7 Fundamental Changes

7 Fundamental Changes

1. Insensitivity to growth inhibitory signals

   • RB tumour suppressor
     • RB enforces gap btw G0 and G1 – determines if cell can continue
     • Recessive gene, so require homozygous allele mutation
     • >> Retinoblastoma = interocular cancer (+ breast, bladder, lung)
     • DNA viruses can render Rb non-functional (HPV, HBV, EBV)
       • Binds to Rb and prevents functioning
   • p53 gene
     • Guardian of the genome!
     • Tumour supressor gene STOP neoplasm
       • Activates quiescence (temp cell arrest)
       • Activates senescence (permanent)
       • Triggers apoptosis
     • Monitors cell stress and directs best response
     • Homozygous loss of p53
       • DNA damage unrepaired
       • Mutations remain in dividing cells
       • Malignant transformation
     • DNA viruses can render Rb non-functional (HPV, HBV, EBV)

2. Tissue invasion and apoptosis

   • Invasion of ECM
     • ECM = BM + interstitial CT
     • 1. Detach tumour cells from oneathother
     • 2. Degrade ECM and ICT
     • 3. Change attachment of tumour cells to ECM proteins
     • 4. Migration of tumour cells through degraded BM and ICT directed by tumor cell derived cytokines
     • See diagram!
   • Vascular dissemination and homing of tumour cells
     • Tumour cells in circulation are vulnerable to host immunity
     • 1. Attach to leuk/platelets > emboli > protected from anti tumour host cell
     • 2. Extravasation – tumour cells/emboli attach to EN >> through BM >> into parenchyma
     • Predict site of extravasation/metastasis
       • Location of primary tumour
       • Vascular/lymph drainage of primary tumour

3. Self-sufficiency in growth signals

   • Oncogenes promote autonomous Ca cell growth
   • > Promoted out of quiescent stage with no add stimulus
   • > By synthesizing GF + generate constant mitotic signals to cell
   • > Autonomous and disregulated

4. Limitless replicative potential

   • Normal cells lose capacity to divide after 60/70 times
   • = sensence d/t shortened telomeres (p53/Rb)
   • p53/Rb checkpoints disabled so Ca must overcome mitotic catastrophe
     • Tumour cell reactivates telomerase >> activates stem cells
   • Telomerase maintenance in 85-95% Ca
     • >> Break cycle of fusion and breakage
   • >> Avoid cell death

5. Sustained angiogenesis

   • Tumour needs nutrients/O2 + waste removal bigger than 1-2mm > products can diffuse
   • = neo-angiogenesis + vasculogenesis >> new vessels from capillaries + endothelial cells from bone marrow
   • BUT vessels are abnormal and leaky
   • Supports tumour growth
     • O2/nutrient supply + waste removal
     • EN cells stimulate new tumour cell growth by GF
     • >> supplies new channels for metastases

6. Evading apoptosis

   • Inc in neoplastic cells + mutations in genes that regulate apoptosis
   • >> Inc in cells + << in apoptosis

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