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L31 - Pathogenesis of Cancer Understand that cancer develops and…

- - - - Tissue invasion = Malignancy
        A primary tumour must invade surrounding tissue to be labelled malignant
        
        A benign tumour is non-invasive
        
        Metastasis
        When invasive cancer cells spread via blood or lymph to colonise distant organs - metastasis
  - - - The great majority of cancers are 2° to external factors
        E.g. UV radiation
  - - - Initiation
        mutation in a single cell → “initiated” cell
        
        Promotion
        initiated cell proliferates >> normal cells → clonal expansion → additional mutations
        
        Malignant conversion
        → critical irreversible mutation
        
        Progression
        → malignant cells continue to mutate
- - - - Polycyclic aromatic hydrocarbons (PAH)
        e.g. benzo[a]pyrene*
      - Compounds in smoke are initiators:
        
        Metabolic activation (PAHs/NNK) → reactive forms → DNA adducts → gene mutations (C→A transversions)
        
        Smoke is also an irritant → inflammation, i.e. promoter
      - Heavy metals
        e.g. chromium, lead
      - Tobacco specific nitrosamines
        e.g. NNK
      - Volatile organics
        Aldehydes, e.g. acrolein, formaldehyde
- - - - Normal Growth Factor Signalling
        In order to maintain tissue homeostasis (architecture) and prevent mutation, ells only divide when appropriate
        
        Cells are quiescient until tey receive mitogenic GFs
        
        GF release positive growth sign. and induce re-entry into the cell cycle
        
        EC=>IC
        
        GFs issue commonands by binding to EC tyrosine kinase receptors.
        
        Growth Inhibitory Factors
        
        If sensing division isn't appropriate, local cells may also release GIFs
        
        Signal Transduction
        
        GF = EC ligand
        
        GF-R (tyrosine Kinase)
        
        IC signalling cascade actvated
        
        SUstaine through phosphorylation
        
        Activation of TFs which regulate gene exp.
        
        Signalling can be co-opted (commandeered) at any step to cause uncontrolled proliferation
      - Oncogene activation -
        Cells produces own growth signals:
        
        Autocrine GF production (e.g. PDGF - Glioblastoma)
        
        Over-expression of GF-R (EGFR-breast stomach)
        
        Constituitive activation of GF-R
        
        Constituitive activation of IC signalling
        
        Leads to Accelerated:
        
        Ras/Raf/MAPK proliferation pathway
        
        PI3K/Akt growth/survival pathway
    - - Deaf to Inhibition
        
        Normal cells respond to anti-proliferative signals - sense if it’s OK for division to go ahead → brake
        
        Many of these signals are routed through tumour suppressors - i.e. products of anti-oncogenes
        
        Breaks regulat cell fate
        
        Force cell into G^0
        
        Induce terminal differentiation
      - Retinoblastoma Pathway
        
        Most EC anti-proliferative signals rely upon RB pathway to suppress growth
        
        Constituents of the RB pathway are encoded by TSG (tumour suppressor genes)
        
        Normal Cells
        
        Hypophophorylated Rb → sequesters E2F to block G1/S cell cycle progression
        
        GFs → hyperphophorylated Rb → releases E2F → cell enters cell cycle, i.e. G1→S
        
        Oncogenic Cells
        Mutated Rb gene (1 allele) causes Rb to be constituitively hyperphosphorylate
        
        Uncontrolled proliferation
        
        Children develop bilateral retinoblastoma
    - - Resistance to Apoptosis
        
        Anti-apoptotic Protein Levels
        
        Anti-apoptotic protein expression levels ↑ - B cell lymphomas often show upregulation of Bcl-2
        
        Hormone Receptors
        
        Increased expression of ER & AR hormone receptors = Increased activation of survival SP
        
        p53 mutation
        
        Most common pathway affected - mutations of the p53 tumour suppressor gene*
        
        p53 is a key DNA damage sensor - activates apoptosis in cells with severe DNA damage or metabolic problems*
        
        p53 mutations are seen in ~50% of tumours
      - Regulated Cell Death
        Cell structure degraded, nuclear fragmented, cell corpse engulfed (no-scarring)
    - - Hayflck's # - Telomere Shortening
        
        Normal cells divide a finite # of times (Hayflick #)
        
        Tumour cells must inactivate this mechanism → achieve immortality
        
        Telomeres - mitotic “counting device” with multiple TTAGGG repeats (100-1000s)
        
        Telomere loss → induces senescence &/or apoptosis*
        
        Telomerase
        Telomerase - specialised DNA polymerase with a template to transcribe 6bp telomere repeats
        
        Normally expressed only in embryological development
        
        Re-expression of telomerase is used to
        immortalise cells → experimental cell lines
        
        85-90% Tumours have increased Telomerase Expression
    - - Angiogenesis/Neovascularisation
        Involves +ve and -ve signals
        
        +’ve - vascular endothelial GF (VEGF), basic fibroblast GF (bFGF)
        
        -‘ve - thrombospondin-1 (Tsp-1), angiostatin
        
        Shfting the balance of signalling proteins => angiogenesis
        Tumour and stromal cells contribute to altered balance
    - - Haematogenous Spread
        
        Intravasation
        
        Extravasation
  - - - Retinoblastoma (Rb)
        
        Li-Fraumeni syndrome (TP53)controls entry into apoptosis
        
        Neurofibromatosis (NF1) - RasGAP
        
        Von Hippel-Lindau disease (VHL) - controls HIF-1 levels
        
        Familial Adenomatosis Polyposis (APC) - controls β-catenin
    - - Lynch syndrome (HNPCC) - MSH2, MLH1, MSH6, PMS2, PMS1
        
        Breast and ovarian cancers - BRCA1 & BRCA2*
- - - - Dysplasia - cells no longer
        look normal
        
        Carcinoma - adenoma or
        papilloma (visible lump)
        
        Local Invasion - breaching of
        the basement membrane
        
        Metastasis - colonies in
        distant organs