GKA deel 1 college 15

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  • GK 2009 a.a.m.thomas@uu.nl
  • GK 2009 a.a.m.thomas@uu.nl
  • GK 2009 a.a.m.thomas@uu.nl
  • GK 2009 a.a.m.thomas@uu.nl
  • GKA deel 1 college 15

    1. 2. The hallmarks of cancer Hanahan & Weinberg, Cell 100, 2000, 57-70 GK 2009
    2. 3. The hallmarks of cancer Hanahan & Weinberg, Cell 100, 2000, 57-70 GK 2009 Mantovani Nature 457, 36-37(2009)
    3. 4. Infectious causes of cancer and their detection Dalton-Griffin and Kellam, J of Biology 2009, 8:67doi:10.1186/jbiol168 GK 2009 Figure 1.                                                                                                                                                  
    4. 5. The hallmarks of cancer Hanahan & Weinberg, Cell 100, 2000, 57-70 GK 2009 Tumour development is an evolutionary process
    5. 6. The hallmarks of cancer Hanahan & Weinberg, Cell 100, 2000, 57-70 <ul><li>Independence from signals </li></ul><ul><ul><li>Proto-oncogen </li></ul></ul><ul><li>Independence from proliferation inhibitory signals </li></ul><ul><ul><li>Tumor-suppressor </li></ul></ul><ul><li>Escape from apoptosis </li></ul><ul><li>Unlimited proliferation </li></ul><ul><ul><li>Telomeres-senescence </li></ul></ul><ul><li>Up-regulation angiogenesis </li></ul><ul><li>Tissue invasion- metastasis </li></ul><ul><li>Forgotten? DNA repair! </li></ul><ul><ul><li>Acts like a tumor-suppressor </li></ul></ul><ul><li>Order is not fixed!! </li></ul>GK 2009 Deranged processes in tumor cell: Tumour development is an evolutionary process
    6. 7. Tumor morphology Hanahan & Weinberg GK 2009
    7. 8. Blueprint of a cell Hanahan & Weinberg GK 2009 3 3 2 1 4 5 2 Red: identified mutations in cancer cells
    8. 9. Blueprint of a cell Hanahan & Weinberg GK 2009 3 3 2 1 4 5 2 Red: identified mutations in cancer cells
    9. 10. Blueprint of a cell Hanahan & Weinberg GK 2009 3 3 2 1 4 5 2 Red: identified mutations in cancer cells
    10. 11. Blueprint of a cell Hanahan & Weinberg GK 2009 3 3 2 1 4 5 2 Red: identified mutations in cancer cells
    11. 12. Blueprint of a cell Hanahan & Weinberg GK 2009 3 3 2 1 4 5 2 Red: identified mutations in cancer cells
    12. 13. Blueprint of a cell Hanahan & Weinberg GK 2009 3 3 2 1 4 5 2 Red: identified mutations in cancer cells
    13. 14. Blueprint of a cell Hanahan & Weinberg GK 2009 3 3 2 1 4 5 2 Red: identified mutations in cancer cells
    14. 15. Blueprint of a cell Hanahan & Weinberg GK 2009 3 3 2 1 4 5 2 Red: identified mutations in cancer cells
    15. 16. Mutations in glioblastomas The Cancer Genome Atlas Research Network Nature 455, (2008) 1061-1068 Comprehensive genomic characterization defines human glioblastoma genes and core pathways GK 2009 Inserted 17-11-2008
    16. 17. Mutations in lung adenocarcinomas Ding et al., Nature 455 (2008)1069-1075 GK 2009 Inserted 17-11-2008
    17. 18. Growth factor-independence Hanahan & Weinberg <ul><li>Tumor cell produces GF </li></ul><ul><ul><li>Autocrine instead of paracrine or endocrine </li></ul></ul><ul><ul><ul><li>PDGF and TGF-  </li></ul></ul></ul><ul><li>Induction from neighboring cells (stroma) </li></ul><ul><li>Overexpression receptor </li></ul><ul><ul><li>EGF/erb-B, Her-2/neu </li></ul></ul><ul><li>Deletion part of receptor (truncation) </li></ul><ul><ul><li>Independent of ligand GF </li></ul></ul><ul><li>Change of type of integrin to growth-stimulating integrins (next slide) </li></ul><ul><li>Downstream: Ras </li></ul><ul><ul><li>MAPK-pathway, growth-proliferation </li></ul></ul><ul><ul><li>PI3K-pathway, survival, anti-apoptotic </li></ul></ul>GK 2009
