Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Spotlight
  • Published:

Autocrine VEGF mediates the antiapoptotic effect of CD154 on CLL cells

Leukemia volume 19, pages 524–530 (2005)Cite this article

Abstract

CD154 is an important regulator of chronic lymphocytic leukaemia (CLL)-cell survival. In CLL, high serum levels of VEGF are a feature of advanced disease, and we and others have previously shown that CLL cells produce and secrete this growth factor. Since CD154 stimulates VEGF production in other cell types, and VEGF is known to promote cell survival, we examined whether the cytoprotection of CLL cells by CD154 involves VEGF. We report for the first time that treatment of CLL cells with CD154 results in increased VEGF production and demonstrate involvement of NF-κB in this process. Moreover, we show that CD154-induced CLL-cell survival is reduced by anti-VEGF-neutralising antibody and by inhibiting VEGF receptor (VEGFR) signalling with SU5416. However, addition of exogenous VEGF alone or blocking secreted autocrine VEGF had little or no effect on CLL-cell survival. We therefore conclude that CLL-cell cytoprotection in the presence of CD154 requires combined signalling by both CD40 and VEGFR. This combined signalling and resulting cytoprotection were shown to involve NF-κB activation and increased survivin production. In conclusion, our findings identify autocrine VEGF as an important mediator of the antiapoptotic effect of CD40 ligation, and thus provide new insights into CLL-cell rescue by CD154 in lymphoreticular tissues.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

References

  1. Rozman C, Montserrat E . Chronic lymphocytic leukemia. N Engl J Med 1995; 333: 1052–1057.

    Article  CAS  PubMed  Google Scholar 

  2. Kipps TJ . Chronic lymphocytic leukemia. Curr Opin Hematol 2000; 7: 223–234.

    Article  CAS  PubMed  Google Scholar 

  3. Reed JC . Molecular biology of chronic lymphocytic leukemia. Semin Oncol 1998; 25: 11–18.

    CAS  PubMed  Google Scholar 

  4. Guipaud O, Deriano L, Salin H, Vallat L, Sabatier L, Merle-Beral H et al. B-cell chronic lymphocytic leukaemia: a polymorphic family unified by genomic features. Lancet Oncol 2003; 4: 505–514.

    Article  PubMed  Google Scholar 

  5. Chen H, Treweeke AT, West DC, Till KJ, Cawley JC, Zuzel M et al. In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells. Blood 2000; 96: 3181–3187.

    CAS  PubMed  Google Scholar 

  6. Kay NE, Bone ND, Tschumper RC, Howell KH, Geyer SM, Dewald GW et al. B-CLL cells are capable of synthesis and secretion of both pro- and anti-angiogenic molecules. Leukemia 2002; 16: 911–919.

    Article  CAS  PubMed  Google Scholar 

  7. Molica S, Vitelli G, Levato D, Gandolfo GM, Liso V . Increased serum levels of vascular endothelial growth factor predict risk of progression in early B-cell chronic lymphocytic leukaemia. Br J Haematol 1999; 107: 605–610.

    Article  CAS  PubMed  Google Scholar 

  8. Ferrajoli A, Manshouri T, Estrov Z, Keating MJ, O'Brien S, Lerner S et al. High levels of vascular endothelial growth factor receptor-2 correlate with shortened survival in chronic lymphocytic leukemia. Clin Cancer Res 2001; 7: 795–799.

    CAS  PubMed  Google Scholar 

  9. Kini AR, Kay NE, Peterson LC . Increased bone marrow angiogenesis in B cell chronic lymphocytic leukemia. Leukemia 2000; 14: 1414–1418.

    Article  CAS  PubMed  Google Scholar 

  10. Alon T, Hemo I, Itin A, Péer J, Stone J, Keshet E . Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1995; 1: 1024–1028.

    Article  CAS  PubMed  Google Scholar 

  11. Masood R, Cai J, Zheng T, Smith DL, Hinton DR, Gill PS . Vascular endothelial growth factor (VEGF) is an autocrine growth factor for VEGF receptor-positive human tumors. Blood 2001; 98: 1904–1913.

    Article  CAS  PubMed  Google Scholar 

  12. Gerber HP, Malik AK, Solar GP, Sherman D, Liang XH, Meng G et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 2002; 417: 954–958.

    Article  CAS  PubMed  Google Scholar 

  13. Lee YK, Bone ND, Strege AK, Shanafelt TD, Jelinek DF, Kay NE . VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG), in B-cell chronic lymphocytic leukemia. Blood 2004; 104: 788–794.

    Article  CAS  PubMed  Google Scholar 

  14. Zhang R, Xu Y, Ekman N, Wu Z, Wu J, Alitalo K et al. Etk/Bmx transactivates VEGFR2 and recruits phosphatidylinositol 3-kinase to mediate TNF-induced angiogenic pathway. J Biol Chem 2003; 278: 51267–51276.

