Exploitation of astrocytes by glioma cells to facilitate invasiveness: a mechanism involving matrix metalloproteinase-2 and the urokinase-type plasminogen activator-plasmin cascade.
The presence of reactive astrocytes around glioma cells in the CNS suggests the possibility that these two cell types could be interacting. We addressed whether glioma cells use the astrocyte environment to modulate matrix metalloproteinase-2 (MMP-2), a proteolytic enzyme implicated in the invasiveness of glioma cells. We found that astrocytes in culture produce significant amounts of the pro-form of MMP-2 but undetectable levels of active MMP-2. However, after coculture with the U251N glioma line, astrocyte pro-MMP-2 was converted to the active form. The mechanism of pro-MMP-2 activation in glioma-astrocyte coculture was investigated and was found to involve the urokinase-type plasminogen activator (uPA)-plasmin cascade whereby uPA bound to uPA receptor (uPAR), leading to the conversion of plasminogen to plasmin. The latter cleaved pro-MMP-2 to generate its active form. Furthermore, key components (i.e., uPAR, uPA, and pro-MMP-2) were contributed principally by astrocytes, whereas the U251N glioma cells provided plasminogen. In correspondence with this biochemical cascade, the transmigration of U251N cells through Boyden invasion chambers coated with an extracellular matrix barrier was increased significantly in the presence of astrocytes, and this was inhibited by agents that disrupted the uPA-plasmin cascade. Finally, using resected human glioblastoma specimens, we found that tumor cells, but not astrocytes, expressed plasminogen in situ. We conclude that glioma cells exploit their astrocyte environment to activate MMP-2 and that this leads to the increased invasiveness of glioma cells.
Le
Duc M
DM
Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
Besson
Arnaud
A
Fogg
Darrin K
DK
Choi
Kyu-Sil
KS
Waisman
David M
DM
Goodyer
Cynthia G
CG
Rewcastle
Barry
B
Yong
V Wee
VW
D016475:3T3 Cells; D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D016543:Central Nervous System Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D004793:Enzyme Reactivators; D005341:Fibrinolysin / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D005910:Glioma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009368:Neoplasm Transplantation; D010958:Plasminogen / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D004792:Enzyme Precursors; D004793:Enzyme Reactivators; C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D010958:Plasminogen; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2