EMT/MET Flashcards
Why is EMT/MET a good area to study?
- required for embryonal development
- can be altered or reactivated in cancer
- could be a route of treatment
What are the 4 primary tissues?
- muscle
- connective tissue
- nerve tissue
- epithelial tissue
What are the characteristics of epithelial cells? (3)
- usually a single organised layer
- connected by tight adhesions that prevent migration from the monolayer
- regularly spaced junctions and adheions between cells
What are the 4 types of junction between epithelial cells?
- tight adhesions control passage of fluids and solutes and maintain cellular polarity by erstricting the movement of membrane proteins and lipids
- gap junctions direct cell-cell communication
- adherens junctions - contacts between cells
- desmosomes - mechanical strength ant stability in tissues under high mechanical pressure such as the skin and heart
- all allow the movement of nutrients ions and signalling molcules and maintain structure and adhesion
Why is epithelium important / what does it do? (4)
- maintains shape and structure
- absorption and secretion
- apical-basal polarity i.e the sides can interact with different molecules and perform different functions
- first protective layer against pathogens and damage
What are the characteristics of a mesenchymal cell? (5)
- lack of regimented structure
- stretched and elongated in shape
- often form irregular compositions and densities
- fewer tight junctions allow movement from the tissue
- can migrate and invade the basement membrane
What is EMT?
- epithelial to mesenchymal transition
- cell-cell and cell-ECM adhesions are lost to allow the cell to come away from the epithelial monolayer
- cytoskeleton rearrangements allow 3D movement of cells in teh ECM
- altered genetic program to maintain the new mesenchymal phenotype
- reversible process
Name 2 changes in cell structure seen in EMT
- from cortical actin to actin stress fibres
- polarity from apical-basal to front-back
What are the 3 types of EMT?
- development - cycles of EMT and MET involved in producing tissues during development
- chronic injury - cells undergo EMT to replace damaged cells due to injury - can become chronic
- malignancy - change in phenotype of tumour cells from epithelial to mesenchymal can allow them to migrate and metastasise
Describe one of the first EMTs in development
- production of the germ layers
- ectoderm - mesoderm EMT
- mesoderm - endoderm MET
- neural crest cells undergo MET to migrate around the body and form neurons
Give some examples of cells derived from mesoderm EMT and neural crest EMT
- mesoderm produces bone, muscles and blood
- neural crest produces neurons, glial cells and skeletal muscle
What signalling occurs in embryonic EMT gastrulation signalling?
- leads to mesoderm ingression
- TGF-B and nodal -> SMAD, slug snail and twist (downregulate e-cadherin and upregulate n-cadherin and other mesenchymal markers)
- Wnt -> B-catenin can also modulate these genes
- FGF activates MAPK/ERK and movement
What signalling occurs in embyronic EMT neural crest development?
- Wnt, notch and FGF
- notch involved in determining cell fate
- trigger enzymes and TFs such as sox9
- signalling cascade leading to neural crest delamination
How does Wnt act in EMT? as an example
- wnt can cause B-catenin to enter the nucleus and begin the transcription of SNAIL1/2 or activate other genes in EMT
How do inflammation and hypoxia lead to emt?
inflammation can signal STAT3 and cause EMT
hypoxia can signal Hif1-alpha and cause EMT
EMT and MET are essential in development. They are hyjacked in cancer and implicated in:
- cancer dissemination
- cancer initiation
- metastasis
- drug resistance
- CSC generation
What kind of signals might trigger EMT in cancer? (5)
- physical constrains
- hypoxia
- inflammation
- oncogenic stress
- metaboolic stress
Name 4 signalling pathways seen in EMT
- Wnt
- Notch
- Hif1/2
- TGF-B
Name 3 TFs involved in EMT
- SNAIL 1/2
- TWIST 1/2 seen mutated in colon cancer
- ZEB1/2 seen mutated in pancreatic cancer
How generally might EMT TFs cause primary lesions and invasion?
- might inhibit p53/Rb and alter differentiation and stemness
- may inhibit cell polarity and cell-cell contacts to allow migration
What are the roles of EMT/MET in normal adult tissue?
- wound healing
- hypothesised to be the way adult stem cells are created
Name 5 roles of EMT/MET in cancer progression
- cancer initiation
- cancer dissemination
- metastasis
- CSC generation
- drug resistance
How is EMT/MET involved in cancer dissemination?
- EMT
- early in cancer development cells can undergo EMT and enter the blood stream
- travel to other parts of the body and remain dormant there
How is EMT/MET involved in cancer initiation?
- EMT
- cancer cells need to interact with stromal cells such as fibroblasts and immune cells
- cells need to break through and invade the basement membrane to do so and so need a mesenchymal phenotype
How is EMT/MET involved in cancer metastasis?
- tumour cells undergo EMT to break away from the tissue and enter the blood stream
- when they reach secondary sites, they can undergo MET to settle at new organs and form secondary tumours
How are EMT/MET involved in cancer stem cell generation?
- cells can undergo partial EMT
- can enter a stemness window where they have the properties of a stem cell
- quasiepithelial/quasimesenchymal cells can migrate, invade and devide at distant sites
- express genes to maintain stemness such as Oct4
How do cancer stem cells contribute to chemoresistance?
- many cancer cells are receptive to epigenetic treatments such as HDACs to silence oncogene activity
- when cells undergo partial EMT they develop new surface molecules and phenotypes that treatments don’t work on
- treatment needs to get rid of cancer stem cells or cancer will always return
What occurs in regards to EMT/MET to cause Wilm’s tumour?
- failure of mesenchymal differentiation (MET)
- tumours ressemble developing kidney structures and stroma
- due to WT1 gene imprinting failure
How can miRNAs regulate EMT-MET?
-transcriptional regulators act in feedback loops with miRNAs
- let-7 is essential for development and inhibits RAS and other oncogenes in MET
- epigenetic regulators such as polycomb proteins also interact with miR-200 and E-cadehin in feedback loops.
What is the role of E-cadherin?
maintenance of epithelial phenotype - suppresses EMT
What is the role of B-catenin?
regulation of EMT genes to turn them on (Wnt)
