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GKA deel 1 college 15
 

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 GKA deel 1 college 15 Presentation Transcript

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