    Article  CAS  PubMed  Google Scholar 

  15. Banchereau J, Bazan F, Blanchard D, Briere F, Galizzi JP, van Kooten C et al. The CD40 antigen and its ligand. Annu Rev Immunol 1994; 12: 881–922.

    Article  CAS  PubMed  Google Scholar 

  16. Schattner EJ . CD40 ligand in CLL pathogenesis and therapy. Leukemia Lymphoma 2000; 37: 461–472.

    Article  CAS  PubMed  Google Scholar 

  17. van Kooten C, Banchereau J . CD40-CD40 ligand: a multifunctional receptor–ligand pair. Adv Immunol 1996; 61: 1–77.

    Article  CAS  PubMed  Google Scholar 

  18. Melter M, Reinders ME, Sho M, Pal S, Geehan C, Denton MD et al. Ligation of CD40 induces the expression of vascular endothelial growth factor by endothelial cells and monocytes and promotes angiogenesis in vivo. Blood 2000; 96: 3801–3808.

    CAS  PubMed  Google Scholar 

  19. Cho CS, Cho ML, Min SY, Kim WU, Min DJ, Lee SS et al. CD40 engagement on synovial fibroblast up-regulates production of vascular endothelial growth factor. J Immunol 2000; 164: 5055–5061.

    Article  CAS  PubMed  Google Scholar 

  20. Tai YT, Podar K, Gupta D, Lin B, Young G, Akiyama M et al. CD40 activation induces p53-dependent vascular endothelial growth factor secretion in human multiple myeloma cells. Blood 2002; 99: 1419–1427.

    Article  CAS  PubMed  Google Scholar 

  21. Wang D, Freeman GJ, Levine H, Ritz J, Robertson MJ . Role of the CD40 and CD95 (APO-1/Fas) antigens in the apoptosis of human B-cell malignancies. Br J Haematol 1997; 97: 409–417.

    Article  CAS  PubMed  Google Scholar 

  22. Romano MF, Lamberti A, Tassone P, Alfinito F, Costantini S, Chiurazzi F et al. Triggering of CD40 antigen inhibits fludarabine-induced apoptosis in B chronic lymphocytic leukemia cells. Blood 1998; 92: 990–995.

    CAS  PubMed  Google Scholar 

  23. Furman RR, Asgary Z, Mascarenhas JO, Liou HC, Schattner EJ . Modulation of NF-kappa B activity and apoptosis in chronic lymphocytic leukemia B cells. J Immunol 2000; 164: 2200–2206.

    Article  CAS  PubMed  Google Scholar 

  24. Grdisa M . Influence of CD40 ligation on survival and apoptosis of B-CLL cells in vitro. Leukemia Res 2003; 27: 951–956.

    Article  CAS  Google Scholar 

  25. Zamzami N, Marchetti P, Castedo M, Zanin C, Vayssiere JL, Petit PX et al. Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo. J Exp Med 1995; 181: 1661–1672.

    Article  CAS  PubMed  Google Scholar 

  26. Lin YZ, Yao SY, Veach RA, Torgerson TR, Hawiger J . Inhibition of nuclear translocation of transcription factor NF-kappa B by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence. J Biol Chem 1995; 270: 14255–14258.

    Article  CAS  PubMed  Google Scholar 

  27. Granziero L, Ghia P, Circosta P, Gottardi D, Strola G, Geuna M et al. Survivin is expressed on CD40 stimulation and interfaces proliferation and apoptosis in B-cell chronic lymphocytic leukemia. Blood 2001; 97: 2777–2783.

    Article  CAS  PubMed  Google Scholar 

  28. Itokawa T, Nokihara H, Nishioka Y, Sone S, Iwamoto Y, Yamada Y et al. Antiangiogenic effect by SU5416 is partly attributable to inhibition of Flt-1 receptor signaling. Mol Cancer Ther 2002; 1: 295–302.

    CAS  PubMed  Google Scholar 

  29. 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: 3883–3889.

    Article  CAS  PubMed  Google Scholar 

  30. Karin M, Lin A . NF-kappaB at the crossroads of life and death. Nat Immunol 2002; 3: 221–227.

    Article  CAS  PubMed  Google Scholar 

  31. Kim I, Moon SO, Kim SH, Kim HJ, Koh YS, Koh GY . Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-kappa B activation in endothelial cells. J Biol Chem 2001; 276: 7614–7620.

    Article  CAS  PubMed  Google Scholar 

  32. Park JE, Chen HH, Winer J, Houck KA, Ferrara N . Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 1994; 269: 25646–25654.