    18. 19. Role of integrins From: Yamada & Even-Ram, Nature Cell Biology 4, 2002, E75-E76 GK 2009 Integrins are required for survival For adults only
    19. 20. Role of integrins From: Yamada & Even-Ram, Nature Cell Biology 4, 2002, E75-E76 GK 2009 Integrins are required for survival
    20. 21. Anti-proliferation Hanahan & Weinberg <ul><li>Mostly by pRB or 2 family members: p107, p130 </li></ul><ul><ul><li>Viral influence on, zoals E7 van HPV </li></ul></ul><ul><ul><li>Mutation in CDK4, required for p15-binding </li></ul></ul><ul><ul><li>Deletion Rb-gene </li></ul></ul><ul><li>Downregulation TGF-R </li></ul><ul><ul><li>(Right top corner ‘Cell blueprint’) </li></ul></ul><ul><ul><li>Non-functional TGF-R </li></ul></ul><ul><ul><li>Elimination SMAD-4 </li></ul></ul><ul><ul><li>Elimination p15 locus </li></ul></ul>GK 2009
    21. 22. Properties of apoptosis Hanahan & Weinberg <ul><li>Loss of cell membrane </li></ul><ul><li>Blebbing of cytosol </li></ul><ul><li>Degradation chromosomal DNA </li></ul><ul><li>Nucleus fragmentation </li></ul><ul><li>Phagocytosis by neighboring cells </li></ul><ul><li>Sensors, extra-cellular and transmembrane </li></ul><ul><ul><li>IGF1-R, ligand IGF-1 and –2 </li></ul></ul><ul><ul><li>IL-3 –Receptor </li></ul></ul><ul><ul><li>Fas-receptor </li></ul></ul><ul><ul><li>TNF  -receptor </li></ul></ul><ul><ul><li>Cell-cell or cell-ECM receptors </li></ul></ul><ul><li>Effectors </li></ul><ul><ul><li>Caspases; caspase 8 and 9 are inductors </li></ul></ul>GK 2009
    22. 23. Escape from apoptosis Hanahan & Weinberg, Cell 100, 2000, 57-70 <ul><li>Deletion or inactivation p53 </li></ul><ul><li>Mutations in PKB-pathway </li></ul><ul><ul><li>Anti-apoptotic signaling </li></ul></ul><ul><li>Up-regulation decoy Fas-ligand </li></ul>GK 2009
    23. 24. Unlimited cell division Hanahan & Weinberg <ul><li>Limited number of cell divisions </li></ul><ul><ul><li>20-60x </li></ul></ul><ul><ul><li>Cell autonomous mechanism </li></ul></ul><ul><ul><li>Hayflick-limit </li></ul></ul><ul><ul><ul><li>Senescence </li></ul></ul></ul><ul><ul><ul><li>Prevented by p53- en Rb-mutations </li></ul></ul></ul><ul><ul><li>Crisis: 1:10 7 -cellen immortalised </li></ul></ul><ul><li>Counting mechanism </li></ul><ul><ul><li>Telomeres </li></ul></ul><ul><ul><li>Ends of DNA-strands </li></ul></ul><ul><ul><li>Telomerase </li></ul></ul>GK 2009
    24. 25. Continuous angiogenesis Hanahan & Weinberg <ul><li>Endothelial cells </li></ul><ul><ul><li>Positive: </li></ul></ul><ul><ul><ul><li>VEGF (vascular endothelial growth factor) </li></ul></ul></ul><ul><ul><ul><li>FGF (fibroblast growth factor) </li></ul></ul></ul><ul><ul><li>Negative </li></ul></ul><ul><ul><ul><li>Thrombospondin </li></ul></ul></ul><ul><ul><ul><li>Endostatin </li></ul></ul></ul><ul><ul><ul><li>Angiostatin </li></ul></ul></ul><ul><ul><li>Expression classes of integrins </li></ul></ul>GK 2009
    25. 26. Order of mutations Hanahan & Weinberg <ul><li>First mutations in DNA repair? </li></ul><ul><ul><li>Cause or consequence? </li></ul></ul><ul><li>How about cancer stem cells? </li></ul>GK 2009
    26. 27. CSC: the cancer stem cell Rosen and Jordan (2009) Science 324: 1670-1673 <ul><li>Assay for stem cell: </li></ul><ul><ul><li>Transplant individual cancer cell into SCID-mouse </li></ul></ul>GK 2009 Inserted 2-12-2009
    27. 28. The end! GK 2009 Einde van 1 e helft van de cursus. Veel succes met het studeren… DNA repair

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