Medical Biotechnology Master’s Programmes
at the University of Pécs and at the University of Debrecen
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
SIGNALLING IN TUMOR CELLS
Tímea Berki and Ferenc Boldizsár Signal transduction
Medical Biotechnology Master’s Programmes
at the University of Pécs and at the University of Debrecen
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
Immune selection in the development of cancer: no two tumors are alike
Initiation, proliferation, diversification
Microevolution, selection of immune resistance
Immune escape and
unchecked proliferation
Tumor and activated T cells
Activated T cell Immune escape Tumor cell
DF3/MUC1 CD28
CTLA4
B7-1/2
MHC I TCR
Growth arrest
Proliferation
Cell death
RCAS1R
Cytokine receptors
Cytokines
RCAS1
FasL DcR3
Fas FasL
What happens when Fas-stimulated immune cells resist to die?
Tissue environment?
Cytokines?
Fas FasL
Tumor cells
Immune cells
TGF-b signaling in tumor signaling and cancer progression
Tumor cell
Stromal cell Latent TGF-b
ActiveTGF-b
Proteases Thrombospondin
Integrins Decorin
Betaglycan
Effects on tumor cells
Growth inhibition (early)
Invasion (late)
Effects on tumor environment
Stroma
↑
Proteases↑
ECM productionEndothelial cells
↑
AngiogenesisImmune cells
↓
Fas-L activity↓
NK cells↓
T cells↓
B cellsFas signal
PKC
MAPK FasL
FADD FADD
CAP3 CAP3
c-FLIP
AIF TPA
Death substrates
Type II Type I
Fas
Caspase-8
Caspase-3
tBid
Caspase-9 Cytc
Cytc Apaf-1
Bcl-2 Bcl-xL
Caspase-8
APOPTOSIS DISC
Growth factors (GFs)
• Small molecular weight soluble mediators
• They control:
1 Proliferation 2 Survival
3 Metabolism
4 Tissue differentiation
• Important implication in tumors
• Cytokines – growth factors
Receptor tyrosine kinase (RTK) families
• 90 unique Tyr kinases in the human genome, 58 are RTKs
• Growth factor, cytokine and hormone receptors
• Classes:
I – EGFR family (ErbB) X – LTK family
II – Insulin rec. family XI – TIE family
III – PDGF family XII – ROR family
IV – FGF family XIII – DDR family
V – VEGF family XIV – RET family
VI – HGF family (c-Met) XV – KLG family
VII – Trk family XVI – RYK family
VIII – Eph family XVII – MuSK family
IX – AXL family
GF signaling pathways
Proliferation Survival Migration Cell cycle progression Transcription
RTK
Ligand
P
P P P P
P P P Dimerization
Src
SOS GRB2
Ras
Raf Erk PKC
PLC
STAT JAK
Akt PI3K PDK1
GF receptors as therapeutic targets
PDGF-C
Cell survival Proliferation Apoptosis resistance Metastasis Angiogenesis
P
P P P P
P P P
P
P P P P
P P P P
P P P P
P P P P
P P P P
P P P
P
P P P P
P P P P
P P P P
P P P
P
P P P P
P P P
P
P P P P
P P P P
P P P P
P P P
EGFR Her2 Her3 Her4 VEGFR1 VEGFR2 VEGFR3 PDGFR-a PDGFR-b c-kit
EGF TGF
β-cellulin Amphiregulin
HB-EGF
No specific
ligands Heregulins
β-cellulin NRG2
NRG3 VEGF-B VEGF-A VEGF-C VEGF-D PDGF-A
PDGF-B
PDGF-D SCF
SOS
GRB2 Ras Rac CDC42 Rho
MEK1/2
Erk Raf ERK pathway
MKK4/7
JNK MEKK JNK pathway
MKK3/6
p38 Tak p38 pathway
Akt
mTor PI3K
Everolimus Imatinib Trastuzumab Leflunomide Lapatinib Gefitinib Erlotinib Panitumumab Sorafenib
Cetuximab Bevacizumab Vandetanib Sunitinib Enzastaurin Pazopanib Motesanib Midostaurin Temsirolimus Sirolimus
P
P P P P
P P P
HER gene family
• HER1/EGFR(1): ligands known (TNF, EGF etc), kinase activity
• HER2/EGFR2: no ligand, kinase activity
• HER3/EGFR3: ligands known (TNF, EGF etc), no kinase activity
• HER4/EGFR4: ligands known, kinase activity
Characteristic: co-operations
HER2 genetics in cancer
HER2 mutation amplification
Breast cancer: DIC EC-delp95 +
Gastric cancer +
Ovarian cancer +
Endometrian cancer +
Anti-EGFR resistance in NSCLC
• EGFR resistance mutation 790M
• K-RAS mutation
• C-MET amplification
• EGFR negativity (protein?)
Colorectal cancer and EGFR
• EGFR expression (mRNS and protein): 75-80%
• Intensity variable (1-100% cell)
• EGFR amplification: 0.6-15%
• Chr. 7 polisomy: 30%
• Chr.7 LOH: 8% (loss)
• TK-mutation: 12% (only Asia)
• EC-LD R497K polimorphism
• SP1-216 promoter G/T polimorphism
VEGFR2 receptor signaling in endothelial cells
P
P P P P
P P P
P
P P P P
P P P
VEGFR1 VEGFR2 VEGFR3
P
P P P P
P P P
VEGF-B VEGF VEGF-C
VEGF-D
SOS GRB2
Ras Raf
MEK TSAd
PLC
PKC
Erk eNOS
Src
Akt
PI3K Ca2+
Caspase-9 Bad
Cell survival Cell migration
Angiogenesis Monocyte migration
Lymphangiogenesis
Vascular permeability Cell proliferation VEGF-E
Kinase inhibitory profiles of anti- angiogenic agents
KIT
Angioblast FLT3
Angioblast VEGFR1 Blood vessel
VEGFR2 Blood vessel
VEGFR3 Lymph
vessel
PDGFR
Pericyte FGFR1 Blood vessel
EGFR MET
Gleevec
+ - - - - + - - -
Sunitinib
+++ +++ - +++ - ++ + - -
Sorafenib
++ ++ - ++ ++ ++ + - -
PTK787
+ - ++ ++ + + - - -
AG-137736
+++ - +++ +++ +++ +++ - - -
GW-786034
+ - ++ ++ ++ ++ + - -
ZD6474
- - ++ + - - - + -
ZD2171
+ ++ +
Döme, Tímár, AntiCancer Agents, 2007
Overview of EGF signaling
EGFR
JNK SOS
Ras GRB2
C-Fos Raf
MAPKK
AP1
MAPK PAK1
Nck
GRB2
Gab1
Shp2
WASP Src
Shc
Bad FKHR
CREB
RSK2 p53 Jun
MAPK p38 JNK
Cdc42 /Rac Vav2
EGF
Cytoskeleton Cell cycle
Apoptosis
STAT1 STAT3
Target genes
ADAM
HB-EGF PTP
Rac H2O2
NADPH
synthesis Gab1
PI3K
PIP3 E2Ub
Targets
DOK
Akt PDK1
Cbl
MKK2 MKK4
MEKK MEKK4
Rac FAK
CAS
Paxillin Src
Targets Ca2+
PKC
DAG PLC
IP3
MAPK
Ras GAP +
- -
- -
- +
- +
