PMID- 17628016
OWN - NLM
STAT- MEDLINE
DCOM- 20071227
LR  - 20220825
IS  - 1549-4918 (Electronic)
IS  - 1066-5099 (Print)
IS  - 1066-5099 (Linking)
VI  - 25
IP  - 10
DP  - 2007 Oct
TI  - Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells 
      in glioblastoma.
PG  - 2524-33
AB  - Brain tumors can arise following deregulation of signaling pathways normally 
      activated during brain development and may derive from neural stem cells. Given 
      the requirement for Hedgehog in non-neoplastic stem cells, we investigated 
      whether Hedgehog blockade could target the stem-like population in glioblastoma 
      multiforme (GBM). We found that Gli1, a key Hedgehog pathway target, was highly 
      expressed in 5 of 19 primary GBM and in 4 of 7 GBM cell lines. Shh ligand was 
      expressed in some primary tumors, and in GBM-derived neurospheres, suggesting a 
      potential mechanism for pathway activation. Hedgehog pathway blockade by 
      cyclopamine caused a 40%-60% reduction in growth of adherent glioma lines highly 
      expressing Gli1 but not in those lacking evidence of pathway activity. When 
      GBM-derived neurospheres were treated with cyclopamine and then dissociated and 
      seeded in media lacking the inhibitor, no new neurospheres formed, suggesting 
      that the clonogenic cancer stem cells had been depleted. Consistent with this 
      hypothesis, the stem-like fraction in gliomas marked by both aldehyde 
      dehydrogenase activity and Hoechst dye excretion (side population) was 
      significantly reduced or eliminated by cyclopamine. In contrast, we found that 
      radiation treatment of our GBM neurospheres increased the percentage of these 
      stem-like cells, suggesting that this standard therapy preferentially targets 
      better-differentiated neoplastic cells. Most importantly, viable GBM cells 
      injected intracranially following Hedgehog blockade were no longer able to form 
      tumors in athymic mice, indicating that a cancer stem cell population critical 
      for ongoing growth had been removed. Disclosure of potential conflicts of 
      interest is found at the end of this article.
FAU - Bar, Eli E
AU  - Bar EE
AD  - Johns Hopkins University School of Medicine, Department of Pathology, 720 Rutland 
      Avenue, Ross Building 558, Baltimore, Maryland 21205, USA.
FAU - Chaudhry, Aneeka
AU  - Chaudhry A
FAU - Lin, Alex
AU  - Lin A
FAU - Fan, Xing
AU  - Fan X
FAU - Schreck, Karisa
AU  - Schreck K
FAU - Matsui, William
AU  - Matsui W
FAU - Piccirillo, Sara
AU  - Piccirillo S
FAU - Vescovi, Angelo L
AU  - Vescovi AL
FAU - DiMeco, Francesco
AU  - DiMeco F
FAU - Olivi, Alessandro
AU  - Olivi A
FAU - Eberhart, Charles G
AU  - Eberhart CG
LA  - eng
GR  - K23 CA107040/CA/NCI NIH HHS/United States
GR  - K23 CA107040-04/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070712
PL  - England
TA  - Stem Cells
JT  - Stem cells (Dayton, Ohio)
JID - 9304532
RN  - 0 (GLI1 protein, human)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (SHH protein, human)
RN  - 0 (Transcription Factors)
RN  - 0 (Veratrum Alkaloids)
RN  - 0 (Zinc Finger Protein GLI1)
RN  - 3K9958V90M (Ethanol)
RN  - ZH658AJ192 (cyclopamine)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor/drug effects
MH  - Ethanol/pharmacology
MH  - Gamma Rays
MH  - Glioblastoma/*pathology
MH  - Hedgehog Proteins/*antagonists & inhibitors/biosynthesis/genetics/physiology
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - Neoplasm Proteins/*antagonists & inhibitors/biosynthesis/genetics/physiology
MH  - Neoplasm Transplantation
MH  - Neoplastic Stem Cells/cytology/*drug effects/radiation effects
MH  - RNA, Messenger/biosynthesis/genetics
MH  - RNA, Small Interfering/pharmacology
MH  - Signal Transduction/*drug effects/physiology/radiation effects
MH  - Transcription Factors/biosynthesis/genetics/physiology
MH  - Veratrum Alkaloids/*pharmacology
MH  - Zinc Finger Protein GLI1
PMC - PMC2610257
MID - NIHMS81584
COIS- Disclosure of Potential Conflicts of Interest The authors indicate no potential 
      conflicts of interest.
EDAT- 2007/07/14 09:00
MHDA- 2007/12/28 09:00
PMCR- 2008/12/25
CRDT- 2007/07/14 09:00
PHST- 2007/07/14 09:00 [pubmed]
PHST- 2007/12/28 09:00 [medline]
PHST- 2007/07/14 09:00 [entrez]
PHST- 2008/12/25 00:00 [pmc-release]
AID - 2007-0166 [pii]
AID - 10.1634/stemcells.2007-0166 [doi]
PST - ppublish
SO  - Stem Cells. 2007 Oct;25(10):2524-33. doi: 10.1634/stemcells.2007-0166. Epub 2007 
      Jul 12.