TGF-beta and cancer 3/a...Cells that survive to TGF-beta respond to this cytokine inducing EMT...
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TGF-beta and cancer Isabel Fabregat Departament de Ciències Fisiòlogiques II, Universitat de Barcelona Institut de Investigació Biomèdica de Bellvitge (IDIBELL) E-mail: [email protected] Máster en Oncología Molecular, Marzo 2011
Transcript of TGF-beta and cancer 3/a...Cells that survive to TGF-beta respond to this cytokine inducing EMT...
TGF-beta and cancer
Isabel Fabregat Departament de Ciències Fisiòlogiques II, Universitat de Barcelona
Institut de Investigació Biomèdica de Bellvitge (IDIBELL) E-mail: [email protected]
Máster en Oncología Molecular, Marzo 2011
Index: • TGF-β Family. Receptors. Signal transduction. Regulation of Smad family. • Biological functions: role as tumor suppressor. Growth inhibitor. Inducer of apoptosis. Effects on cell differentiation. • Role of TGF-β in tumor progression. Epithelial to mesenchymal transition. Increase in migration and invasion. Effects on angiogenesis and on the tumor stroma. • Summary: Dual role of TGF-β in cancer: Tumor suppression in early stages. Tumor promoter in advanced tumors. Role in metastasis.
Bernhard Schmierer and Caroline S. Hill
Nature 2007
TGF-β family and their receptors
Itoh and ten Dijke Current Opinion in Cell Biology, 2007
Massagué, Seoane and Wotton
Genes & Dev. 2005
Histone acetylation
Histone desacetylation
Shi and Massagué, Cell 2003
Massagué, Seoane and Wotton Genes & Dev. 2005
Molecular mechanisms that attenuate Smad activation by TGF-β
It can induce or inhibit
TGF-β inhibits growth, induces apoptosis and mediates cell differentiation
Adapted from:
TGF-β induces apoptosis in hepatocytes
Sánchez et al. J. Biol. Chem. 1996
B
D
C T
M1
C CONTROL
TGF-β
M1=3.47±0.36
M1=16.2±2.14
M1
A TGF-β
Proposed mechanisms for TGF-beta-induced apoptosis
Adaptado de Moustakas and Heldin. J Cell Sci 2005
ROS
NADPH oxidasa
Cyt c
ALB-VIM CK19-CK18
CO
NT
RO
L
EG
F-T
GFβ
TGF-β, when combined with EGF or HGF, induces hepatocyte differentiation
Sánchez et al. Exp Cell Res 1998
Bierie and Moses Nature 2006
Role of TGF-β as tumor suppressor
Levy and Hill. Cytokine & Growth Factor Reviews 2006
Alterations in TGF-beta signaling in human tumors
Massagué, Cell 2008
Bierie and Moses Nature 2006
ROS
ROS Glutathione
ΔΨm
cit-C
APOPTOSIS
Caspase-9 Caspase-3
TGF-β
EGFR
Herrera et al. FASEB J 2001, Free Radic Biol Med 2004
TGF-α
HB-EGF
TACE
Liver tumor cells Murillo et al., Oncogene 2005 Caja et al., Cell Signal 2007 Caja et al., J Hepatol 2011
MEK/ERKs
Caja et al., Cancer Res 2009
Hepatocellular carcinoma
PI3K, ERKs
SURVIVAL
Carmona-Cuenca et al., J Cell Physiol 2006, J Hepatol 2008
Moderador
Notas de la presentación
As you all know, during the last years, Isabel group has been studying the TGF-b pathway in the liver under different physio-pathological conditions. In foetal hepatocytes our group has described that TGF-b plays a dual role in the control of apoptosis. On one side, TGF-b induces apoptosis activating NAPDH oxidase transcription which seems to be responsible for an increase in the oxidative stress state of the cell, followed by a decrease in the glutathione levels and loss of mitochondrial transmembrane potential. All these events preceded the release of cytochrome c from the mithocondria and the activation of Caspases. However, TGF-b is also able to induce survival signals by increasing the expression of EGFR ligands, and activating the metalloprotease TACE responsible of the shedding of TGF-a and HB-EGF. These two EGF-like ligands bind to EGFR and promote PI3K activation which impairs NAPDH oxidase activation and ROS production. The balance between pro- and anti-apoptotic signals decides the cell fate. Cells that survive to TGF-beta respond to this cytokine inducing EMT processes, which might contribute to an increase in the migratory and invasive properties of those cells.
