Cancer - Basics

Based on undergrad Australian lecture

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  • Created by: nCaitlyn
  • Created on: 04-11-15 10:29
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  • Cancer
    • Origin
      • Stem Cell Model
        • Cell of Origin = first cancer cell
        • new differentiated cells can onl self-renew and produce more cells of its type
        • CoO is stem cell that self renews and differentiates
          • oncogenes and k/o TSG allow cancer cells to gain self-renewal ability through FoxO, telomerase, BRCA2/RAD50, and loss of Sox2, cMYC,  DMNT3a/b
      • Plasticity Model
        • like stem cell model, but differentiated cells can revert to original stem cell
        • melanomas present with 29% tumourigenic cells, therefore no hierarchy, therefore PLASTICITY MODEL
      • Clonal Evolution Model
        • all cells can self-renew and differentiate to create new cells, because genetic mutations to random cells, rather than to stem cells
        • no hierarchy of heterogeneity within tumour
        • cells can also revert to original form
      • Experimental Tests
        • dissociate tumour cells into different populations, and plant each into different mice to see which one will grow
          • if only one population grows = STEM CELL MODEL
            • Stem Cell Model
              • Cell of Origin = first cancer cell
              • new differentiated cells can onl self-renew and produce more cells of its type
              • CoO is stem cell that self renews and differentiates
                • oncogenes and k/o TSG allow cancer cells to gain self-renewal ability through FoxO, telomerase, BRCA2/RAD50, and loss of Sox2, cMYC,  DMNT3a/b
          • melanomas present with 29% tumourigenic cells, therefore no hierarchy, therefore PLASTICITY MODEL
    • Cause
      • Origin
        • Plasticity Model
          • like stem cell model, but differentiated cells can revert to original stem cell
        • Clonal Evolution Model
          • all cells can self-renew and differentiate to create new cells, because genetic mutations to random cells, rather than to stem cells
          • no hierarchy of heterogeneity within tumour
          • cells can also revert to original form
        • Experimental Tests
          • dissociate tumour cells into different populations, and plant each into different mice to see which one will grow
            • if only one population grows = STEM CELL MODEL
        • Oncogenes
          • Drive growth and entry into cell cycle
          • MYB for CRC and breast cancer
            • if you knock out Lop5 for MYB, then you have no MYB
              • in cancer-prone mice, this let them survive longer, therefore MYB is necessary for tumourigenesis
          • transcription factors vs receptor kinases
        • Tumour Suppressor Genes
          • Knudson's 2 hit model to completely lose TSG
          • p53 = major transcription factor controlling several cellular pathways, including DNA repair and apoptosis
            • induces apoptosis through PUMA, Noxa and BAX genes
              • PUMA and Noxa -> Cyt C release and Bcl inhibition
              • BAX -> cytochrome C release and caspase activation
              • loss of p53 has greater effect on tumour growth compared to loss of PUMA, or other downstream components
                • Knudson's 2 hit model to completely lose TSG
                • p53 = major transcription factor controlling several cellular pathways, including DNA repair and apoptosis
                  • induces apoptosis through PUMA, Noxa and BAX genes
                    • PUMA and Noxa -> Cyt C release and Bcl inhibition
                    • BAX -> cytochrome C release and caspase activation
                    • loss of p53 has greater effect on tumour growth compared to loss of PUMA, or other downstream components
                      • to prevent tumour resistance to p53, nutlin binds with p53-inhibitor MDM2
                      • Bax/cyt C activation with Abt199 inhibition of Bcl2 inhibitors
                • to prevent tumour resistance to p53, nutlin binds with p53-inhibitor MDM2
                • Bax/cyt C activation with Abt199 inhibition of Bcl2 inhibitors
          • gatekeeper genes - monitor cell cycle entry (p53, RB)
          • caretaker genes - DNA repair (BRCA1 and BRCA2)
        • Characteristics
          • loss of differentiation
          • disease of aging
          • less inclined to stop growing, rather than growing faster
      • Support
        • Cancer Associated Fibroblasts
          • promoting tumour growth by acting as reservoir of growth factors and use paracrine signalling
          • causes EMT
          • allows chemotherapy resistance due to promotion of FAK signalling to avoid using BRAF, so that apoptosis is inhibited and allow continued growth (?)
            • also CAF and ECM create protective shield around cancer cells
          • factors produced depend on purpose
            • TGF(b) to help tumour cell grow and recruit new cells, IL1 to modify immune response and collagen to set up the microenvironment
            • MMP for space to grow, as well as for angiogenesis (VEGF)
              • angiogenesis
                • Tumour Associated Macrophages
                  • Macrophages recruited by CSF-1 chemotactic factors  and matured into M2, by Il4
                  • produces MMP for angiogenesis, and EGF for general growth and division
                  • high production of IL6 and 8
                • occurs by exisitng vasculature's growth into tumour OR chemotactic factors that draw cells in to create entirely new blood vessels
                • HIF1 = transcritipn factor only stable at low oxygen, promote tumour division and growth
        • Tumour Associated Macrophages
          • Macrophages recruited by CSF-1 chemotactic factors  and matured into M2, by Il4
          • produces MMP for angiogenesis, and EGF for general growth and division
          • high production of IL6 and 8
        • Endothelial cells
          • supplying nutrients and oxygen
          • angiogenesis
            • occurs by exisitng vasculature's growth into tumour OR chemotactic factors that draw cells in to create entirely new blood vessels
            • HIF1 = transcritipn factor only stable at low oxygen, promote tumour division and growth
      • Metastasis
        • Invasion
          • MMP secretion to break down ECM for movement towards vessel
          • EMT to acquire mobile phenotype, assisted by CAF?
            • environmental signals (TGF) promote EMT
          • oncogenes, and epigentic changes allow movement and invasion
            • Oncogenes
              • Drive growth and entry into cell cycle
              • MYB for CRC and breast cancer
                • if you knock out Lop5 for MYB, then you have no MYB
                  • in cancer-prone mice, this let them survive longer, therefore MYB is necessary for tumourigenesis
              • transcription factors vs receptor kinases
            • Less E-cadherin and (b)-catenin
            • More fibronectin and vimentin
        • Intravasation
          • triad formation with macrophages and endothelial cells to squeeze into blood vessel
        • Circulation
          • Tropism
            • Seed and soil hypothesis: tumour cells prefer specific regions of body that accomodate its growth and expansion
            • Mechanical circulation hypothesis: tumour cells follow the circulation to the next organ (e.g. gut to liver, breast to bone marrow and lungs, etc.)
          • harsh environment with shearing forces and immune cells
          • high % of cancer cells die in circulation
          • travel in clusters ensures survival
        • Extravasation
          • tumour cells enhance "stickiness" at target region,  platelets accumlulate angiopoietin-like protein 4 to open gaps in vessel walls
          • platelets help tumour cells sto stop circulating and adhere to endothelial wall
        • Survival
          • high % die
          • dormancy or colonisation
            • epigenetic changes to allow MET and E-cadherin production
          • requires: tumour-initiating properties, growth factors, angiogenesis

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