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CAN - Coggle Diagram

- - - - colorectal cancer highly effected as seen is high rates in Germany and low rates in Greece
      - red meat is probable carcinogen causing a fifth of colorectal cancers yet small amounts are good for zinc
      - processed meat is carcinogen causing multiple cancers
    - - low fibre may cause bowel cancer, from fruit and vegetables
    - - 6% of all cancers, especially breast and colorectal
      - breast cancer mechanism
        
        obesity promotes metastasis and growth by altering microenvironment via inflammatory cytokine il1b release
        
        tumour cells become addicted to obesity's high nutrients and inflammation
        
        increases myofibroblast composition of stroma stiffening the Ec matrix stimulating invasion and metastasis
        
        increased adipocytes activated by il1b release tgf alpha cuasing angiogenesis and metastasis
        
        adipose inflammation leads to necrosis and macrophage activation causing CLSs or crown like structures
        
        increases aromatase activity in post-menopausal women increasing nf-kb transcription activating cancer signalling
  - - - particulate matter
        
        carcinogens varying in size and organic nature
        
        NO, SO2, ozone, CO
        
        causes lung cancer
        
        PAH- polycyclic aromatic hydrocarbons- 500 types linked to cancer
      - sources
        
        transport, industry, fossil fuel power stations, farming, natural pollutants, and cooking/heating fuels
      - molecular mechanisms
        
        sustained proliferation, cell death resistance, genome instability, angiogenesis, tumour promoting inflammation and metastasis
    - - sources
        
        burning solid fossil fuels or moreso in UK secondhand smoke
      - molecular mechanisms
        
        carcinogens
        
        DNA adducts causing permanent miscoding- if p53, prb or ras are mutated by this lung cancer forms
        
        nicotine
        
        binds to receptors activating PKA and AKT to resist apoptosis and increase cell transoformation- addictive
        
        co-carcinogens
        
        in tobacco, tumour promoters via PKC and AP1 to enhance carcinogeneity
  - - - atomic bomb leukaemia, radon miners lung cancer, sunbatehrs melanoma, radium luminous painters bone cancer, and radiologists skin cancer
- - - - beta catenin usually degraded by APCs which are usually lost in cancer meaning free molecules accumulate allowing metastasis and allowing beta catenin to bind to let/TCF trans factors in nuclei causing upreg of oncogene MYC furthering metastatic ability
  - - - cancer cells can do glycoyltic switch in response to hypoxia or just normally to use anaerobic energy generation giving tumour cells advantage to outcompete for nutrients and acidify the microenvironment via lactic acid production killing non-tumour cells facilitating invasion
        
        cancer cells upregulate glucose transporters and glycolysis enzymes to become better at this
        
        utilised by fdg PET scans looking for cancer cells using glucose
- - - - initiating gene mutation due to lapse in DNA repair or environment causes cell to escape apoptosis, senesence, and immune surveillance so cell has survival advantage
      - this is monoclonal i.e. 1 cell type to begin with
        
        evidenced by G6PD enzyme mutation neoplasms in females only being expressed in roughly half their cells due to the mosaic nature of cells (G6PD is produced by x chromosome)
    - - advantageous mutations means cell proliferates creating monoclonal population
      - additional driver mutations accumulate causing heterogeneity and more proliferation
    - - cells break through basement membrane into surrounding stroma
      - genetic microenvironments, damaged stroma signals, and immune cells provide additional stimulation via growth factors
    - - only a few cells manage to escape the many boundaries to metastasise, depending on the anatomical closeness and microenvironment similarities
  - - - self sufficiency and independence from external growth signals to proliferate
      - in normal cells GFRs responses are ligand-dependent
      - mutations lead to ligand-independent firing of GFRs due to constitutive activation or over-expression of GFRs
        
        transmembrane transduction mutations
        
        autocrine signalling of own growth factor acting on membrane increases firing independently
        