NOX (NADPH Oxidases) family of enzymes
NOX family
NOX 1 NOX 2 NOX 3 NOX 4 NOX 5
DUOX 1 DUOX 2
Brown and Griendling Free Radic Biol Med 2009
NADPH NADP+
O2 O2-
TGF-β
Smad3
nox4
ROS
Cell death Nucleus
rac1
Rac1 NOX1
ROS
NF-κB egfr ligands
Survival
Other survival signals
NOX4
NADPH oxidases control both survival and apoptosis in liver tumor cells
Patricia Sancho
Murillo et al., Biochem J 2007 Carmona-Cuenca et al., J Hepatol 2008 Sancho et al. BBA- Mol Cell Res 2008 Sancho et al. J Biol Chem 2010
Irene Carmona
Miguel Murillo
Control TGFβ
Control TGFβ Phalloidin
FaO rat hepatoma cells
TGF-β treatment induces loss in cell adhesion and confers cell migratory properties
Esther Bertran
1 day 3 days Control
E-CADHERIN
DAPI
RT - 3 5 8 16 24 36 48
snail
E- cadherin
+ TGFβ (h)
alb FaO hepatoma cells
Bertran et al. Cell Signal 2009
TGF-β induces epithelial-mesenchymal transition (EMT) in rat hepatoma cells
.. and in human hepatocellular carcinoma cells
Laia Caja
Dr. Nelson Fausto, Univ. Washington
Seattle
Caja et al. J Cell Physiol
2011
Proposed models for the molecular mechanisms that mediate EMT by TGF-β in epithelial cells
Moustakas and Heldin. J Cell Sci 2005
0 h
4 h
24 h
48 h
FaO TβT-FaO EMT confers invasive and migratory properties
Bertran et al. Cell Signal 2009
EMT confers liver stem cell properties Hep3B cells
The TGF-β-induced EMT is a reversible process
Massagué, Cell 2008
Anti (A) and pro-(B) tumorigenic effects of TGF-β on cell differentiation
Up-regulation of Snail not only mediates EMT, but also resistance to apoptosis in liver cells
Angela Nieto
Sonia Vega Jèssica Mainez
Instituto de Neurociencias CSIC/UMH, Alicante
Franco et al., J. Cell science 2010
Model of transgenic mice expressing Tamoxifen-inducible Snail1
Adult hepatocytes from these mice show EMT features…
Apop
totic
nuc
lei (
%)
10
30
20
Cas
pase
-3 A
ctiv
ity
(% C
ontr
ol)
100
200
300 40
TGF-β - + - + TAM - - + +
TGF-β - + - + TAM - - + +
..and are completely resistant to TGF-β-induced apoptosis
TGF-β
Growth inhibition
Suppressor role
Smad 2,3 Smad4
EGFR
EGFR Ligands
TACE RII
RI
Apoptosis
Summary
Migration Invasion
Stem cell properties
Pro-tumorigenic properties
Snail
EMT
TGF-β as a tumor promoter
Massagué Cell 2008
CONCLUSIONS
Joan Fernando
Isabel Fabregat Esther Bertran
Laia Caja
Jèssica Mainez Eva Crosas
Patricia Sancho
Estanis Navarro
TGF-β Liver lab
Biological clues of the metastatic and invasive phenotype
IDIBELL Group
Straight collaboration with Drs. Àngels Fabra, Angels Sierra, Joan Gil, Emilio
Ramos, IDIBELL
New members: Edgar Baguena Joaquim Moreno
Fac. Farmacia,UCM, Madrid
César Roncero Margarita Fernández Arancha Sánchez
Blanca Herrera
Instituto de Neurociencias, CSIC-Univ. Miguel Hernández, Alicante
Sonia Vega Ángela M. Nieto
Universidad de Extremadura Alberto Álvarez-Barrientos
University of Vienna Austria Wolfgang Mikulits lab
University of Washington, Seattle, USA
Nelson Fausto lab
IIB- Alberto Sols (CSIC/UAM) Ángela M. Valverde
Universitat de Barcelona Gustavo Egea
CIEMAT, Madrid Jose Carlos Segovia
Fundación Hospital de Alcorcón, Madrid Conrado Fernández
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