Cancer stem cells

• What can we infer about cancer from stem cells?

  Many similarities bewteen stem cells and cancer cell characteristics

  
  

  Suggests the origin of cancer cells are closer to stem cells rather than fully differentiated somatic cells that just acquire mutations (to become cancerous)
• What 3 factors must be balanced for development of an organism?

  • Differentiation
  • Proliferation (growth)
  • Apoptosis (death)
• What happens when the 3 factors needed for development are unbalanced?

  Results in the accumulation of non-functional cells

  Occurs in cancer cells
• List reasons that suggest cancer is not a mutation of somatic cells

  • Cancer is a disease of proliferating cells - but most mature cells do not proliferate, or do so slowly
  • Tumours are often heterogenous in terms of cellular differentiation - but cancers are clonal (arise from a single cell)
  • Cancer involves the accumulation of mutations in a single cell (clonal disease - but most mature cells have a finite liftime and don't survive long enough to accumulate mutations
  • Only a small number of cancer cells can recolonise - but mature cells of the same type have the some ability to recolonise
• Why are stem cells thought to be the origin of cancer?

  • If all the cells in a tumour were the same, it is expected any one of the cells could regrow into a tumour
  • In reality, only a small number of tumour cells are metastatic and regrow a new tumour mass
  • This suggests not all tumours are the same - they do not come from a single somatic cell
  • If the origins were stem cells, it would explain many tumour characteristics
• What is the definition of self-renewal?

  Unchecked, inherent proliferative capacity of unspecialised cells to reproduce themselves (in unspecialised form) and/or generate more specialised cells
• What type of cells are embryonic stem cells?

  Pluripotent
• Explain asymmetric reproduction

  • One daughter cell will be undifferentiated like the parent cell whilst the other will be slightly more specialised
  • Specialised daughter cell forms intermediate cells known as precursors/progenitor cells that produce a certain type of cell (differentiate)
  • Proliferative capacity is lost going down the specialisation pathway
• What are adult stem cells?

  Adult stem cells are undifferentiated cells found in various tissues of the body (cord blood, bone marrow, adipose) that can differentiate into different cell types and help in tissue repair and regeneration

  
  

  Oldest cells in the body, present in small numbers and normally kept inactive until needed (to produce new cells that differentiate)
• What allows undifferentiated/partially differentiated stem cells to form tumours when implanted into tissue?

  Self-renewal capacity and ability to migrate through the body
• List reasons that suggest stem cells are the origin of tumours

  • More likely that an unspecialised cell differentiates and switches off its proliferative ability, than a differentiated cell dedifferentiatiating and reacquiring the ability to proliferate
  • Stem cells are long-lived and self-renew - have more opportunity to accumulate mutations
  • Asymmetric division in stem cells may account for heterogenous cellular differentiation
  • Adult stem cells have shown the ability to recolonise
  • Many of the signalling pathways involved in self-renewal are activated and mutated in cancer cells
• What is the stem cell niche?

  Microenvironment where stem cells reside and receive signals for self-renewal and differentiation
• How are stem cells controlled in the stem cell niche?

  Cells surrounding the niche secrete anti-growth factors to suppress self-renewal
• How do cancer stem cells escape suppression from the stem cell niche?

  Undergo mutations to become niche-independent - no longer suppressed and free to self-renew
• What are the theories on how stem cells escape suppression?

  1. Expansion of the normal stem cell niche permits expansion of cancer stem cells that arose from normal stem cells
  2. Cancer stem cells that arose from normal stem cells adapt to a different niche allowing their expansion
  3. Cancer stem cells that arose from normal stem cells become niche-independent and self-renewal is cell-autonomous
  4. Failure to switch off proliferative capacity

  Could also be a combination of all of these
• What pathways do stem cells use for self-renewal that have been identified as overactive in cancer cells?

  1. Wnt pathway
  2. Hedgehog pathway

  The average healthy somatic cell does not use these pathways - only in embryogenesis before being switched off
• What is the Wnt pathway?

  • Proto-oncogene pathway
  • Mutated in 90% colon cancers
  • Loss of function of APC (tumour suppressor gene) = cannot regulate pathway = increased activation of B-catenin (transcription factor) activity = drives cell growth
  • Wnt (growth factor ligand) binds to Frizzled (receptor) = Frizzled sequesters GSK-3, relasing B-catenin to act as a TF to drive c-myc and cyclin D expression and proliferation
• What is the Hedgehog pathway?

  • Sonic-, desert-, and Indian-hedgehog binds to Patched (receptor, tumour suppresor gene)
  • This releases inhibition of Smoothened
  • Signalling pathways release Gli (TF) to drive proliferation
  • Overexpression of Hh or Gli, or loss of function of Patched will activate this pathway
• What agents use the Wnt pathway as a target for cancer?

  Site of intervention used depends on the mutation

  
  

  Top of pathway (ligand, receptor)

  • Wnt ligand and receptor inhibitors, e.g. mAbs, Porcupine inhibitors (decrease Wnt ligand secretion)
  • Use when Wnt ligand/receptor is overexpressed

  Further down pathway (B-catenin destruction complex)

  • Axin inhibitors, e.g. tankyrase (PARP inhibitors)
  • Targeting axin (as part of the complex) may help in absence of APC

  Bottom of pathway (B-catenin)

  • B-catenin inhibitors
  • Disrupt B-catenin TF function and ability to drive self-renewal
• What other characteristics do stem cells and cancer cells share?

  Telomerase enzyme ability

  
  

  Did cancer cells reactivate their telomerase enzymes or were they never switched off in the first place (because their origins are stem cells)?
• What are telomerases?

  Telomerases are reverse transcriptase enzymes containing an RNA template to add TTAGGG repeats to lengthen telomeres - when they get too short, they are recognised as damaged DNA and activated p53 will induce senescence or even apoptosis

  
  

  Telomeres are tandem repeats found on the ends of chromosomes which aid in chromosomal replication
• What additional properties link stem cells to cancer?

  Epithelial-mesenchymal transition (EMT)

  • Responsible for cancer cells metastasising

  Epigenetic regulation of differention (Polycomb Group proteins (PcG))

  • Repress differentiation genes
  • Inhibit CDKIs
  • Inhibit p53 activators (p14ARF)
  • Work by inhibiting transcription, chromatin compaction

  Blocking PcG pushes cancer cells to differentiate, slow proliferation, and extend time for treatment