VEGF-A promotes lymphoma tumour growth by activation of STAT proteins and inhibition of p27(KIP1) via paracrine mechanisms

Berber D. Roorda, Arja ter Elst, Frank J. G. Scherpen, Tiny G. J. Meemusen-de Boer, Willem A. Kamps, Eveline S. J. M. de Bont*

*Corresponding author for this work

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12 Citations (Scopus)

Abstract

Increased levels of circulating VEGF-A have been demonstrated in patients with non-Hodgkin lymphoma (NHL) and are associated with progressive disease and poor clinical outcome. We investigated the role of VEGF-A in lymphoma tumour growth on a molecular level in order to identify the mechanism of VEGF-A-promoted tumour growth and to identify the potential targets for therapy. We used a model in which Daudi (human Burkitt lymphoma) tumour cells were transduced with VEGF-A165 or an empty vector (negative control) and subcutaneously injected in NOD/SCID mice. The weight of tumours over-expressing VEGF-A was increased 4-fold compared to that of control tumours (p <0.0001), whereas no in vitro growth advantage was demonstrated upon VEGF-A overexpression. VEGF-A-tumours were associated with increased microvessel densities (p = 0.004) and increased tumour cell proliferation (Ki67; p <0.001) compared to control tumours. VEGF-A-tumours were characterised by upregulation of phosphorylated STAT-4 and STAT-6 and downregulation of phospho-p27(KIP1), a crucial cell cycle inhibitor (p <0.05). This was accompanied by increased levels of phosphorylated receptor tyrosine kinases, including EGFR (ErbB-2 and ErbB-4, p <0.05), an upstream regulator of STAT proteins. We demonstrated that various mouse-derived cytokines produced by mouse-derived tumour stromal cells are upregulated in VEGF-A-tumours compared to control tumours (p <0.05). These results indicate an important role for the tumour microenvironment in paracrine promotion of lymphoma tumour growth in response to tumour-derived VEGF-A. In conclusion, lymphoma-derived VEGF-A promoted lymphoma tumour growth in a paracrine loop by activation of tumour stromal cells. Our study reveals VEGF-A and STAT proteins as potential additional targets in the treatment of lymphoma. (C) 2009 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)974-982
Number of pages9
JournalEuropean Journal of Cancer
Volume46
Issue number5
DOIs
Publication statusPublished - Mar-2010

Keywords

  • VEGF-A
  • Lymphoma
  • Paracrine
  • Cytokines
  • STAT proteins
  • Angiogenesis
  • Proliferation
  • Signal transduction
  • NON-HODGKINS-LYMPHOMA
  • DEPENDENT KINASE INHIBITOR
  • ACUTE MYELOID-LEUKEMIA
  • MANTLE CELL LYMPHOMA
  • PROGNOSTIC-SIGNIFICANCE
  • SIMULTANEOUS ELEVATION
  • SERUM CONCENTRATIONS
  • MULTIPLE-MYELOMA
  • EXPRESSION
  • ANGIOGENESIS

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