PMID- 19617536
OWN - NLM
STAT- MEDLINE
DCOM- 20090928
LR  - 20220408
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 106
IP  - 30
DP  - 2009 Jul 28
TI  - Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion.
PG  - 12530-5
LID - 10.1073/pnas.0804273106 [doi]
AB  - Diffuse infiltration of glioma cells into normal brain tissue is considered to be 
      a main reason for the unfavorable outcomes of patients with malignant gliomas. 
      Invasion of glioma cells into the brain parenchyma is facilitated by 
      metalloprotease-mediated degradation of the extracellular matrix. 
      Metalloproteases are released as inactive pro-forms and get activated upon 
      cleavage by membrane bound metalloproteases. Here, we show that membrane type 1 
      metalloprotease (MT1-MMP) is up-regulated in glioma-associated microglia, but not 
      in the glioma cells. Overexpression of MT1-MMP is even lethal for glioma cells. 
      Glioma-released factors trigger the expression and activity of MT1-MMP via 
      microglial toll-like receptors and the p38 MAPK pathway, as deletion of the 
      toll-like receptor adapter protein MyD88 or p38 inhibition prevented MT1-MMP 
      expression and activity in cultured microglial cells. Microglial MT1-MMP in turn 
      activates glioma-derived pro-MMP-2 and promotes glioma expansion, as shown in an 
      ex vivo model using MT1-MMP-deficient brain tissue and a microglia depletion 
      paradigm. Finally, MyD88 deficiency or microglia depletion largely attenuated 
      glioma expansion in 2 independent in vivo models.
FAU - Markovic, D S
AU  - Markovic DS
AD  - Cellular Neuroscience, Max Delbruck Center for Molecular Medicine, 13125 Berlin, 
      Germany.
FAU - Vinnakota, K
AU  - Vinnakota K
FAU - Chirasani, S
AU  - Chirasani S
FAU - Synowitz, M
AU  - Synowitz M
FAU - Raguet, H
AU  - Raguet H
FAU - Stock, K
AU  - Stock K
FAU - Sliwa, M
AU  - Sliwa M
FAU - Lehmann, S
AU  - Lehmann S
FAU - Kalin, R
AU  - Kalin R
FAU - van Rooijen, N
AU  - van Rooijen N
FAU - Holmbeck, K
AU  - Holmbeck K
FAU - Heppner, F L
AU  - Heppner FL
FAU - Kiwit, J
AU  - Kiwit J
FAU - Matyash, V
AU  - Matyash V
FAU - Lehnardt, S
AU  - Lehnardt S
FAU - Kaminska, B
AU  - Kaminska B
FAU - Glass, R
AU  - Glass R
FAU - Kettenmann, H
AU  - Kettenmann H
LA  - eng
GR  - R01 NS046006/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20090715
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Enzyme Precursors)
RN  - 0 (Myd88 protein, mouse)
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (Toll-Like Receptors)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.4.24.- (Gelatinases)
RN  - EC 3.4.24.- (progelatinase)
RN  - EC 3.4.24.80 (Matrix Metalloproteinase 14)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Brain Neoplasms/genetics/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Enzyme Precursors/metabolism
MH  - Female
MH  - Gelatinases/metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - Glioma/genetics/metabolism/*pathology
MH  - Green Fluorescent Proteins/genetics/metabolism
MH  - Humans
MH  - Immunohistochemistry
MH  - Male
MH  - Matrix Metalloproteinase 14/genetics/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Microglia/metabolism/*pathology
MH  - Myeloid Differentiation Factor 88/genetics/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction
MH  - Toll-Like Receptors/metabolism
MH  - Tumor Burden
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
PMC - PMC2718387
COIS- The authors declare no conflict of interest.
EDAT- 2009/07/21 09:00
MHDA- 2009/09/29 06:00
PMCR- 2010/01/28
CRDT- 2009/07/21 09:00
PHST- 2009/07/21 09:00 [entrez]
PHST- 2009/07/21 09:00 [pubmed]
PHST- 2009/09/29 06:00 [medline]
PHST- 2010/01/28 00:00 [pmc-release]
AID - 0804273106 [pii]
AID - 8651 [pii]
AID - 10.1073/pnas.0804273106 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12530-5. doi: 
      10.1073/pnas.0804273106. Epub 2009 Jul 15.