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Signalling in tumor cells

Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s P rogrammes at the University of Pécs and at the University of Debrecen Identification number : TÁMOP-4.1.2-08/1/A-2009-0011.

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Signalling in tumor cells

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

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Tímea Berki and Ferenc Boldizsár Signaltransduction Signallingin tumor cells

  3. Immuneselectioninthedevelopment of cancer: no twotumorsarealike Initiation, proliferation, diversification Microevolution, selection of immune resistance Immune escape and unchecked proliferation

  4. Tumor and activated T cells Activated T cell Immune escape Tumor cell Cytokines Cytokinereceptors RCAS1 TCR MHC I RCAS1R Growtharrest CTLA4 B7-1/2 CD28 Proliferation Cell death FasL Fas FasL DcR3 DF3/MUC1

  5. WhathappenswhenFas-stimulatedimmunecellsresistto die? Cytokines? FasL Fas Tissue environment? Immunecells Tumor cells

  6. TGF-bsignalingin tumor signaling and cancerprogression Stromalcell Tumor cell LatentTGF- Proteases Thrombospondin Integrins Decorin Betaglycan ActiveTGF- Effectson tumor cells Effectsontumor environment Stroma Endothelial cells Immune cells ↓Fas-Lactivity ↓ NK cells ↓ T cells ↓ B cells ↑Proteases ↑ECM production Growth inhibition (early) Invasion (late) ↑Angiogenesis

  7. Type II Type I Fassignal FasL TPA Fas FADD FADD CAP3 CAP3 PKC DISC MAPK c-FLIP Caspase-8 tBid Bcl-2 Bcl-xL Cytc Cytc Caspase-9 Apaf-1 AIF Caspase-3 Caspase-8 Deathsubstrates APOPTOSIS

  8. 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

  9. Receptortyrosinekinase(RTK)families • 90 unique Tyr kinases in the human genome, 58 are RTKs • Growth factor, cytokine and hormone receptors • Classes:

  10. GF signalingpathways Ligand RTK Dimerization P P P P P P P P GRB2 SOS PI3K PDK1 JAK PLC Ras Akt PKC Src Raf STAT Erk Proliferation Survival Migration Cell cycle progression Transcription

  11. GF receptorsastherapeutictargets EGF TGF β-cellulin Amphiregulin HB-EGF PDGF-C β-cellulin NRG2 NRG3 No specific ligands PDGF-B PDGF-D Heregulins VEGF-B VEGF-A VEGF-C VEGF-D PDGF-A SCF P P P P P P P P EGFR Her2 Her3 Her4 VEGFR1 VEGFR2 VEGFR3 PDGFR-a PDGFR-b c-kit P P P P P P P P P P P P P P P P P P GRB2 SOS Ras Rac CDC42 Rho P P P P P P P P P P P P P P P P P P ERK pathway JNK pathway p38 pathway Raf MEKK Tak PI3K Sorafenib Sirolimus P P P P P P P P P P P P P P P P P P Panitumumab Temsirolimus Erlotinib Midostaurin MEK1/2 MKK4/7 MKK3/6 P P P P P P P P P P P P P P P P P P Akt Gefitinib Motesanib Lapatinib Pazopanib Erk JNK p38 mTor Leflunomide Enzastaurin Trastuzumab Sunitinib Imatinib Vandetanib Everolimus Bevacizumab Cellsurvival Proliferation Apoptosisresistance Cetuximab Metastasis Angiogenesis

  12. HER genefamily • HER1/EGFR(1): ligandsknown (TNFa, EGF etc), kinaseactivity • HER2/EGFR2: no ligand, kinaseactivity • HER3/EGFR3:ligandsknown (TNFa, EGF etc), no kinaseactivity • HER4/EGFR4: ligandsknown, kinaseactivity • Characteristic:co-operations

  13. HER2 geneticsincancer

  14. Anti-EGFRresistancein NSCLC • EGFR resistancemutation 790M • K-RAS mutation • C-MET amplification • EGFR negativity (protein?)

  15. Colorectalcancer and EGFR • EGFR expression (mRNS and protein): 75-80% • Intensityvariable (1-100% cell) • EGFR amplification: 0.6-15% • Chr. 7 polisomy: 30% • Chr.7 LOH: 8% (loss) • TK-mutation: 12% (onlyAsia) • EC-LD R497K polimorphism • SP1-216 promoter G/T polimorphism

  16. VEGFR2 receptor signalinginendothelialcells VEGF-B VEGF VEGF-E VEGF-C VEGF-D P P P P P P VEGFR1 VEGFR2 VEGFR3 P P P P P P TSAd P P P P P P PLC Src GRB2 P P P P P P PKC Angiogenesis Monocytemigration Lymphangiogenesis PI3K Ca2+ Akt Raf SOS Ras Cellmigration MEK Caspase-9 Erk Bad eNOS Cellsurvival Vascularpermeability Cellproliferation

  17. Kinaseinhibitoryprofiles of anti-angiogenicagents Döme, Tímár, AntiCancerAgents, 2007

  18. Overview of EGF signaling EGF Vav2 EGFR PTP + E2Ub - - STAT1 STAT3 PLC H2O2 GRB2 Cbl IP3 NADPH synthesis DAG Gab1 SOS Targetgenes Shc Ca2+ + - - Cdc42 /Rac PKC Rac PI3K Ras Src DOK Targets PIP3 - Raf MEKK MEKK4 Akt PDK1 ADAM Ras GAP MAPKK MKK2 MKK4 Nck + GRB2 - Targets HB-EGF FAK Bad FKHR MAPK MAPK p38 JNK Gab1 Src PAK1 Paxillin C-Fos MAPK Shp2 RSK2 p53 Jun CAS WASP Rac JNK AP1 Apoptosis CREB Cell cycle Cytoskeleton

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