1. Manifestation of Novel Social Challenges of the European Union in the Teaching Material of 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

2. SIGNALLING IN TUMOR CELLS Tímea Berki and Ferenc Boldizsár Signal transduction Manifestation of Novel Social Challenges of the European Union in the Teaching Material of 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

3. 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

4. TÁMOP-4.1.2-08/1/A-2009-0011 Tumor and activated T cells Activated T cell Immune escape Tumor cell DF3/MUC1 CD28 CTLA4 B7-1/2 MHC ITCR Growth arrest Proliferation Cell death RCAS1R Cytokine receptors Cytokines RCAS1 FasLDcR3 FasFasL

5. TÁMOP-4.1.2-08/1/A-2009-0011 What happens when Fas- stimulated immune cells resist to die? Tissue environment? Cytokines? FasFasL Tumor cells Immune cells

6. TÁMOP-4.1.2-08/1/A-2009-0011 TGF-  signaling in tumor signaling and cancer progression Tumor cellStromal cell Latent TGF-  ActiveTGF-  Proteases Thrombospondin Integrins Proteases Thrombospondin Integrins Decorin Betaglycan Decorin Betaglycan Effects on tumor 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

7. TÁMOP-4.1.2-08/1/A-2009-0011 Fas signal PKC MAPK FasL FADD CAP3 c- FLIP AIF TPA Death substrates Type II Type I Fas Caspase-8 Caspase-3 tBid Cytc Caspase-9 Cytc Apaf -1 Bcl- 2 Bcl-xL Caspase-8 APOPTOSIS DISC

8. TÁMOP-4.1.2-08/1/A-2009-0011 Growth factors (GFs) Small molecular weight soluble mediators They control: 1 1Proliferation 2 2Survival 3 3Metabolism 4 4Tissue differentiation Important implication in tumors Cytokines – growth factors

9. 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 family II – Insulin rec. family XI – TIE family III – PDGF familyXII – ROR family IV – FGF familyXIII – DDR family V – VEGF familyXIV – RET family VI – HGF family (c-Met) XV – KLG family VII – Trk familyXVI – RYK family VIII – Eph familyXVII – MuSK family IX – AXL family

10. TÁMOP-4.1.2-08/1/A-2009-0011 GF signaling pathwaysTranscription RTK Ligand P P P P P P P P Dimerization Src PKC PLC STAT JAK Akt

11. TÁMOP-4.1.2-08/1/A-2009-0011 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 EGFRHer2Her3Her4VEGFR1VEGFR2VEGFR3PDGFR-aPDGFR-bc-kit EGF TGF  β-cellulin Amphiregulin HB-EGF No specific ligands Heregulins β-cellulin NRG2 NRG3 VEGF-BVEGF-AVEGF-CVEGF-DPDGF-A PDGF-B PDGF-D SCF SOS GRB2 Ras Rac Rho CDC42 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

12. 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 activity Characteristic: Characteristic: co-operations

13. TÁMOP-4.1.2-08/1/A-2009-0011 HER2 genetics in cancer HER2mutationamplification Breast cancer: DICEC-delp95+ Gastric cancer+ Ovarian cancer+ Endometrian cancer+

14. 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?)

15. 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

16. TÁMOP-4.1.2-08/1/A-2009-0011 VEGFR2 receptor signaling in endothelial cells P P P P P P P P P P P P P P P P VEGFR1VEGFR2VEGFR3 P P P P P P P P VEGF-BVEGF VEGF-C VEGF-D SOS GRB2 Ras Raf MEK TSAd PLC  PKC Erk eNOS Src Akt PI3K Ca 2+ Caspase-9 Bad Cell survival Cell migration Angiogenesis Monocyte migration Lymphangiogenesis Vascular permeability Cell proliferation VEGF-E

17. TÁMOP-4.1.2-08/1/A-2009-0011 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 EGFRMET Gleevec +----+--- Sunitinib +++ - -+++-- Sorafenib ++ - +-- PTK787 +-++ ++--- AG-137736 +++- --- GW-786034 +-++ +-- ZD6474 --+++---+- ZD2171 ++++ Döme, Tímár, AntiCancer Agents, 2007

18. TÁMOP-4.1.2-08/1/A-2009-0011 Overview of EGF signaling