PMID- 19770591
OWN - NLM
STAT- MEDLINE
DCOM- 20100621
LR  - 20211020
IS  - 1555-8576 (Electronic)
IS  - 1538-4047 (Print)
IS  - 1538-4047 (Linking)
VI  - 8
IP  - 19
DP  - 2009 Oct
TI  - Molecular mechanisms of necrosis in glioblastoma: the role of glutamate 
      excitotoxicity.
PG  - 1791-7
AB  - Glioblastomas continue to rank among the most lethal primary human tumors. 
      Despite treatment with the most rigorous surgical interventions along with the 
      most optimal chemotherapeutic and radiation regimens, the median survival is just 
      12-15 mo for patients with glioblastoma. Among the histological hallmarks of 
      glioblastoma, necrosis has been demonstrated to be a powerful predictor of poor 
      patient prognosis. Over the years, there have been many advances in our 
      understanding of the molecular mechanisms underlying glioblastoma formation, yet 
      the mechanisms that lead to tumor necrosis remain unclear. One pathway that may 
      lead to necrosis in glioblastoma involves the neurotransmitter, glutamate, which 
      has been shown to accumulate in the peritumoral fluid as a result of decreased 
      cellular uptake by glioblastoma cells. This accumulation leads to subsequent 
      glutamate excitotoxicity and probable necrosis through a massive elevation of 
      intracellular Ca(2+) and reduction in cellular ATP levels. We propose that a 
      pathway involving tumor necrosis factor-alpha (TNFalpha), astrocyte-elevated 
      gene-1 (AEG-1) and nuclear factor-kappaB (NFkappaB) leads to decreased glutamate 
      uptake through coordinated downregulation of the excitatory amino acid 
      transporter 2 (EAAT2), the glutamate transporter responsible for the majority of 
      glutamate uptake in the human brain. In addition, we suggest that AEG-1 
      signaling, loss of phosphatase and tensin homolog (PTEN), and ionotropic 
      glutamate receptor activity lead to AKT pathway activation, which results in 
      nutrient overconsumption and necrosis. Together, these pathways provide a new 
      perspective on glioblastoma necrosis involving the process of glutamate 
      excitotoxicity. Future research should address the components of these molecular 
      pathways in order to better understand the mechanism of necrosis in glioblastoma 
      and to begin to develop targeted therapies that may improve patient prognosis in 
      the future.
FAU - Noch, Evan
AU  - Noch E
AD  - Department of Neuroscience, Center for Neurovirology, Temple University School of 
      Medicine, Philadelphia, PA, USA.
FAU - Khalili, Kamel
AU  - Khalili K
LA  - eng
GR  - R01 CA094804/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Review
PL  - United States
TA  - Cancer Biol Ther
JT  - Cancer biology & therapy
JID - 101137842
RN  - 0 (Glutamates)
SB  - IM
MH  - Central Nervous System Neoplasms/*metabolism/*pathology
MH  - Glioblastoma/*metabolism/*pathology
MH  - Glutamates/*metabolism
MH  - Humans
MH  - Necrosis
PMC - PMC4503249
MID - NIHMS697927
EDAT- 2009/09/23 06:00
MHDA- 2010/06/22 06:00
PMCR- 2015/07/15
CRDT- 2009/09/23 06:00
PHST- 2009/09/23 06:00 [entrez]
PHST- 2009/09/23 06:00 [pubmed]
PHST- 2010/06/22 06:00 [medline]
PHST- 2015/07/15 00:00 [pmc-release]
AID - 9762 [pii]
AID - 10.4161/cbt.8.19.9762 [doi]
PST - ppublish
SO  - Cancer Biol Ther. 2009 Oct;8(19):1791-7. doi: 10.4161/cbt.8.19.9762.