Cancer 11: Invasion regulation of cell migration Flashcards
How does detachment from primary tumour and migration occur?
1)
What are the molecular mechanisms that regulate motility?
- microfilaments
- regulation of actin dynamics
- cytoskeleton proteins
- signalling proteins
What are the steps in tumour progression?
1) homeostasis - cells attached to each other on top of a basement membrane
2) genetic alterations
3) hyperproliferation
4) de-differentiation: 1. Disassembly of cell-cell contacts 2. loss of polarity (lose their shape)
5) invasion: 1. increased motility 2. cleavage ECM proteins
Describe the process of metastasis
Epithelial cells in primary tumours are tightly bound together
Metastatic tumour cells become mobile mesenchyme-type cells and enter the bloodstream.
Metastatic cells then travel through the blood stream to a new location in the body
Metastatic cells exit the circulation and invade a new organ
Cancer cells lose their mesenchymal characteristics and form a new tumour
What are the different types of tumour cell migration
1) Individual cells can migrate
2) Collective cell migration
Ameoboid - round structures (lymphoma, leukaemia)
Mesenchymal (single/chain cells) - (fibrosarcoma, anaplastic tumours)
Cluster/cohorts - epithelial cancer
Multicellular strands/sheets - epithelial cancer
All require cadherins and gap junctions integrins and proteases. Cadherins and gap junctions for the cluster and multicellular strands
Tumour cell metastasis mimic morphogenetic events
All invasive tumours have a leader cells push and degrade the ECM,
- 2D sheets
- vascular sprouting
- border cells
Compare the expression profile of invasive cells and a primary tumour?
Invasive cells have upregulated of genes involved in:
- cytoskeleton regulation
- motility machinery
- higher EGF receptors (makes sense because they move towards the GF)
What stimulus cause cell movement?
- organogenesis
- morphogenesis
- GF/chemoattractants
- dedifferentiation
Cell movement = changing cell shape
When do cells stops moving?
Contact-inhibition
Where do cells go?
Directionality (polarity) - they form a mesenchymal shape?
How do cells move?
Through specialised structures (focal adhesion, lamellae, filopodium)
What are the cells attached to?
Attachment to substratum (ECM proteins)
Focal adhesions
Filamentous actin attach to these FA so that they are anchored to move.
What structures are used for motility?
Filopodia - finger-like protrusions rich in actin filaments
- Actin
- Vinculin
Lamellipodia - sheet-like protrusions rich in actin filaments
Describe the control of cell movement
Control is needed:
- within a cell to coordinate what is happening in different parts
- regulate adhesion/release of cell-extracellular matrix receptors. This ensure they can move in one direction
- from outside to respond to external influences –
sensors
directionality (where to go)
Describe all the steps of motility (the way they move)?
Think about rock climbing
- Form a FA
- Extension: Laemellipodium (the cell moves forward feeling for a new FA) During this stage you get all the different actin filament processes - disassembly, nucleation, branching, severing, capping and bundling. Polymerisation
- Adhesion: Form a new FA - attachment of ECM. Gel/sol transition also occurs.
- Translocation: The cell body contracts and moves towards the new FA
- De-adhesion: The old FA at the back is released.
Describe all the steps of motility (the way they move)?
Think about rock climbing
- Form a FA
- Laemellipodium
- Form a new FA
- The cell body contracts and moves towards the new FA
- The old FA at the back is released.
What are the main cytoskeletal structures that give shape to the cell?
Actin filaments: G-actin –> F-actin
The filaments have a polarity - plus and minus end.
If there is a signal such as a nutrient source the cell will dissemble filaments and reassembly the filaments at the new site moving the cell towards the signal. See slide 16 for diagram
Describe the organisation of the filaments in lamellipodium and filapodium. Remodelling of actin filaments.
Slide 17-18
The cell can assemble a variety of structures
What is nucleation?
This is a how a single monomer of actin becomes a filament. This requires energy.
Arp2 and 3 proteins form a complex where an actin monomer can bind forming a trimer. This is basis from which elongation can begin.
This favoured at the minus end of the filament. The plus end is where the monomers add onto.
What is elongation?
Profilin helps elongation
Thyrmosin blocks elongation
What is capping?
A capping protein will bind to the plus and minus end blocking elongation.
What is severing?
The severing protein will destabilise the filaments and break it down.
After severing there are three options for the filament
- Barbed end capping
- annealing
Growth from pre-existing end
What is cross-linking and bundling?
Bundles filaments togther
fascin, fimbrin and alpha-actinin all bundle the actin filaments together. They are connected parallel to each other.
Spectrin
filamin
dystrophin
Cooperation of actin functions to organise filaments
slide 24
What is the gel-sol transition by actin filament severing?
Gel (rigid) and sol (can flow)
The severing protein clips the filaments so it can flow.
What is the gel-sol transition by actin filament severing?
Gel (rigid) and sol (can flow(
The severing protein clips the filaments so it can flow.
What actin formations are required for the production of lamellae protrusion?
Polymerisation, disassembly, branching and capping.
This structure pulls the membrane forward.
See slides for diagrams
What actin formations are required for the production of filopodia?
Actin polymerization, bundling and crosslinking.
See slides for diagrams
See slide 31
31
What mechanism regulates the actin cytoskeleton?
1 - ion flux changes (i.e. intracellular calcium)
2 - Phosphoinositide signalling (phospholipid binding)
3 - Kinases/phosphatases (phosphorylation cytoskeletal proteins)
4 - Signalling cascades via small GTPases
Participation of small GTPases on cell migration?
Extension: Rac modulates actin polymerization and branching
Adhesion: Rac and Rho modulates FA and assembly
Translocation: Rho controls the contraction of the cell
De-adhesions: Rho controls de-adhesion
Cdc42 - filopodia, polarized motility and actin polymerization.
