Cell cycle and TME

• Describe how growth factor production in dysregulated in cancer

  • Growth factors can be stimulated and produced by the tumour and the stroma, which leads to overactivation of RTKs, independent of RTK mutation
  • One of the most common dysfunctional phenotypes of cancer cells is expressing receptors not associated to their tissue of origin.
• Describe RTK Autocrine signalling

  • EGF stimulates Ras to stimulate TGF-alpha synthesis
  • TGF-alpha stimulates EGF receptors on the same cell
  • This drives mitogenic response via feed forward mechansim
• Describe the 4 checkpoints of the cell cycle

  • Restriction point: sufficient metabolites and growth factors required to enter S phase
  • DNA synthesis checkpoint: DNA synthesis must be complete before entering the G2 phase
  • M phase checkpoint: organelle synthesis and cell size ready to enter M phase
  • Anaphase checkpoint: chromatid assembly on mitotic spindle
• Order of cyclin-CDK complexes in the cell cycle

  Cyclins bind to CDKs to activate them to phosphorylate target molecules and stimulate expression of specific genes:

  • G1: Cdk4/6 with cyclin D
  • Late G1/ early S phase: CDK2 with cyclin E
  • S phase: CDK2 with cyclin A
  • M phase: CDK1 with cyclin B

  CDK expression is stable throughout the cell cycle, whereas cyclin transcription and proteolysis controls the cell cycle.
• Describe the G1 to S phase transition

  Growth factors bind to receptors stimulate the expression of cyclin D1 via multiple different signalling pathways. Cyclin D cdk4/6 activates mTOR.
• Describe CDK inhibitors and give examples

  • CDK inhibitors are induced by growth suppressors, such as TGF-beta and p53
  • CDK4/6 inhibitors, e.g., p16
  • CDK2 inhibitors, e.g., p21
  • Antagonised by oncogenes, e.g., Myc and Akt
• Describe how oncogenes antagonise p27

  P27 can inhibit cyclin E cdk2, which prevents hyperphosphorylation of Rb and results in cell cycle arrest. However, phosphorylation of p27 by Akt leads to ubiquitylation and degradation.
• Describe the action of TGF-beta

  TGF-beta is a growth inhibitory ligand:

  • activates transcription of the inhibitory protein, p15
  • p15 inhibits CDK4/6 cyclin D complex, which prevents Rb hyperphosphorylation.
  • Also increases expression of p21, which inhibits CDK2 complexes
• Describe the action of EGF

  EGF is a growth stimulatory ligand:

  • Stimulates P13K pathway, which inhibits the action of p21 and p27 and weakens the actions of TGF-beta
  • Increases expression of cyclin D1