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TNF-alpha- and TRAIL-resistant glioma cells undergo autophagy-dependent cell death induced by activated microglia

Rodrigo Mora1, Anette Abschuetz, Tim Kees

  • 1INSERM U701, German Cancer Research Centre, Program Infection and Cancer, Heidelberg, Germany.

Glia
|October 24, 2008
PubMed

Insights

Activated microglia can kill glioma cells resistant to apoptosis by inducing autophagy-dependent cell death. This finding offers a new strategy for brain tumor immunotherapies.

Area of Science:

  • Neuroscience
  • Immunology
  • Oncology

Background:

  • Microglia, the brain's resident macrophages, play a complex role in glioma biology, often supporting tumor growth despite their cytotoxic potential.
  • Targeting microglia for anti-tumor activity presents a promising avenue for enhancing brain tumor immunotherapies.

Purpose of the Study:

  • To characterize the anti-tumor activities of activated mouse primary microglia against glioma cells resistant to tumor necrosis factor-alpha (TNF-alpha) and TNF-related apoptosis-inducing ligand (TRAIL).
  • To elucidate the mechanism of glioma cell death induced by activated microglia.

Main Methods:

  • Primary mouse microglia were stimulated with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma).
  • Glioma cell lines resistant to TNF-alpha and TRAIL were cultured as monolayers, spheroids, and in collagen-embedded tumor explants.
  • Microglia-conditioned media was applied to glioma cells, and cell death mechanisms were analyzed, including autophagosome formation and caspase activity.

Main Results:

  • Stimulated microglia secreted factors that inhibited glioma cell proliferation and migration, and induced specific glioma cell death.
  • Glioma cell death was characterized by early acidic vesicle accumulation, phosphatidylserine exposure, and double-membrane cytoplasmic vesicles, indicative of an autophagic process.
  • Inhibition of autophagosome formation protected glioma cells, while caspase inhibition only partially affected cell death, indicating an autophagy-dependent mechanism.
  • Microglia supernatant blocked the basal autophagic flux in glioma cells, leading to cell death.

Conclusions:

  • Appropriately activated microglia can specifically kill apoptosis-resistant glioma cells through an autophagy-dependent death pathway.
  • This study demonstrates a novel mechanism for targeting glioma cells and suggests a potential therapeutic strategy for brain tumors.

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