Molecular Basis of Cancer 2

• What is replicative immortality?

  Unrestricted proliferative capacity, avoiding cellular senescence & mitotic catastrophe

  Hallmark of cancer
• What are the barriers that prevent normal cells from replicative immortality?

  Senescence

  Crisis
• Define senescence.

  Cells exist long-term in non-growing but viable state
• What does crisis involve?

  Apoptotic death of cell
• How do 'normal' cells lose ability to divide?

  Normal doubling capacity = 60 - 70 doublings

  Telomeres progressively shorten -> cells lose dividing ability
• What are telomeres?

  Repetitive DNA sequences at the ends of chromosomes.

  Protective cap
• Tumour metastases are the causes of the majority of cancer deaths.
• What are the mechanisms of cancer spread?

  Direct spread (local invasion)

  Lymphatic spread

  Haematogenous spread

  Transoelomic spread

  Perineural spread
• Lymphatic tumour spread

  Pattern of lymph node involvement -> follows natural routes of drainages

  Regional nodes act as a barrier to further spread, but only for an amount of time
• Haematogenous cancer spread.

  Usually cells invade veins & follow the venous flow (enters systemic circulation)
• Transcoelomic cancer spread

  Metastasis across a body cavity (e.g. peritoneal, joint space, subarachnoid)
• Perineural cancer spread.

  Spread along the course of nerve bundles

  Common in prostate carcinoma & some basal cell carcinoma
• What is EMT?

  Epithelial mesenchymal transition

  Process where epithelial cells disaggregate & exhibit shape changes

  Essentially de-differentiation
• What are mesenchymal properties?

  Increased migratory capacity

  Increased contractility (ability to move)

  Increased production of ECM proteins
• Epithelial vs mesenchymal cells - expression of proteins

  Epithelial

  • E-cadherin
  • Occludins
  • Cytokeratins

  Mesenchymal

  • N-cadherin
  • FSP-1
  • Vimentin
  • alpha-SMA
  • Fibronectin
  • Collagen 1
• Epithelial vs mesenchymal cells - phenotypes

  Epithelial

  • cuboidal shape
  • presence of cell junctions
  • apicobasal polarity

  Mesenchymal

  • spindle-like shape
  • increased contractility
  • increased matric deposition
• What is MET?

  Mesenchymal epithelial transition

  Opposite of EMT -> often not full transition back to what it was
• How can cells escape crisis?

  activating hTERT telomerase -> elongates telomeric DNA
• Carcinogenesis is a multistep process -> accumulation of multiple mutations (develop independently).
• Multi-step hypothesis of cancer.

  1st mutation - 1 cell has slight growth advantage

  2nd mutation - in progeny cell, descendents grow more uncontrollably & form a small benign tumou

  3rd mutation - in cell within tumour -> allows to overcome constraints imposed by TME

  4th mutation - allows progeny to escape into bloodstream & colonises at other sites
• Fill in the blanks

  A) Normal epithelium

  B) Low grade intraepithelial neoplasia

  C) High grade intraepithelial neoplasia

  D) Invasive carcinoma

  
• Metastasis

  Primary tumour → locally invasive → in situ cells breach BM → downregulates E-cadherin expression → cells detach from tumour → secrete proteolytic enzymes → degrade & attach to ECM components → degrade BM → intravasation →transport to distant site → tumour cells may become trapped → platelets adhere to cancer cell → microthrombus →cancer cell push aside endothelium → direct contact w/ BM → days, microthrombus dissolved by proteases → cancer cell proliferates in lumen → cancer cell breaks through BM & invades tissue parenchyma → extravasation (dormant macrometastases) → colonise
• What is organ tropism?

  Organ tropism refers to the preference of a virus or pathogen for infecting specific organs or tissues in the body.
• What might organ tropism be related to?

  Tumour cells may have adhesion molecules whose ligands are expressed on endothelial cells of the target organ

  Target tissue may be a non permissive environment (e.g. skeletal muscle (well vascularized) are rarely a site of metastasis)