In vivo glioma growth requires host-derived matrix metalloproteinase 2 for maintenance of angioarchitecture.
Glioma, the most common form of brain tumor, has been shown mostly by in vitro studies to utilize matrix metalloproteinase (MMP) for invasive growth through degradation of the extracellular matrix. In order to examine the in vivo role of MMP, we established a rodent model of glioma progression using C6 rat glioma cells and analyzed the effect of tissue inhibitors of metalloproteinases (TIMPs). TIMP-2 rather than TIMP-1 caused significant reduction of the tumor size accompanied by the presence of degenerated blood vessels and ischemic necrosis. Because TIMP-2 inhibits MMP-2 preferentially, we then examined glioma growth in MMP-2-deficient mice and observed essentially identical consequences. While MMP-2 activity was present in the tumor and adjacent tissues of the wild-type mice, no MMP-2 activity was detected even in the tumor of the null mice, although C6 cells are known to express MMP-2. These observations suggest that glioma induces MMP-2 and utilizes its activity in the host tissue to support angiogenesis and to maintain angioarchitecture.
Takahashi
Megumi
M
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Fukami
Shinjiro
S
Iwata
Nobuhisa
N
Inoue
Keiichi
K
Itohara
Shigeyoshi
S
Itoh
Hiroshi
H
Haraoka
Jo
J
Saido
Takaomi
T
D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000235:genetics; D003342:Corpus Striatum / Q000098:blood supply / Q000201:enzymology*; D004388:Dura Mater / Q000098:blood supply / Q000201:enzymology*; D005910:Glioma / Q000098:blood supply / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000494:pharmacology / Q000627:therapeutic use; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2