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Cell and Tumor Biology

A Hypoxia-Driven Vascular Endothelial Growth Factor/Flt1 Autocrine Loop Interacts with Hypoxia-Inducible Factor-1α through Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase 1/2 Pathway in Neuroblastoma

Bikul Das, Herman Yeger, Rika Tsuchida, Risa Torkin, Matthew F.W. Gee, Paul S. Thorner, Masabumi Shibuya, David Malkin and Sylvain Baruchel
Bikul Das
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Herman Yeger
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Rika Tsuchida
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Risa Torkin
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Matthew F.W. Gee
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Paul S. Thorner
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Masabumi Shibuya
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David Malkin
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Sylvain Baruchel
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DOI: 10.1158/0008-5472.CAN-04-4575 Published August 2005
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Abstract

Flt1, an “fms-like tyrosine kinase” receptor, has been suggested to play an active role in vascular endothelial growth factor (VEGF)–mediated autocrine signaling of tumor growth and angiogenesis. Here, we used a neuroblastoma model to investigate the role of VEGF/Flt1 signaling in hypoxia-mediated tumor cell survival, drug resistance, and in vivo angiogenesis. SK-N-BE(2), a highly malignant neuroblastoma cell line resistant to hypoxia-induced apoptosis expresses active Flt1 but lacks VEGFR2 expression. We found that 24-hour hypoxia (<0.1% O2) alone (no serum deprivation) showed sustained activation of extracellular signal-regulated kinase 1/2 (ERK1/2) associated with bcl-2 up-regulation and resistance to etoposide-induced (5 μmol/L) apoptosis. Treatment with anti-VEGF and anti-Flt1 antibodies inhibited ERK1/2 activation, down-regulated bcl-2, and reversed the hypoxia-mediated drug resistance to etoposide. Similar results were obtained with U0126 and ursolic acid, specific and nonspecific inhibitors of ERK1/2, respectively. We confirmed the protective role of Flt1 receptor by small interfering RNA knockout and Flt1 overexpression studies. Subsequently, we found that inhibition of VEGF/Flt1 autocrine signaling led to reduced hypoxia-inducible factor-1α (HIF-1α) phosphorylation. Furthermore, the reduced phosphorylation was associated with down-regulation of basic fibroblast growth factor, a downstream target of the HIF-1α and VEGF pathways. Our findings suggested an expanded autocrine loop between VEGF/Flt1 signaling and HIF-1α. We investigated the angiogenic activity of the loop in an in vivo Matrigel plug assay. The hypoxia-treated conditioned medium induced a strong angiogenic response, as well as the cooption of surrounding vessels into the plugs; ursolic acid inhibited the angiogenesis process. We also found that three other Flt1-expressing neuroblastoma cell lines show hypoxia-mediated drug resistance to etoposide, melphalan, doxorubicin, and cyclophosphamide. Taken together, we conclude that a hypoxia-driven VEGF/Flt1 autocrine loop interacts with HIF-1α through a mitogen-activated protein kinase/ERK1/2 pathway in neuroblastoma. The interaction, in the form of an autocrine loop, is required for the hypoxia-driven cell survival, drug resistance, and angiogenesis in neuroblastoma.

  • HIF-1α
  • VEGF/Flt1
  • neuroblastoma
  • MAPK/ERK 1/2
  • hypoxia-mediated drug resistance
  • angiogenesis

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received December 22, 2004.
  • Revision received April 30, 2005.
  • Accepted May 27, 2005.
  • ©2005 American Association for Cancer Research.
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Cancer Research: 65 (16)
August 2005
Volume 65, Issue 16
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A Hypoxia-Driven Vascular Endothelial Growth Factor/Flt1 Autocrine Loop Interacts with Hypoxia-Inducible Factor-1α through Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase 1/2 Pathway in Neuroblastoma
Bikul Das, Herman Yeger, Rika Tsuchida, Risa Torkin, Matthew F.W. Gee, Paul S. Thorner, Masabumi Shibuya, David Malkin and Sylvain Baruchel
Cancer Res August 15 2005 (65) (16) 7267-7275; DOI: 10.1158/0008-5472.CAN-04-4575

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A Hypoxia-Driven Vascular Endothelial Growth Factor/Flt1 Autocrine Loop Interacts with Hypoxia-Inducible Factor-1α through Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase 1/2 Pathway in Neuroblastoma
Bikul Das, Herman Yeger, Rika Tsuchida, Risa Torkin, Matthew F.W. Gee, Paul S. Thorner, Masabumi Shibuya, David Malkin and Sylvain Baruchel
Cancer Res August 15 2005 (65) (16) 7267-7275; DOI: 10.1158/0008-5472.CAN-04-4575
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