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Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • D S Markovic
  • K Vinnakota
  • S Chirasani
  • M Synowitz
  • H Raguet
  • K Stock
  • M Sliwa
  • S Lehmann
  • R Kälin
  • N van Rooijen
  • Holmbeck, Kenn
  • F L Heppner
  • J Kiwit
  • V Matyash
  • S Lehnardt
  • B Kaminska
  • R Glass
  • H Kettenmann

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.

OriginalsprogEngelsk
TidsskriftProceedings of the National Academy of Sciences of the United States of America
Vol/bind106
Udgave nummer30
Sider (fra-til)12530-5
Antal sider6
ISSN0027-8424
DOI
StatusUdgivet - 28 jul. 2009

ID: 201165473