Up-regulation of angiopoietin-2, matrix metalloprotease-2, membrane type 1 metalloprotease, and laminin 5 gamma 2 correlates with the invasiveness of human glioma.
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.
Guo
Ping
P
Department of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213-1863, USA.
Imanishi
Yorihisa
Y
Cackowski
Frank C
FC
Jarzynka
Michael J
MJ
Tao
Huo-Quan
HQ
Nishikawa
Ryo
R
Hirose
Takanori
T
Hu
Bo
B
Cheng
Shi-Yuan
SY
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
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
Hepatology. 2004 Feb;39(2):528-39
14768007
Cancer Res. 2003 Aug 15;63(16):4757-62
12941789
J Pathol. 2004 Mar;202(3):382-8
14991905
Cancer Lett. 1996 Jun 5;103(2):201-8
8635158
Neurosurgery. 1996 Aug;39(2):235-50; discussion 250-2
8832660
Science. 1997 Jul 11;277(5323):225-8
9211848
J Histochem Cytochem. 1998 Mar;46(3):397-403
9487122
Int J Cancer. 1998 Mar 16;75(6):864-72
9506531
Int J Cancer. 1998 Mar 30;76(1):63-72
9533763
Cancer Chemother Pharmacol. 1999;43 Suppl:S42-51
10357558
J Cell Biol. 2000 Feb 7;148(3):615-24
10662785
J Pathol. 2000 Jul;191(3):245-56
10878545
Nature. 2000 Sep 14;407(6801):242-8
11001067
Cancer Res. 2001 Feb 15;61(4):1255-9
11245414
Cancer Res. 2001 Mar 1;61(5):2145-53
11280779
Lab Invest. 2001 Apr;81(4):613-27
11304581
Genes Dev. 2001 Jun 1;15(11):1311-33
11390353
Cancer Res. 2001 Aug 15;61(16):6248-54
11507079
Cancer Res. 2001 Sep 1;61(17):6322-7
11522618
Cancer. 2001 Sep 1;92(5):1138-43
11571726
Annu Rev Cell Dev Biol. 2001;17:463-516
11687497
J Mol Diagn. 2001 Nov;3(4):129-32
11687595
Cancer Res. 2001 Dec 1;61(23):8569-77
11731444
Int J Cancer. 2001 Dec 15;94(6):763-7
11745475
Nat Rev Mol Cell Biol. 2002 Mar;3(3):207-14
11994741
Int J Cancer. 2003 Feb 10;103(4):466-74
12478661
Am J Pathol. 2003 Apr;162(4):1083-93
12651601
J Cell Biol. 2003 Apr 14;161(1):197-209
12695504
Cancer Lett. 2003 May 8;194(1):1-11
12706853
Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8904-9
12861074
Int J Oncol. 2004 Mar;24(3):539-47
14767538