Invasion Flashcards
What are the steps of tumour progression?
- homeostasis
- genetic alterations
- hyper-proliferation
- de-differntiation (disassembly of cell-cell contacts and loss of cell polarity)
- invasion (increased motility and cleavage of ECM proteins)
What are the two types of migration?
Individual cell migration:
- Amoeboid – e.g. lymphomas
- Mesenchymal (single) – e.g. Fibrosarcoma
Collective cell migration:
- Mesenchymal (chains) – e.g. Fibrosarcoma
- Cluster/cohorts – e.g. Epithelial cancers
- Multicellular strands/sheets – e.g. Epithelial cancers
- Collective cell migration requires more coordination to metastasise and so still has some cell-cell junctions
How do tumour cells migrate?
MIMICS PHYSIOLOGICAL morphogenic events.
- E.G. Branching morphogenesis in the mammary glands
- E.G. Migration of primary glial cells to repair a scratch wound (the cells stop migrating when the contact is made) – conversely, tumour cells will have no clear migration front and no sense of direction
What are some stimuli to move cells?
- Organogenesis and morphogenesis
- Wounding
- Growth factor/Chemoattractants
- De-differentiation
How do cells attach to ECM?
integrins
What do cells use for motility?
Filopodia – finger-like projections rich in actin filaments
- A bundle of parallel filaments
Lamellipodia – sheet-like protrusions rich in actin filaments
- Branched and cross linked filaments.
Why is control needed in motility?
to:
- Coordinate happenings inside the cell itself
- Regulate adhesion/release of cell-ECM
- To respond to external influences
How do cells move?
Contraction of Filopodia and Lamellipodia can break old adhesions, allowing the cell to maintain a motion
A signal to move could be a nutrient source and the filaments can rapidly disassemble and then reassemble at a new site to move the cell
Actin filaments have a polarity – there is a plus and minus end on which different proteins can bind
- Depending on the proteins that bind, the actin filaments can carry out different functions
What happens in nucleation?
- Attachment of the actin to the cell inner membrane
- ARP proteins form a complex and bind to actin monomers to create a nucleated actin filament (ARPs bind to the minus end)
- This is the limiting step in actin dynamics
What happens in elongation?
- Profilin facilitates actin monomer binding to the actin filament
- Thymosin reduces actin monomer binding by sequestering the free monomers so they are not available to bind to the actin filament
What is capping and severing?
Capping – addition of a capping molecule (to + or – end) to limit elongation
- Plus-end caps – Cap Z, Gelsolin, Fragmin/Severin
- Minus-end caps – Tropomodulin, Arp complex
Severing – breaking up actin filaments:
- Unsevered actin filaments grow/shrink slowly
- Severed populations grow/shrink more rapidly
> Proteins – gelsolin, ADF/cofilin, fragmin/severin
What are the proteins involved in crosslinking?
- produces differing arrangements of actin filaments
Proteins involved include:
- a-actinin
- Fimbrin
- Filamin
- Spectrin
- Villin
- Vinculin
What happens in branching?
arp complex enables branches of actin to come off at 70 degree angles
What is Gel-sol transition by actin severing?
Gels are rigid and have NOT been severed
Sols are not rigid (i.e. can flow) and HAVE been severed
- look at diagram
How is cell movement regulated?
signalling pathways on cytoskeleton
- Ion-flux changes – i.e. intracellular calcium
- Phosphoinositide signalling – i.e. phospholipid binding
- Kinases/phosphatases – i.e. phosphorylation of cytoskeletal proteins
- Signalling cascades via small GTPases
