PMID- 22730244
OWN - NLM
STAT- MEDLINE
DCOM- 20130124
LR  - 20211203
IS  - 1549-4918 (Electronic)
IS  - 1066-5099 (Linking)
VI  - 30
IP  - 9
DP  - 2012 Sep
TI  - Hedgehog-GLI signaling drives self-renewal and tumorigenicity of human 
      melanoma-initiating cells.
PG  - 1808-18
LID - 10.1002/stem.1160 [doi]
AB  - The question of whether cancer stem/tumor-initiating cells (CSC/TIC) exist in 
      human melanomas has arisen in the last few years. Here, we have used nonadherent 
      spheres and the aldehyde dehydrogenase (ALDH) enzymatic activity to enrich for 
      CSC/TIC in a collection of human melanomas obtained from a broad spectrum of 
      sites and stages. We find that melanomaspheres display extensive in vitro 
      self-renewal ability and sustain tumor growth in vivo, generating human melanoma 
      xenografts that recapitulate the phenotypic composition of the parental tumor. 
      Melanomaspheres express high levels of Hedgehog (HH) pathway components and of 
      embryonic pluripotent stem cell factors SOX2, NANOG, OCT4, and KLF4. We show that 
      human melanomas contain a subset of cells expressing high ALDH activity 
      (ALDH(high)), which is endowed with higher self-renewal and tumorigenic abilities 
      than the ALDH(low) population. A good correlation between the number of 
      ALDH(high) cells and sphere formation efficiency was observed. Notably, both 
      pharmacological inhibition of HH signaling by the SMOOTHENED (SMO) antagonist 
      cyclopamine and GLI antagonist GANT61 and stable expression of shRNA targeting 
      either SMO or GLI1 result in a significant decrease in melanoma stem cell 
      self-renewal in vitro and a reduction in the number of ALDH(high) melanoma stem 
      cells. Finally, we show that interference with the HH-GLI pathway through 
      lentiviral-mediated silencing of SMO and GLI1 drastically diminishes tumor 
      initiation of ALDH(high) melanoma stem cells. In conclusion, our data indicate an 
      essential role of the HH-GLI1 signaling in controlling self-renewal and tumor 
      initiation of melanoma CSC/TIC. Targeting HH-GLI1 is thus predicted to reduce the 
      melanoma stem cell compartment.
CI  - Copyright (c) 2012 AlphaMed Press.
FAU - Santini, Roberta
AU  - Santini R
AD  - Laboratory of Tumor Cell Biology, Core Research Laboratory-Istituto Toscano 
      Tumori, Florence, Italy.
FAU - Vinci, Maria C
AU  - Vinci MC
FAU - Pandolfi, Silvia
AU  - Pandolfi S
FAU - Penachioni, Junia Y
AU  - Penachioni JY
FAU - Montagnani, Valentina
AU  - Montagnani V
FAU - Olivito, Biagio
AU  - Olivito B
FAU - Gattai, Riccardo
AU  - Gattai R
FAU - Pimpinelli, Nicola
AU  - Pimpinelli N
FAU - Gerlini, Gianni
AU  - Gerlini G
FAU - Borgognoni, Lorenzo
AU  - Borgognoni L
FAU - Stecca, Barbara
AU  - Stecca B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Stem Cells
JT  - Stem cells (Dayton, Ohio)
JID - 9304532
RN  - 0 (GLI1 protein, human)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (KLF4 protein, human)
RN  - 0 (Klf4 protein, mouse)
RN  - 0 (Kruppel-Like Factor 4)
RN  - 0 (Transcription Factors)
RN  - 0 (Zinc Finger Protein GLI1)
RN  - EC 1.2.1.3 (Aldehyde Dehydrogenase)
SB  - IM
MH  - Aldehyde Dehydrogenase/metabolism
MH  - Animals
MH  - Cell Growth Processes/physiology
MH  - Cell Line, Tumor
MH  - Cell Transformation, Neoplastic/genetics/*metabolism/pathology
MH  - Female
MH  - HEK293 Cells
MH  - Hedgehog Proteins/antagonists & inhibitors/genetics/*metabolism
MH  - Humans
MH  - Kruppel-Like Factor 4
MH  - Melanoma/genetics/*metabolism/pathology
MH  - Mice
MH  - Mice, Nude
MH  - Neoplastic Stem Cells/*metabolism/pathology
MH  - Signal Transduction
MH  - Transcription Factors/antagonists & inhibitors/genetics/*metabolism
MH  - Transplantation, Heterologous
MH  - Zinc Finger Protein GLI1
EDAT- 2012/06/26 06:00
MHDA- 2013/01/25 06:00
CRDT- 2012/06/26 06:00
PHST- 2012/06/26 06:00 [entrez]
PHST- 2012/06/26 06:00 [pubmed]
PHST- 2013/01/25 06:00 [medline]
AID - 10.1002/stem.1160 [doi]
PST - ppublish
SO  - Stem Cells. 2012 Sep;30(9):1808-18. doi: 10.1002/stem.1160.