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

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Flashcards in lecture 23: epithelial to mesenchymal transition (EMT) and stem cells Deck (18):
1

Can epithelial cells transition to mesenchymal cells?

  • yes, and vice versa 

2

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 

3

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 

4

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 

5

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 

6

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 

7

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 

8

What are snail proteins?

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

9

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 

10

What genes regulate EMT?

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

11

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 

12

What is seen in intestinal epithelial stem cells?

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

13

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 

14

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 

15

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 

16

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

  • enables breast cancer cell plasticity and enhances tumourigenecity 

17

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 

18

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