Autophagy & Cancer L4

• Cancer occurs when:

  • Transformation requires alternation of genes invovled in cell growth and differentiation
  • Affected genes
  • Oncogenes = promote cell growth + differentiation --> allow survival instead of apoptosis
  • Tumour Supressors --> inhibit cell division or suvival
• Changes in many genes are required to transform a normal cell into a cancer cell
• Environments promote repeated genetic damage!
• Disease progresses to become invasion, remodel the vasculature linked to metabolic needs
• Tumours are under metabolic stress
• Growing tumours promote vascularisation via angiogenesis, growth occurs haphazardly --> vessels are disorganised, dilated tortuous and far apart, thus no efficent blood flow --> hypoxia
• Hypoxia in cancer triggers adaption and autophagy.

  • Also makes drug treatment difficult and places the tumour under metbaolic stress
• Hypoxia produces cancer in survival strategies

  • Triggers autophagy to allow survival in low nutrient microenvironments by adaptation
  • Adapted cells are MORE AGGRESSIVE and RESISTANT
• Tumours under stress are autophagy triggered.
• Hypoxia triggers angiogenesis
• Cancer autophagy tumorigenesiss?


  Autophagy suppresses tumorigenesis by limiting necrosis, inflammation & genome instability
• Autophagy delays apoptosis by providing nutrients for metabolism and cellular quality control by degrading damaged protein and organelles and promotes stress adaptation, changing the tumour metabolism leading to cellular remodelling
• Under prolonged stress, cells exit the cell cycle and become dormant basically through remodelling (altered gene expression and metabolism changes to conserve energy)
• Stress addition / removal --> dormant cells re-enter cell cycle to restart proliferation, the tumour regenerates and promotes further tumour formation and often much more aggressive
• Autophagy addiction?


  Cancer cells have naturally high levels of basal autophagy and is enhanced by the RAS oncogene
• Tumour suppression pathway invovled with autophagy, restore autophagy when decreased has what effects?

  ~~~~~~~~Cells have autophagy completely lost

  • Limit inflammation
  • Limit tissue damage
  • Limit oxidative stress

  No tumour formed --> optimal cells
• Alternative pathway where cells are metabolically starved has what effects?

  ~~~~~~~~~~ Cells that have increased levels of autophagy at basal level

  • Metabolism is under stress due to the hypoxia present in the cells
  • Enables cell dormancy + metabolic remodelling

  Increased / induced autophagy will enhance cancer cell survival
• Autophagy addicted cancer cells has what effects?

  Critically required in those addicted cells, has HIGH basal level of autophagy

  • Lack stress adaptation as theyre already stressed
  • Limiting / decreasing autophagy produces more stress and cells die

  Decreased autophagy induces cancer cell death
• Autophagy supresses tumorgenesis by limit necrosis and inflammation?


  metabolic stress due to hypoxia causes nutrient deprivation and oncogene activation that triggers proliferation and induces apoptosis that limites tumour growth

  Also activates autophagy to protect cells

  • Autophagy competend cells survive
  • Autophagy deffective --> die and promote chronic inflammatory site that promotes tumour growth
• Limiting tissue damage can suppress tumorigenesis
• Autophagy limits genomic instability?

  metabolic stress also induces oxidative damage and p62 accumulation

  In autophagy compotent cells the damaged proteins and lipids and organelles are degraded w/ p62 to protect the genome

  In autophagy-defective cells --> degraded toxic material prevented

  • seen with high levels of p62 & p62 aggregates
  • damaged mitochondira
  • ROS production damages DNA, and create chromosomal instability --> promote tumourgenesis
• autophagy defective ells reduce viability but promote tumorigenesis how?


  metabolic stress triggers senescence / apoptosis

  autophagy --> delays apoptossis

  apoptotic defective cells survive through autophagy-mediated stress adaptation

  Prolonged stress --> cell exit cell cycle --> alter gene expression + metabolism --> conserve energy --> dormant cells

  Removing stress --> dormant cells awaken and resume proliferation --> regenerate tumour