    CAS  PubMed  Google Scholar 

  33. Meyer M, Clauss M, Lepple-Wienhues A, Waltenberger J, Augustin HG, Ziche M et al. A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. EMBO J 1999; 18: 363–374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yoshida S, Ono M, Shono T, Izumi H, Ishibashi T, Suzuki H et al. Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis. Mol Cell Biol 1997; 17: 4015–4023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Huang S, Pettaway CA, Uehara H, Bucana CD, Fidler IJ . Blockade of NF-kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene 2001; 20: 4188–4197.

    Article  CAS  PubMed  Google Scholar 

  36. Shibata A, Nagaya T, Imai T, Funahashi H, Nakao A, Seo H . Inhibition of NF-kappaB activity decreases the VEGF mRNA expression in MDA-MB-231 breast cancer cells. Breast Cancer Res Treat 2002; 73: 237–243.

    Article  CAS  PubMed  Google Scholar 

  37. Abeyama K, Eng W, Jester JV, Vink AA, Edelbaum D, Cockerell CJ et al. A role for NF-kappaB-dependent gene transactivation in sunburn. J Clin Invest 2000; 105: 1751–1759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kiriakidis S, Andreakos E, Monaco C, Foxwell B, Feldmann M, Paleolog E . VEGF expression in human macrophages is NF-kappaB-dependent: studies using adenoviruses expressing the endogenous NF-kappaB inhibitor IkappaBalpha and a kinase-defective form of the IkappaB kinase 2. J Cell Sci 2003; 116: 665–674.

    Article  CAS  PubMed  Google Scholar 

  39. Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem 1998; 273: 30336–30343.

    Article  CAS  PubMed  Google Scholar 

  40. Gerber HP, Dixit V, Ferrara N . Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J Biol Chem 1998; 273: 13313–13316.

    Article  CAS  PubMed  Google Scholar 

  41. Tran J, Rak J, Sheehan C, Saibil SD, LaCasse E, Korneluk RG et al. Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells. Biochem Biophys Res Commun 1999; 264: 781–788.

    Article  CAS  PubMed  Google Scholar 

  42. Reinders ME, Sho M, Robertson SW, Geehan CS, Briscoe DM . Proangiogenic function of CD40 ligand–CD40 interactions. J Immunol 2003; 171: 1534–1541.

    Article  CAS  PubMed  Google Scholar 

  43. Marumo T, Schini-Kerth VB, Busse R . Vascular endothelial growth factor activates nuclear factor-kappaB and induces monocyte chemoattractant protein-1 in bovine retinal endothelial cells. Diabetes 1999; 48: 1131–1137.

    Article  CAS  PubMed  Google Scholar 

  44. Oyama T, Ran S, Ishida T, Nadaf S, Kerr L, Carbone DP et al. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol 1998; 160: 1224–1232.

    CAS  PubMed  Google Scholar 

  45. Dikov MM, Oyama T, Cheng P, Takahashi T, Takahashi K, Sepetavec T et al. Vascular endothelial growth factor effects on nuclear factor-kappaB activation in hematopoietic progenitor cells. Cancer Res 2001; 61: 2015–2021.

    CAS  PubMed  Google Scholar 

  46. Dadgostar H, Zarnegar B, Hoffmann A, Qin XF, Truong U, Rao G et al. Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes. Proc Natl Acad Sci USA 2002; 99: 1497–1502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dallman C, Johnson PW, Packham G . Differential regulation of cell survival by CD40. Apoptosis 2003; 8: 45–53.

    Article  CAS  PubMed  Google Scholar 

  48. Kroll J, Waltenberger J . The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. J Biol Chem 1997; 272: 32521–32527.

    Article  CAS  PubMed  Google Scholar 

  49. Aramoto H, Breslin JW, Pappas PJ, Hobson RW, Duran WN . Vascular endothelial growth factor stimulates differential signaling pathways in in vivo microcirculation. Am J Physiol Heart Circ Physiol 2004; 287: H1590–H1598.

    Article  CAS  PubMed  Google Scholar 

  50. Kitada S, Zapata JM, Andreeff M, Reed JC . Bryostatin and CD40-ligand enhance apoptosis resistance and induce expression of cell survival genes in B-cell chronic lymphocytic leukaemia. Br J Haematol 1999; 106: 995–1004.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the North West Cancer Research Fund (UK) and LRF (UK).

Author information

Authors and Affiliations

  1. Department of Haematology, University of Liverpool, Royal Liverpool University Hospital, Liverpool, UK

    M Farahani, A T Treweeke, C H Toh, K J Till, R J Harris, J C Cawley, M Zuzel & H Chen

Authors
  1. M Farahani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A T Treweeke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C H Toh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K J Till
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R J Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J C Cawley
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Zuzel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Farahani.

Additional information

Supplementary Information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Farahani, M., Treweeke, A., Toh, C. et al. Autocrine VEGF mediates the antiapoptotic effect of CD154 on CLL cells. Leukemia 19, 524–530 (2005). https://doi.org/10.1038/sj.leu.2403631

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403631

Keywords

This article is cited by

Search

Advanced search

Quick links