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Pathogenesis of Cancer (6 Capabilities of Cancer Cells (:five: Can promote…

- - - - Melanoma - Australia 155X Japan
      - Stomach - Japan 8X US
      - Liver - China 50X Canada
- - - - Contains at least 60 carcinogens
      - Volatile Organics - Aldehydes, e.g. Acrolein, formaldehyde
      - Polycyclic aromatic hydrocarbons (PAH), e.g. Benzo[a]pyrene
      - Tobacco specific nitrosamines, e.g. NNK
      - Heavy metals - E.g. Chromium lead
      - Compounds in smoke are initiators
        
        Metabolic activation (PAHs/NNK) → reactive forms →
        DNA adducts → gene mutations (C→A transversions)
- - - - Autocrine GF production (PDGF - glioblastoma)
      - Over-expression of GF-R (EGFR - breast, stomach)
      - Constitutive activation of GF-R (EGFR)
      - Constitutive activation of intracellular signalling
        
        Ras/Raf/MAPK proliferation pathway
        
        PI3K/Akt growth/survival pathway
  - - - Force cells out of cell cycle and into G(0) or
      - Induce cells to enter a post-mitotic state (i.e. undergo terminal differentiation)
    - - Dozens of tumour suppressor genes (TSGs) - limit cell proliferation
      - Familial cancers - often due to inheritance of a mutated allele in a TSG
      - Prototypical TSG - retinoblastoma (Rb)
      - Rb pathway is disrupted in most human cancers
  - - - Carefully regulated process - cell structures degraded, nucleus fragmented, cell corpse engulfed (no scarring)
      - Essential for normal development - E.g. Finger webs
      - Important in adult homeostasis - Cell damage sensors look for abnormal / stressed cells - Apoptosis
      - Yet highly abnormal tumour cells evade apoptosis
      - Mechanisms of Apoptosis
        Evasion in Tumours
        
        Resistance to apoptosis can be via
        
        Hormone receptor (ER & AR) expression ↑ - Survival signal
        
        Anti-apoptotic protein expression levels ↑ - B cell lymphomas often show upregulation of Bcl-2
        
        Most common pathway affected - mutations of p53 tumour suppressor gene
        
        p53 - A key DNA damage sensor - Activates apoptosis in cells with severe DNA damage or metabolic problems
        
        Dominant negative (interfere with WT protein) or inactivating p53 mutations are seen in ~50% of tumours
  - - - Normal cells divide a finite # of times (Hayflick #)
      - Tumour cells must inactivate this mechanism - immortality
      - Telomeres - Mitotic "counting device" with multiple TTAGGG repeats (100-1000s)
        
        Telomerase: Vital for telomere maintenance
        
        Telomerase - Specialised DNA polymerase with a template to transcribe 6bp telomere repeats
        
        Normally expressed only in the embryo
        
        Re-expression of telomerase is used to immortalise cells - Experimental cell lines
        
        85-90% of tumours ↑ telomerase expression
      - 50-100bp lost / division - DNA polymerases can't replicate 3' ends of chromosomes
      - Telomere loss - Senescence and/or apoptosis
  - - - Angiogenesis / Neovascularisation - Complex process
      - Involves many +ve and -ve signals
        
        +ve: Vascular endothelial GF (VEGF), basic fibroblast GF (bFGF)
        
        -ve: Thrombospondin-1 (Tsp-1), angiostatin
      - Shifts in the balance of signaling proteins (e.g. VEGF↑) → angiogenesis
      - Tumour cells and stromal cells contribute to altered balance
  - - - Genome Instability
      - Inflammation
  - - - Cancer cells get further help from the microenvironment
        
        O(2) & nutrients - Vascular network (New Blood Vessels)
        
        Invasion and spread
        
        :seven: Avoiding immune detection
        
        The immune system patrols tissues and routinely eliminates the vast majority of abnormal cells
        
        The immune system is a barrier to tumour progression
        
        Successful tumours evade the immune system
        
        They co-opt immune cells to ↑growth &
        encourage invasion
        
        E.g. TAMs, Tregs, iDCs
        
        BREACH #7 Cancer cells evade immune detection
- - - - GF - ligand (EC)
      - GF-R - RTK
      - IC signalling cascade
      - Phosphorylation +++
      - Activation of targets
      - Signalling can be co-opted at any step in the signal transduction pathway → Uncontrolled Proliferation