title: Up-regulation of angiopoietin-2, matrix metalloprotease-2, membrane type 1 metalloprotease, and laminin 5 gamma 2 correlates with the invasiveness of human glioma.
abstract: 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.
authors.affiliation: Department of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213-1863, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Guo
authors.forename: Yorihisa
authors.initials: Y
authors.lastname: Imanishi
authors.forename: Frank C
authors.initials: FC
authors.lastname: Cackowski
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jarzynka
authors.forename: Huo-Quan
authors.initials: HQ
authors.lastname: Tao
authors.forename: Ryo
authors.initials: R
authors.lastname: Nishikawa
authors.forename: Takanori
authors.initials: T
authors.lastname: Hirose
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.forename: Shi-Yuan
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D042702:Angiopoietin-2 / Q000096:biosynthesis*; D000818:Animals; D001254:Astrocytoma / Q000378:metabolism; D001706:Biopsy; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D007763:Lac Operon; D007797:Laminin / Q000096:biosynthesis*; D053511:Matrix Metalloproteinase 14; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D051379:Mice; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D042702:Angiopoietin-2; C400567:LAMC2 protein, human; C498522:Lamc2 protein, mouse; D007797:Laminin; C507096:Mmp14 protein, mouse; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14
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