymphoma. 2004;45:1369–73.

    Article  PubMed  Google Scholar 

  20. Yao Q, et al. FLT3 expressing leukemias are selectively sensitive to inhibitors of the molecular chaperone heat shock protein 90 through destabilization of signal transduction-associated kinases. Clin Cancer Res. 2003;9:4483–93.

    PubMed  CAS  Google Scholar 

  21. Valbuena JR, et al. Expression of heat-shock protein-90 in non-Hodgkin’s lymphomas. Modern Pathology. 2005;18:1343–9.

    Article  PubMed  CAS  Google Scholar 

  22. Xiao K, Liu W, Qu S, Sun H, Tang J. Study of heat shock protein HSP90 alpha, HSP70, HSP27 mRNA expression in human acute leukemia cells. J Tongji Med Univ. 1996;16:212–6.

    Article  PubMed  CAS  Google Scholar 

  23. Campos L, Chautard S, Viallet A, Guyotat D. Expression of heat-shock proteins in acute leukaemia cells. Haematologica. 1999;84:13.

    Google Scholar 

  24. Lauten M, et al. Expression of heat-shock protein 90 in glucocorticoid-sensitive and -resistant childhood acute lymphoblastic leukaemia. Leukemia. 2003;17:1551–6.

    Article  PubMed  CAS  Google Scholar 

  25. Biamonte MA, et al. heat shock protein 90: inhibitors in clinical trials. J Med Chem. 2010;53:3–17.

    Article  PubMed  CAS  Google Scholar 

  26. Neckers L, Ivy SP. Heat shock protein 90. Curr Opin Oncol. 2003;15:419–24.

    Article  PubMed  CAS  Google Scholar 

  27. Thomas X, et al. Expression of heat-shock proteins (HSPs) is associated with major adverse prognostic factors in acute myeloid leukemia (AML). Blood. 2003;102(suppl. 1):611a.

    Google Scholar 

  28. Kasimir-Bauer S, et al. Impact of the expression of P glycoprotein, the multidrug resistance-related protein, bcl-2, mutant p53, and heat shock protein 27 on response to induction therapy and long-term survival in patients with de novo acute myeloid leukemia. Exp Hematol. 2002;30(11):1302–8.

    Article  PubMed  CAS  Google Scholar 

  29. Molica S, et al. Serum angiogenin is not elevated in patients with early B-cell chronic lymphocytic leukemia but is prognostic factor for disease progression. Eur J Haematol. 2004;73:36–42.

    Article  PubMed  CAS  Google Scholar 

  30. Yetgin S, Yenicesu I, Çetin M, Tuncer M. Clinical importance of serum vascular endothelial and basic fibroblast growth factors in children with acute lymphoblastic leukemia. Leuk Lymphoma. 2001;42(1–2):83–8.

    Article  PubMed  CAS  Google Scholar 

  31. Faderl S, et al. Angiogenic factors may have a different prognostic role in adult acute lymphoblastic leukemia. Blood. 2005;106:4303–7.

    Article  PubMed  CAS  Google Scholar 

  32. Kim JG, et al. Clinical implication of angiogenic factors in patients with: Hepatocyte growth factor levels have prognostic impact, especially in patients with acute myeloid leukemia. Leuk Lymphoma. 2005;46:885–91.

    Article  PubMed  Google Scholar 

  33. Bellamy WT, Richter L, Frutiger Y, Grogan TM. Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res. 1999;59:728–33.

    PubMed  CAS  Google Scholar 

  34. Aguayo A, et al. Clinical relevance of intracellular vascular endothelial growth factor levels in B-cell chronic lymphocytic leukemia. Blood. 2000;96:768–70.

    PubMed  CAS  Google Scholar 

  35. El-Obeid A, Sunnuqrut N, Hussain A, et al. Immature B cell malignancies synthesize VEGF, VEGFR–1 (Flt–1) and VEGFR–2 (KDR). Leuk Res. 2004;28:133–7.

    Article  PubMed  CAS  Google Scholar 

  36. Koomagi R, Zintl F, Sauerbrey A, Volm M. Vascular endothelial growth factor in newly diagnosed and recurrent childhood acute lymphoblastic leukemia as measured by real-time quantitative polymerase chain reaction. Clin Cancer Res. 2001;7:3381–4.

    PubMed  CAS  Google Scholar 

  37. Lyu CJ, Rha SY, Won SC. Clinical role of bone marrow angiogenesis in childhood acute lymphocytic leukemia. Yonsei Med J. 2007;48:171–5.

    Article  PubMed  CAS  Google Scholar 

  38. Diffner E, et al. Expression of VEGF and VEGF receptors in childhood precursor B-cell acute lymphoblastic leukemia evaluated by immunohistochemistry. J Pediatr Hematol Oncol. 2009;31:696–701.

    Article  PubMed  Google Scholar 

  39. Schneider P, et al. Endostatin variations in childhood acute lymphoblastic leukaemia—comparison with basic fibroblast growth factor and vascular endothelial growth factor. Leuk Res. 2007;31:629–38.

    Article  PubMed  CAS  Google Scholar 

  40. Aref S, Salama O, Shamaa S, El-Refaie M, Mourkos H. Angiogenesis factor pattern differs in acute lymphoblastic leukemia and chronic lymphocytic leukemia. Hematology. 2007;12:319–24.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology, University of Kocaeli, Medical Faculty, Kocaeli, Turkey

    Abdullah Hacıhanefioglu, Emel Gonullu, Ozgur Mehtap & Hakan Keski

  2. Department of Public Health, University of Kocaeli, Medical Faculty, Kocaeli, Turkey

    Melike Yavuz

  3. Department of Pathology, University of Kocaeli, Medical Faculty, Kocaeli, Turkey

    Cengiz Ercin

Authors
  1. Abdullah Hacıhanefioglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emel Gonullu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ozgur Mehtap
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hakan Keski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Melike Yavuz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cengiz Ercin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abdullah Hacıhanefioglu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hacıhanefioglu, A., Gonullu, E., Mehtap, O. et al. Effect of heat shock protein-90 (HSP90) and vascular endothelial growth factor (VEGF) on survival in acute lymphoblastic leukemia: an immunohistochemical study. Med Oncol 28, 846–851 (2011). https://doi.org/10.1007/s12032-010-9533-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12032-010-9533-0

Keywords

Search

Navigation