lecture 23: epithelial to mesenchymal transition (EMT) and stem cells Flashcards Preview

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Can epithelial cells transition to mesenchymal cells?

  • yes, and vice versa 


What happens when epithelial cells undergo EMT?

  • disassemble cell junctions
  • lose their apico-basal polarity 
  • become more loosely associated 
  • become more motile
  • these characteristics result from changes in gene expression 
  • approximately 4000 genes change 


What is a characteristic of EMT?

  • down regulation of E-cadherin
  • intermediate EMT states allow migration of cell sheets, epithelial remodelling and individual cells with more motile characteristics within the epithelium 


What do adherens junctions do? What is the role of cadherins in these?

  • form a continuous belt below the tight junctions, the zonula adherens, in epithelial cells that bring actin filaments into alignment 
  • cadherins form the transmembrane linkages 


What regulates EMT?

  • multiple signalling pathways 
  • note that many are associated with regulation of stem cell maintenance and differentiation 
  • the transcription facotrs listed are mainly repressors of E-cadherin
    • transcription factors:
      • Snail (Snai1)
      • Slug (Snai2) 
      • Zeb1 
      • Zeb2 (Sip1)
      • Twist1
    • Signalling pathways
      • tgf-beta
      • wnt
      • notch
      • tna-alpha
      • hypoxia
      • receptor tyrosine kinase
    • microRNAs 
      • miR-10b
      • miR-9
      • miR-200 family 


For what is EMT important?

  • in the development of tissues and organs 
  • e.g. 
    • cutaneous structures (hair, feathers, sweat glands, mammary glands) 
    • limb 
    • gut organs
    • foregut and respiratory associated organs 
    • kidney 
    • tooth 


What is the relationship between EMT and cancer?

  • EMT has long been associated with tumour metastasis but recent evidence suggests that EMT is associated with tumour progression and development of cancer stem cells 


What are snail proteins?

  • snail proteins are transcriptional repressors 
  • snail family in drosophila: snail, escargot, worniu
  • snail family in mouse/human: snai1, snai2, snai3


With what are snail proteins associated?

  • radio-resistance 
  • quiescent haematopoietic stem cells (HSCs) are resistant to gamma-irradiation 
  • snai2 mutant HSCs are radiosensitive 
  • irradiation → stabilisation of p53 → Snai2 inhibits puma (normally → apoptosis) 
  • snai2 represses Puma and prevents apoptosis of HSCs 


What genes regulate EMT?

  • Snail genes 
    • inhibit epithelial markers 
    • inhibit proliferation 
    • lead to mesenchymal markers 
    • changes in cell shape, cell movements, invasion 
    • survival 


In what way does EMT generate cells with properties of stem cells?

  • immortalised human mammary epithelial cells (HMECs) expressing Snail or Twist or treated with TGFbeta1 undergo EMT 
  • cells downregulate E-cadherin and upregulate mesenchymal genes 
  • cells express high CD44 and low CD24 (mammary stem cell profile) 
  • cells can efficiently form mammospheres 
  • naturally arising CD44high/CD24low cells exhibit the properties of stem cells and appear to have undergone EMT 
  • normal mouse mammary stem cells express markers of EMT 


What is seen in intestinal epithelial stem cells?

  • express mesenchymal markers 
  • snai1 is prominently expressed in the nuclei of crypts 


Where are the most primitive mammary stem cells found?

  • in basal cells of the epithelial ducts in the mammary gland 
  • snai2 together with sox9 can induce stem cell characteristics in differentiated luminal cells 


What is the role of microRNAs in EMT?

  • play key roles 
  • epithelial cells express high levels of miR-200 family miRNAs that repress stem cell markers 
  • induction of EMT induces expression of Zeb1 which represses miR-200 
  • miR-200c suppresses normal mammary outgrowth in vivo 


What do paracrine and autocrine signals do in the breast?

  • induce and maintain mesenchymal and stem cell states 
  • inducers/maintainers of migration/self-renewal
    • TGF-beta
    • wnt/beta-catenin 
    • wnt5a
  • inhibitors of migration/self-renewal
    • BMP4
    • DKK1 
    • SFRP1 


What is the role of poised chromatin at the ZEB1 promoter?

  • enables breast cancer cell plasticity and enhances tumourigenecity 


What could the link between EMT and stemness indicate?

  • could indicate that upregulation of some EMT inducers could lead to BOTH metastasis and tumour growth 
  • metastatic cells may have an inherent ability to seed new tumours via stem cell properties 


What are the review points?

  • what is epithelial to mesenchymal transition (EMT)?
  • what are characteristics of EMT?
  • EMT causes downregulation of E-cadherin 
  • multiple pathways and transcription factors can induce EMT 
  • EMT associated with tumour progression /development of cancer stem cells 
  • snail genes are associated with acquisition of radio-resistance 
  • evidence that EMT generates cells with properties of stem cells (Mani) 
  • downregulation of specific miRNAs by ZEB1 is observed in stem cells
  • cell signals maintain mesenchymal and stem cell state 
  • poised chromatin allows rapid transition to a cancer stem cell state