        ras intracellular mutations
        
        GTPase, NRas, KRas, or HRas mutations so ras pathways occur independently
    - - insensitivity to anti-growth signals to evade growth suppression
      - in normal cells the cell cycle integrates nutrient status, TGF beta receptros, integrins, TKRs, and GPCRs to decide cycle stage via prb's phosphorylation status
      - tumour cells have prb mutation disabling it from preventing growth
    - - apoptosis evasion
      - due to mutation disabling p53 proapoptotic regulator meaning less apoptosis, DNA repair, senesence, and angiogenesis blocking
      - makes cancer less susceptible to chemo
    - - limitless replication potential
      - in normal cells, replication is limited by telomeres protecting chromosomes from deterioration and fusion yet shorten after each division
      - in cancer telomerase which adds repeats to telomeres is over-expressed allowing limitless replication
    - - sustained tumour angiogenesis vital for nutrients, excretion, and metastasis
      - upregulation of pro-angiogenic factors like VEGF or FGF
      - downregulation of angiogenic inhibitors e.g. thrombospondin, IFN, angiostatin, or endostatin
    - - tissue invasion and metastasis via internal changes
      - includes EMT, adhesion receptor, casherin, integrin, and extracellular protease expression changes
    - - genome instability, downregulating cellular energetics, avoiding immune destruction, microenvironmental changes, and inflammation
- - - - signalling molecule binds to RTK dimerising it
      - tyrosine domains of neighbouring receptors cross-phosphorylate eachother
      - this creates high affinity docking sites for grb-2 adaptor protein with sh2 (src homology 2) domain recognising these phosphorylated tyrosine residues
      - grb-2 has a sh3 (src homology 3) domain that binds to proline domains called sos forming grb-2-sos complex
      - sos is a guanine nucleotide exchange factor (GEF) that activates ras by stimulating it to exchange GDP for GTP
      - activated ras is a GTPase that activates raf by changing its conformation
      - raf is a serine-3-anine kinase that phosphorylates/activates mek
      - mek is a serine-3-anine kinase which activates/phosphorylates erk
      - erk enters the nucleus and phosphorylates kinases and other gene regulators such as c-jun, c-fos, c-myc, c-myb, and cyclin d causing cell growth and proliferation
    - - reversible RTK pathway causing cell proliferation via protein kinases phosphorylating ser, thr and tyr residues on target proteins
      - ras
        
        small g protein oncogene with a covalently bound lipid group attachng it to membranes
        
        mutations in 30% of tumours
        
        inactive form has gdp and active form has gtp
        
        sos stimulated activation and GTPase activating proteins inactivate it by utilising its GTP
      - needs tight regulation as any mutation predisposes to cancer
    - - removal of signal by turning off activated RTKs via protein tyrosine phosphatases (PTPs) like SHP-1 and 2
      - Ras GAPs like p120 GAP neurofibromin
      - dephosphorylation of target proteins by serine and threonine phosphatases
  - - - removal of the extracellular signal by switching off activated RTKs, dephosphorylation of target proteins by serine/threonine phosphatases, and PTEN inositol lipid phosphatase that hydrolyses pip3 back to pip2
    - - PI-3 kinase is activated by binding to phosphorylated tyr residues on RTKs forming pip
      - pip is phosphorylated to pip2 phosphatidylinositol which pi-3 kinase phosphorylates to pip3
      - pip3 is a docking site for pdk1 and akt
      - pdk1 and akt bind and the former phosphorylates/activates the latter making it dissociate
      - activated akt phosphorylates protein bad resulting in inhibitory protein death and apoptosis prevention enabling survival
      - activated akt also phosphorylates mtor (mammalian target of rapamycin) complex 1 stimulating cell growth via ribosome production/protein synthesis and protein degradation inhibition and mtor complex 2 stimulating cell growth via activating akt again to propagate the signal
    - - her2
        
        tyrosine kinase phosphorylating pi-3 kinase which phosphorylates pip2 to pip3 in the egfr2 and erbb2 families (orphan receptor aka no known ligand activated by heterodimerisation with other family members
        
        overexpressed due to mutation in 30% of breast cancers leading to homodimerisation of her2 amplifying the pi-3 kinase pathway triggering growth, reducing survival of patients