Up-regulation of angiopoietin-2, matrix metalloprotease-2, membrane type 1 metalloprotease, and laminin 5 gamma 2 correlates with the invasiveness of human glioma

Am J Pathol. 2005 Mar;166(3):877-90. doi: 10.1016/s0002-9440(10)62308-5.


Diffuse infiltration of malignant human glioma cells into surrounding brain structures occurs through the activation of multigenic programs. We recently showed that angiopoietin-2 (Ang2) induces glioma invasion through the activation of matrix metalloprotease-2 (MMP-2). Here, we report that up-regulation of Ang2, MMP-2, membrane type 1-MMP (MT1-MMP), and laminin 5 gamma 2 (LN 5 gamma 2) in tumor cells correlates with glioma invasion. Analyses of 57 clinical human glioma biopsies of World Health Organization grade I to IV tumors displaying a distinct invasive edge and 39 glioma specimens that only contain the central region of the tumor showed that Ang2, MMP-2, MT1-MMP, and LN 5 gamma 2 were co-overexpressed in invasive areas but not in the central regions of the glioma tissues. Statistical analyses revealed a significant link between the preferential expression of these molecules and invasiveness. Protein analyses of microdissected primary glioma tissue showed up-regulation and activation of MT1-MMP and LN 5 gamma 2 at the invasive edge of the tumors, supporting this observation. Concordantly, in human U87MG glioma xenografts engineered to express Ang2, increased expression of MT1-MMP and LN 5 gamma 2, along with MMP-2 up-regulation, in actively invading glioma cells was also evident. In cell culture, stimulation of glioma cells by overexpressing Ang2 or exposure to exogenous Ang2 promoted the expression and activation of MMP-2, MT1-MMP, and LN 5 gamma 2. These results suggest that up-regulation of Ang2, MMP-2, MT1-MMP, and LN 5 gamma 2 is associated with the invasiveness displayed by human gliomas and that induction of these molecules by Ang2 may be essential for glioma invasion.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiopoietin-2 / biosynthesis*
  • Animals
  • Astrocytoma / metabolism
  • Biopsy
  • Blotting, Western
  • Brain / pathology
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology*
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic*
  • Glioma / pathology*
  • Humans
  • Immunohistochemistry
  • Lac Operon
  • Laminin / biosynthesis*
  • Matrix Metalloproteinase 14
  • Matrix Metalloproteinase 2 / biosynthesis*
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / biosynthesis*
  • Mice
  • Neoplasm Invasiveness
  • Neoplasm Transplantation
  • Neovascularization, Pathologic
  • Time Factors
  • Up-Regulation*


  • Angiopoietin-2
  • LAMC2 protein, human
  • Lamc2 protein, mouse
  • Laminin
  • Mmp14 protein, mouse
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 14