Chapter 11 Notes

• Hallmarks of Cancer


  • Sustaining proliferative signaling
  • Evading growth suppressors
  • Activating invasion and metastasis
  • Enabling replicative immortality
  • Inducing angiogenesis
  • Resisting cell death

  
• Carcinomas


  • Contain epithelial cancer cells and stromal cells

  
• Stromal cell types


  • Fibroblasts
  • Myofibroblasts
  • Endothelial cells
  • Pericytes
  • Smooth muscle cells
  • Adipocytes
  • Macrophages
  • Lymphocytes
  • Mast cells

  
• Heterotypic signaling


  Communication between tumour cells and stromal cells
• Carcinoma cells control the populations of stromal cells near them
• Stromal cells influence cancer cell proliferation, survival, invasion and metastasis

  
• Tumors are wounds that never heal
• Cancer cells seem to activate a wound healing signaling processes to manipulate their microenvironment

  
• Classical stages of wound repair

  1. Hemostasis

  2. Inflammation

  3. Proliferation/Maturation

  4. Remodelling

  
• Platelets


  • Release PDGF which attracts fibroblasts and increases their proliferation
  • Release TGF-β which activates fibroblasts and converts them into myofibroblasts

  
• Matrix metalloproteinases (MMPs)


  Secreted proteases that degrade specific components of the extracellular matrix
• MMPs can be produced by macrophages and myofibroblasts
• MMPs are recruited to the wound site in large numbers
• Myofibroblasts


  • Express α-smooth muscle actin (α-SMA)
  • Use actin-myosin contractile system to generate mechanical tension needed for wound closure
  • Secrete ECM components & ECM re-modelling enzymes (e.g. collagen)
  • Prolonged persistence results in tissue stiffening and deformation = desmoplastic stroma
• Desmoplastic stroma


  Stiff and deformed, found in cancer tissue

  
• Cancer-associated fibroblasts (CAFs)


  The mixed population of fibroblasts and myofibroblasts that are present in the stroma of epithelial tumours

  
• CAFs acquire contractile stress fibres and express α-smooth muscle actin (a-SMA)
• Role of CAF in cancer

  • Create desmoplasia (activated tumour stroma)
  • Secrete large amounts of extracellular matrix (EM) proteins especially collagens
  • Collagen fibres are thicker, more linear, and stiff in cancer EM than in normal tissue EM
  • This promotes cancer progression and makes cancer resistant to chemo- and radio-therapies

  
• Angiogenesis


  1. Endothelial cells join to form the lumen of the capillary

  2. Tight sealing of the PMs of adjacent endothelial cells results in capillary tubes

  3. Pericytes cover the vessels and maintain capillary rigidity and intraluminal blood pressure

  4. Vascular smooth muscle cells coat the outside tubes of the capillaries

  
• Cancer cells far from blood vessels undergo necrosis (cell death)

  
• Distance threshold for oxygen diffusion is ~0.2 mm
• Cells located within 0.2 mm of a blood vessel can rely on oxygen diffusion, cells further away suffer from hypoxia and low pH
• Cancer tissues suffering from hypoxia can become necrotic

  
• Capillary networks are packed densely in both normal and tumour tissues

  
• Vasculature is needed to avoid hypoxia, acquire nutrients, and shed metabolic waste products and carbon dioxide
• Pericytes and smooth muscle cells are loosely attached to tumour-associated blood vessels

  
• Tumour blood vessels have diameters that are 3 times greater than their normal counterparts
• Tumour-associated blood vessels have chaotic organization
• Increased microvessel density is associated with worse prognosis
• Angiogenic factors


  VEGF, FGF, PDGF, TGF-β
• HIF-1 transcription factor regulates the expression of VEGF
• Angiogenesis is normally suppressed by physiological inhibitors
• Newly formed endothelial cells express Fas death receptor, Tsp-1 protein associates with Fas and triggers apoptosis, this pathway does not work in mature endothelial cells
• Tsp-1 is induced by p53