GKA deel 1 college 13

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  • GK 2009 a.a.m.thomas@uu.nl
  • GK 2009 a.a.m.thomas@uu.nl
  • GKA deel 1 college 13

    1. 2. Wereld AIDS dag, 1 december GK 2009
    2. 3. ‘ Helft hiv-baby's sterft voor tweede verjaardag’ <ul><li>Beeld uit de campagne voor aidswezen. </li></ul><ul><li>Van alle kinderen met hiv sterft de helft binnen </li></ul><ul><li>twee jaar, omdat hij of zij niet de juiste </li></ul><ul><li>behandeling krijgt. Als deze hiv-baby's in de </li></ul><ul><li>eerste twaalf weken worden behandeld, daalt </li></ul><ul><li>de kindersterfte met 75 procent. Dat blijkt uit een </li></ul><ul><li>rapport dat Unicefdirecteur Jan Bouke Wijbrandi </li></ul><ul><li>op Wereld Aidsdag in Amsterdam overhandigde aan </li></ul><ul><li>De Nederlandse aidsambassadeur Paul Bekkers. </li></ul><ul><li>Het rapport is opgesteld door Unicef, de </li></ul><ul><li>wereldgezondheidsorganisatie, de VN-aidsorganisatie </li></ul><ul><li>UNAIDS en het Wereldbevolkingsfonds van de VN. </li></ul>GK 2009 Foto GPD/Adriaan Backer
    3. 4. How cancer spreads Ruoslahti Sci Am 275-3, 1996 GK 2009 <ul><li>Metastasis= “uitzaaiingen” </li></ul><ul><li>Often more life threatening than a tumor itself </li></ul>
    4. 5. Invasion and metastasis Ruoslahti, Sci Am 275-3, 1996 GK 2009 Endothelal lining Basement membrane Metastatic cell 1:10.000 Tumor cell adhering to capillary Secondary tumor
    5. 6. Changes of tumorcells to metastasis Ruoslahti <ul><li>From localised to metastatic cell  </li></ul><ul><ul><li>Release from neighboring cells </li></ul></ul><ul><ul><ul><li>Cell-adhesion molecules </li></ul></ul></ul><ul><ul><ul><ul><li>Cadherines (ICAM, ECAM, NCAM) </li></ul></ul></ul></ul><ul><ul><li>Release from ECM: extracellular m atrix </li></ul></ul><ul><ul><ul><li>Integrins </li></ul></ul></ul><ul><ul><li>Invasion into basal membrane </li></ul></ul><ul><ul><ul><li>Proteases, (=collagenase, or gelatinases) </li></ul></ul></ul><ul><ul><ul><ul><li>Membrane-bound proteases, with </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Metal as active component in active centre </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>MMPs </li></ul></ul></ul></ul></ul><ul><ul><li>Invasion into blood- or lymph vessels </li></ul></ul><ul><ul><li>Prevention of apoptosis </li></ul></ul><ul><ul><li>Binding to endothelial cells </li></ul></ul>GK 2009
    6. 7. Area code: integrines and cadherines Ruoslahti, Sci Am 275-3, 1996 <ul><li>Anchorage-dependence </li></ul><ul><li>Released cell: integrin stops activity cyclineE/CDK </li></ul>GK 2009
    7. 8. Cellular adhesion Ruoslahti, Sci Am 275-3, 1996 <ul><li>Metalloproteases </li></ul><ul><ul><li>= Collagenase </li></ul></ul><ul><li>Destroying </li></ul><ul><ul><li>Extracellular matrix (ECM), and </li></ul></ul><ul><ul><li>Basal membrane </li></ul></ul>GK 2009 Hotary et al., A cancer cell metalloprotease triad regulates the basement membrane transmigration program, Genes & Dev. 20, 2006, 2673-2686
    8. 9. Patterns of metastasis Ruoslahti, Sci Am 275-3, 1996 <ul><li>Destination metastasis determined by </li></ul><ul><ul><li>Blood- and lymphvessels </li></ul></ul><ul><ul><li>Integrins </li></ul></ul><ul><ul><ul><li>Such as  v  3 </li></ul></ul></ul>GK 2009
    9. 10. Inhibiting metastasis Ruoslahti, Sci Am 275-3, 1996 <ul><li>RGD (Arg-Gly-Asp) peptide blocks fibronectin binding to integrin </li></ul>GK 2009
    10. 11. Phage library Ruoslahti, Sci Am 275-3, 1996 GK 2009
    11. 12. Phage library Ruoslahti, Sci Am 275-3, 1996 <ul><li>Every tissue has unique receptors, integrins and cadherin combinations </li></ul><ul><li>Summary Ruoslahti: </li></ul><ul><ul><li>Required for metastasis: </li></ul></ul><ul><ul><ul><li>Break cell-cell and </li></ul></ul></ul><ul><ul><ul><li>Cell-ECM contact </li></ul></ul></ul><ul><ul><ul><ul><li>Anchorage </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Integrins </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Apoptosis </li></ul></ul></ul></ul></ul><ul><ul><ul><li>Metalloproteases </li></ul></ul></ul><ul><ul><ul><li>Cadherine </li></ul></ul></ul>GK 2009 ===============
    12. 13. Fighting cancer by attacking its blood supply Folkman Sci Am 275-3, 1996 GK 2009 <ul><li>Angiogenesis </li></ul><ul><ul><li>F ormation new bloodvessels </li></ul></ul><ul><ul><ul><li>endothelial cells </li></ul></ul></ul><ul><li>Obligatory for tumour growth </li></ul><ul><ul><li>Pea ! </li></ul></ul><ul><ul><ul><li>Balance proliferation-necrosis </li></ul></ul></ul>
    13. 14. Fighting cancer by attacking its blood supply Folkman Sci Am 275-3, 1996 GK 2009
    14. 15. Angiogenesis <ul><li>Requires an inductor, a growth factor </li></ul><ul><ul><li>From tumor cells </li></ul></ul><ul><ul><li>From neighboring cels or tissue </li></ul></ul><ul><ul><li>Tumor induces other cells </li></ul></ul><ul><ul><ul><li>Macrophages </li></ul></ul></ul><ul><li>Requires angiogenesis inhibitors  </li></ul><ul><li>Balance between pro- and anti- </li></ul><ul><li>Endothelial cells stimulate proliferation and migration tumor cells (Interleukine-6) </li></ul><ul><li>p53 is Tc-factor of angiogenesis inhibitor </li></ul>GK 2009
    15. 16. Oxygen control of transcription factor activity Sherr (2004) Cell 116:235-246 <ul><li>Oxygen regulates hydroxylation HIF </li></ul><ul><ul><li>Hypoxia-inducible transcription factor </li></ul></ul><ul><ul><ul><li>Induces angiogenesis (VEGF), red blood cell production (epo), glycolysis </li></ul></ul></ul><ul><li>Proline hydroxylation induces degradation </li></ul><ul><ul><li>By VHL tumor suppressor </li></ul></ul><ul><ul><ul><li>Von Hippel-Lindau </li></ul></ul></ul><ul><li>Asparagine (Asn) hydroxylation prevents p300/CBP-binding </li></ul><ul><ul><ul><li>Important Tc- factor </li></ul></ul></ul>GK 2009 Inserted Nov 2009

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