3 options for a tumour?
Form benign tumour mass
invade basement memb
completely dissociate + cleave ECM proteins as they migrate
Once tumour cells become mobile + enter circulation what type of cells do they become?
mesenchymal
When cancer cells find their new location what happens?
lose mesenchymal like cell properties
What do tumour cells not have?
neighbour neighbour contacts
2 ways tumour cells can migrate:
Individual
Collective
Which way of migration has a higher metastatic potential + means more holes must be punctured into ECM?
Collective
How is coordination for collective migration achieved?
Gap junctions-cadherins
What does individual + collective migration require?
Integrins-receptors for ECM molecules
Proteases-to get through ECM
What is a key difference between normal cell vs tumour cell migration?
tumour cells dont have neighbour-neighbour contacts
Which genes are upregulated in invasive cells vs primary tumour?
Cytoskeleton regulation
Motility machinery
4 stimuli for cells to move:
organogenesis/morphogenesis
wounding
growth factors/chemoattractants
de-differentiation
When cells are going to move what do they do (2 points)?
develop polarity
change shape
Cells develop a……
leading edge
When do cells stop moving?
contact inhibiton motility
3 places cells may go?
towards growth factor/chemoattractant/where there is space
What is contact inhibition motility?
stop growing once reaching a neighbouring cell
What are focal adhesions?
cells binding to ECM proteins via integrins
What must adapt in order for cells to bind to ECM proteins?
Cytoskeleton
So extrinsically there is the integrins then……
plaque
What are 2 functions of the plaque?
signalling
attachment to cytoskeleton
What are filopodia?
finger like protrusions rich in actin filaments for motility
What are filopodia for?
motility
How are the actin filaments in filopodia organised?
parallel
What in vinculin?
plaque like molecule that binds to actin
What are lamellipodia?
sheet like protrusions rich in actin filaments
How is actin organised in lamellipodia?
branched + crosslinked
What are stress fibres?
like filopodia but actin filaments are organised anti-parallely
What are the 2 types of motility?
hapoptactic-no purpose
chemotactic-with purpose
Summarise cell motility:
Focal adhesion forms (cell binds to ECM via integrins)
Lamellipodia forms
new focal adhesion
translocation-rear contracts so cell moves forward
deadhesion of old focal adhesion
What are the 2 types of actin?
G-monomers/small subunits
F=filamentous actin
How is actin at the rear of the cell dissassembled?
Cofilin protein
Once F actin–>g actin at rear of cell what happens to the G actin?
Transported to leading edge
Summarise actin polymerisation:
Nucleation-3 G actin monomers + Arp complex intiate polymerisation
Elongation-carried out by profilin (B-thymosin competes)
Capping
How can long filaments be depolymerised quickly?
severing
3 things actin filaments can do:
cross link
bundle
branch (70 degrees)
What must happen for cells to protrude through membranes?
actin structure must be loosened=clipped at particular sites
What are the key regulators of actin cytoskeleton?
small GTPases
