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Up-regulation of vascular endothelial growth factor by membrane-type 1 matrix metalloproteinase stimulates human glioma xenograft growth and angiogenesis

Academic Article
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Overview

authors

  • Deryugina, Elena
  • Soroceanu, L.
  • Strongin, A. Y.

publication date

  • January 2002

journal

  • Cancer Research  Journal

abstract

  • Membrane-type (MT) 1 matrix metalloproteinase (MMP) is up-regulated in many tumor types and has been implicated in tumor progression and metastasis. MT1-MMP is critical for pericellular degradation of the extracellular matrix, thereby promoting tumor cell invasion and dissemination. To grow efficiently in vivo, tumor cells induce angiogenesis in both primary solid tumors and metastatic foci. The present study describes a functional link between the expression of MT1-MMP and vascular endothelial growth factor (VEGF) production in human glioma U251 xenografts in athymic mice. To investigate the effects of MT1-MMP on VEGF expression, U251 cells were stably transfected with MT1-MMP to generate the U-MT cell line overexpressing the enzyme. In vitro, the U-MT cells had an increased rate of proliferation and migration as well as the ability to activate the MMP-2 proenzyme and directionally remodel a three-dimensional collagen matrix. These findings suggested higher tumorigenicity of U-MT cells relative to the vector-control U-neo cells. In agreement with the in vitro data, U-MT xenografts in BALB/c nu/nu mice displayed markedly increased growth rates and elevated levels of angiogenesis. In contrast, U-neo cells formed small, minimally vascularized tumors. The elevated angiogenesis in U-MT xenografts was associated with an up-regulation of VEGF expression in tumor cells. In addition, U-MT cells in vitro secreted twice as much VEGF as the control cells. GM6001, a hydroxamate inhibitor of MMP activity, down-regulated the production of VEGF in U-MT cells to the levels observed in the U-neo control. Our results demonstrate that the enhanced tumorigenicity of glioma cells overexpressing MT1-MMP involves stimulation of angiogenesis through the up-regulation of VEGF production.

subject areas

  • Animals
  • Cell Division
  • Cell Movement
  • Collagen
  • Endothelial Growth Factors
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glioma
  • Humans
  • Lymphokines
  • Matrix Metalloproteinase 14
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Neovascularization, Pathologic
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • Up-Regulation
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
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Identity

International Standard Serial Number (ISSN)

  • 0008-5472

PubMed ID

  • 11809713
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Additional Document Info

start page

  • 580

end page

  • 588

volume

  • 62

issue

  • 2

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