Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease-2.
A hallmark of highly malignant human gliomas is their infiltration of the brain. We analyzed a large number of primary human glioma biopsies and found high levels of expression of an angiogenic regulator, angiopoietin-2 (Ang2), in the invasive areas, but not in the central regions, of those tumors. In the invasive regions where Ang2 was overexpressed, increased levels of matrix metalloprotease-2 (MMP-2) were also apparent. Consonant with these features, intracranial xenografts of glioma cells engineered to express Ang2 were highly invasive into adjacent brain parenchyma compared with isogenic control tumors. In regions of the Ang2-expressing tumors that were actively invading the brain, high levels of expression of MMP-2 and increased angiogenesis were also evident. A link between these two features was apparent, because stable expression of Ang2 by U87MG cells or treatment of several glioma cell lines with recombinant Ang2 in vitro caused activation of MMP-2 and acquisition of increased invasiveness. Conversely, MMP inhibitors suppressed Ang2-stimulated activation of MMP-2 and Ang2-induced cell invasion. These results suggest that Ang2 plays a critical role in inducing tumor cell infiltration, and that this invasive phenotype is caused by activation of MMP-2.
Hu
Bo
B
Cancer Institute and Department of Medicine, University of Pittsburgh, Research Pavilion at the Hillman Cancer Center, Suite 2.19, 5117 Centre Avenue, Pittsburgh, PA 15213-1863, USA. hub@msx.upmc.edu
Guo
Ping
P
Fang
Quan
Q
Tao
Huo-Quan
HQ
Wang
Degui
D
Nagane
Motoo
M
Huang
Hui-Jein Su
HJ
Gunji
Yuji
Y
Nishikawa
Ryo
R
Alitalo
Kari
K
Cavenee
Webster K
WK
Cheng
Shi-Yuan
SY
D043925:Angiogenesis Inducing Agents / Q000502:physiology*; D042702:Angiopoietin-2; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D004789:Enzyme Activation; D005910:Glioma / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D043925:Angiogenesis Inducing Agents; D042702:Angiopoietin-2; D020778:Matrix Metalloproteinase 2