PMID- 22693253
OWN - NLM
STAT- MEDLINE
DCOM- 20121204
LR  - 20220729
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 72
IP  - 16
DP  - 2012 Aug 15
TI  - Resistance of glioblastoma-initiating cells to radiation mediated by the tumor 
      microenvironment can be abolished by inhibiting transforming growth factor-beta.
PG  - 4119-29
LID - 10.1158/0008-5472.CAN-12-0546 [doi]
AB  - The poor prognosis of glioblastoma (GBM) routinely treated with ionizing 
      radiation (IR) has been attributed to the relative radioresistance of 
      glioma-initiating cells (GIC). Other studies indicate that although GIC are 
      sensitive, the response is mediated by undefined factors in the microenvironment. 
      GBM produce abundant transforming growth factor-beta (TGF-beta), a pleotropic cytokine 
      that promotes effective DNA damage response. Consistent with this, radiation 
      sensitivity, as measured by clonogenic assay of cultured murine (GL261) and human 
      (U251, U87MG) glioma cell lines, increased by approximately 25% when treated with 
      LY364947, a small-molecule inhibitor of TGF-beta type I receptor kinase, before 
      irradiation. Mice bearing GL261 flank tumors treated with 1D11, a pan-isoform 
      TGF-beta neutralizing antibody, exhibited significantly increased tumor growth delay 
      following IR. GL261 neurosphere cultures were used to evaluate GIC. LY364947 had 
      no effect on the primary or secondary neurosphere-forming capacity. IR decreased 
      primary neurosphere formation by 28%, but did not reduce secondary neurosphere 
      formation. In contrast, LY364947 treatment before IR decreased primary 
      neurosphere formation by 75% and secondary neurosphere formation by 68%. Notably, 
      GL261 neurospheres produced 3.7-fold more TGF-beta per cell compared with 
      conventional culture, suggesting that TGF-beta production by GIC promotes effective 
      DNA damage response and self-renewal, which creates microenvironment-mediated 
      resistance. Consistent with this, LY364947 treatment in irradiated GL261 
      neurosphere-derived cells decreased DNA damage responses, H2AX and p53 
      phosphorylation, and induction of self-renewal signals, Notch1 and CXCR4. These 
      data motivate the use of TGF-beta inhibitors with radiation to improve therapeutic 
      response in patients with GBM.
CI  - (c)2012 AACR.
FAU - Hardee, Matthew E
AU  - Hardee ME
AD  - Department of Radiation Oncology, New York University School of Medicine, New 
      York, New York 10016, USA.
FAU - Marciscano, Ariel E
AU  - Marciscano AE
FAU - Medina-Ramirez, Christina M
AU  - Medina-Ramirez CM
FAU - Zagzag, David
AU  - Zagzag D
FAU - Narayana, Ashwatha
AU  - Narayana A
FAU - Lonning, Scott M
AU  - Lonning SM
FAU - Barcellos-Hoff, Mary Helen
AU  - Barcellos-Hoff MH
LA  - eng
GR  - T32 CA009161/CA/NCI NIH HHS/United States
GR  - U54 CA149233/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20120612
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (DNA, Neoplasm)
RN  - 0 (HTS 466284)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrroles)
RN  - 0 (Radiation-Sensitizing Agents)
RN  - 0 (Transforming Growth Factor beta)
SB  - IM
MH  - Animals
MH  - Antibodies, Neutralizing/pharmacology
MH  - Brain Neoplasms/drug therapy/metabolism/pathology/*radiotherapy
MH  - Cell Line, Tumor
MH  - Combined Modality Therapy
MH  - DNA Damage
MH  - DNA, Neoplasm/radiation effects
MH  - Female
MH  - Glioblastoma/drug therapy/metabolism/pathology/*radiotherapy
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mink
MH  - Neoplastic Stem Cells/drug effects/metabolism/radiation effects
MH  - Neural Stem Cells/drug effects/metabolism/radiation effects
MH  - Pyrazoles/*pharmacology
MH  - Pyrroles/*pharmacology
MH  - Radiation Tolerance
MH  - Radiation-Sensitizing Agents/*pharmacology
MH  - Signal Transduction
MH  - Transforming Growth Factor beta/*antagonists & inhibitors/metabolism
MH  - Tumor Microenvironment
PMC - PMC3538149
MID - NIHMS393834
EDAT- 2012/06/14 06:00
MHDA- 2012/12/10 06:00
PMCR- 2013/08/15
CRDT- 2012/06/14 06:00
PHST- 2012/06/14 06:00 [entrez]
PHST- 2012/06/14 06:00 [pubmed]
PHST- 2012/12/10 06:00 [medline]
PHST- 2013/08/15 00:00 [pmc-release]
AID - 0008-5472.CAN-12-0546 [pii]
AID - 10.1158/0008-5472.CAN-12-0546 [doi]
PST - ppublish
SO  - Cancer Res. 2012 Aug 15;72(16):4119-29. doi: 10.1158/0008-5472.CAN-12-0546. Epub 
      2012 Jun 12.