Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

SIGNALLING IN TUMOR CELLS

Tímea Berki and Ferenc BoldizsárSignal transduction

Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

TÁMOP-4.1.2-08/1/A-2009-0011Immune selection in the development of cancer: no two tumors are alike

Initiation, proliferation,diversification

Microevolution, selection ofimmune resistance

Immune escape andunchecked proliferation

TÁMOP-4.1.2-08/1/A-2009-0011

Tumor and activated T cells

Activated T cell Immune escape Tumor cell

DF3/MUC1

CD28CTLA4

B7-1/2

MHC ITCR

Growth arrest

Proliferation

Cell death

RCAS1R

Cytokine receptors

Cytokines

RCAS1

FasL DcR3

Fas FasL

TÁMOP-4.1.2-08/1/A-2009-0011What happens when Fas-stimulated immune cells resist to die?

Tissue environment?

Cytokines?

FasFasL

Tumor cellsImmune cells

TÁMOP-4.1.2-08/1/A-2009-0011

TGF-b signaling in tumor signaling and cancer progression

Tumor cellStromal cell Latent TGF-b

ActiveTGF-b

ProteasesThrombospondin

IntegrinsDecorin

Betaglycan

Effects ontumor cells

Growth inhibition(early)Invasion (late)

Effects on tumor environment

Stroma↑Proteases

↑ECM production

Endothelial cells↑Angiogenesis

Immune cells↓Fas-L activity

↓ NK cells↓ T cells↓ B cells

TÁMOP-4.1.2-08/1/A-2009-0011

Fas signal

PKC

MAPK

FasL

FADDFADDCAP3 CAP3

c-FLIP

AIF

TPA

Death substrates

Type IIType IFas

Caspase-8

Caspase-3

tBid

CytcCaspase-9

CytcApaf-

1

Bcl-2Bcl-xL

Caspase-8

APOPTOSIS

DISC

TÁMOP-4.1.2-08/1/A-2009-0011

Growth factors (GFs)• Small molecular weight soluble

mediators• They control:

1Proliferation2Survival3Metabolism4Tissue differentiation

• Important implication in tumors• Cytokines – growth factors

TÁMOP-4.1.2-08/1/A-2009-0011

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 familyII – Insulin rec. family XI – TIE familyIII – PDGF family XII – ROR familyIV – FGF family XIII – DDR familyV – VEGF family XIV – RET familyVI – HGF family (c-Met)

XV – KLG family

VII – Trk family XVI – RYK familyVIII – Eph family XVII – MuSK familyIX – AXL family

TÁMOP-4.1.2-08/1/A-2009-0011

GF signaling pathways

Proliferation MigrationSurvival Cell cycle progression

Transcription

RTK

Ligand

P

PP

PP

PP

P

Dimerization

Src

SOSGRB2Ras

RafErk

PKC

PLC

STAT

JAK

Akt

PI3KPDK1

TÁMOP-4.1.2-08/1/A-2009-0011

GF receptors as therapeutic targets

PDGF-C

Cell survival Proliferation Apoptosis resistance

Metastasis Angiogenesis

P

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

PP

P

EGFR Her2 Her3 Her4 VEGFR1 VEGFR2 VEGFR3 PDGFR-a PDGFR-b c-kit

EGFTGF

β-cellulinAmphiregulin

HB-EGFNo specific

ligands Heregulins

β-cellulinNRG2NRG3 VEGF-B VEGF-A VEGF-C VEGF-D PDGF-A

PDGF-BPDGF-D SCF

SOSGRB2 Ras Rac RhoCDC42

MEK1/2

Erk

Raf

ERK pathway

MKK4/7

JNK

MEKK

JNK pathway

MKK3/6

p38

Tak

p38 pathway

Akt

mTor

PI3K

EverolimusImatinibTrastuzumabLeflunomideLapatinibGefitinibErlotinibPanitumumabSorafenib

CetuximabBevacizumabVandetanibSunitinibEnzastaurinPazopanibMotesanibMidostaurinTemsirolimusSirolimus

P

PP

PP

P

P

P

TÁMOP-4.1.2-08/1/A-2009-0011

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 activityCharacteristic: co-operations

TÁMOP-4.1.2-08/1/A-2009-0011

HER2 genetics in cancer

HER2 mutation amplification

Breast cancer: DIC EC-delp95 +

Gastric cancer +

Ovarian cancer +

Endometrian cancer +

TÁMOP-4.1.2-08/1/A-2009-0011

Anti-EGFR resistance in NSCLC• EGFR resistance mutation 790M• K-RAS mutation• C-MET amplification• EGFR negativity (protein?)

TÁMOP-4.1.2-08/1/A-2009-0011

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

TÁMOP-4.1.2-08/1/A-2009-0011

VEGFR2 receptor signaling in endothelial cells

P

PP

PP

PP

PP

PP

PP

PP

P

VEGFR1 VEGFR2 VEGFR3

P

PP

PP

PP

P

VEGF-B VEGF VEGF-CVEGF-D

SOS

GRB2

Ras Raf

MEK

TSAd

PLC

PKC

ErkeNOS

Src

Akt

PI3K Ca2+

Caspase-9Bad

Cell survival

Cell migration

AngiogenesisMonocyte migration

Lymphangiogenesis

Vascular permeability Cell proliferation

VEGF-E

TÁMOP-4.1.2-08/1/A-2009-0011

Kinase inhibitory profiles of anti-angiogenic agents

KITAngioblast

FLT3Angioblast

VEGFR1Bloodvessel

VEGFR2Bloodvessel

VEGFR3Lymphvessel

PDGFRPericyte

FGFR1Bloodvessel

EGFR MET

Gleevec + - - - - + - - -

Sunitinib +++ +++ - +++ - ++ + - -

Sorafenib ++ ++ - ++ ++ ++ + - -

PTK787 + - ++ ++ + + - - -

AG-137736 +++ - +++ +++ +++ +++ - - -

GW-786034 + - ++ ++ ++ ++ + - -

ZD6474 - - ++ + - - - + -

ZD2171 + ++ +

Döme, Tímár, AntiCancer Agents, 2007

TÁMOP-4.1.2-08/1/A-2009-0011

Overview of EGF signaling

EGFR

JNK

SOS

Ras

GRB2

C-Fos

Raf

MAPKK

AP1

MAPK

PAK1

NckGRB2

Gab1

Shp2

WASP

Src

Shc

Bad FKHR

CREB

RSK2 Junp53

MAPK JNKp38

Cdc42/Rac

Vav2

EGF

CytoskeletonCell cycle

Apoptosis

STAT1 STAT3

Target genes

ADAM

HB-EGF

PTP

Rac

H2O2

NADPHsynthesis 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

RasGAP

+

- -

- -

-

+

-

+