TGF-beta and cancer

Isabel Fabregat Departament de Ciències Fisiòlogiques II, Universitat de Barcelona

Institut de Investigació Biomèdica de Bellvitge (IDIBELL) E-mail: ifabregat@ub.edu

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

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