11: Invasion Flashcards
What are the steps of tumour progression?
- Homeostasis
- Genetic alterations
- Hyper-proliferation
- De-differentiation
- Invasion
What are the steps of tumour progression?
- Homeostasis (normal)
- Genetic alterations
- Hyper-proliferation (BENIGN tumour)
- De-differentiation - loss of cell-cell contact and POLARITY
- Invasion - increased motility, cleavage of ECM proteins, cells break into basement membrane = MALIGNANT tumour
What are the steps of cell movement?
- Disassembly
- Nucleation
- Polymerisation
- Branching/severing/capping/bundling
- Gel/sol transition
- Attachment to ECM
- Contraction
- Detachment
What structures are used for motility?
Filopodia - Finger-like projections rich in actin
Lamellipodia - sheet-like protrusions
What structures are used for motility?
Filopodia - Finger-like projections, PARALLEL filaments
Lamellipodia - branched and crosslinked sheet-like protrusions
What is the limiting step in actin polymerisation?
NUCLEATION - Occurs at the minus end
Requires high energy AND Arp2/3 complex
Formation of trimer key in initiating polymerisation
What is the limiting step in actin polymerisation?
NUCLEATION - Occurs at the minus end
Requires high energy AND Arp complex
Formation of trimer key in initiating polymerisation
Explain elongation
Occurs at PLUS end
REQUIRES ENERGY
Actin monomers can form complexes with either:
PROFILIN (monomer-binding) - promotes polymerisation
THYMOSIN (sequestering) - inhibits polymerisation
What can happen to actin once it has been severed?
It can be recycled into monomers and join the plus end
It can form a cap and join plus end
Severed filament could also grow as its own
Annealing = severed filaments joined together again
What can happen to actin once it has been severed?
It can be recycled into monomers and join the plus end
It can form a cap (Barbed-end capping)
Severed filament could also grow as its own
Annealing = severed filaments joined together again
What happens after elongation?
Cross-linking and bundling
Done by different proteins according to what shape is needed
Explain branching - what protein is responsible?
Occurs at 70 degree angle
Branching protein = ARP complex
What is gel-sol transition?
If cells need to protrude/move forward they need to break rigid cortex and allow the cytoplasm to flow
Gel = rigid Sol = can flow
This is done by actin filament severing
How is lamella protrusion controlled?
Severing, disassembly, polymerisation, branching, capping, contraction pulls cell forward
How is filopodia controlled?
Polymerisation (only at tip), bundling, cross-linking
What are the types of actin-binding proteins?
Monomer-binding: Profilin (polymerisation)
Sequestering: Thymosin (inhibits polymerisation)
Capping: Cap Z/gelsolin/fragmin/severin (+end) or Tropomodulin/Arp complex (-end)
Severing: severin, gelsolin, fragmin
Cross-linking: alpha-actinin, fimbrin
Bundling: filamin, spectrin
Branching: Arp complex
Signalling mechanisms that regulate actin cytoskeleton?
- Ion flux changes
- Kinases/phosphatases
- Phospholipid binding
- Signalling cascades via small GTPases
How is actin cytoskeleton controlled by small G proteins?
Rho subfamily of small GTPases (within Ras family)
Activated by association with GTP
Activated by receptor TK, adhesion receptors and signal transduction pathways
Expression upregulated in different tumours
What does activation of Rho family GTPases in cells result in?
Lamellipodia:
Rac -> polymerisation, branching, adhesion
Rho -> Stress fibres, tension, contraction, detachment
Filopodia:
Cdc42 -> polymerisation
How does signalling from small GTPases regulate cytoskeleton and motility?
They activate actin binding proteins (Arp complexes) via effector proteins
How does metastasis occur
- epithelial cells in primary tumours bound tightly together
- Metastatic tumour cells become mobile and enter bloodstream
- They then exit the circulation and invade a new organ
- Cells lose their motility and form new tumour
Metastasis MIMICS morphogenetic events
Types of tumour cell migration?
Individual cell migration - Ameoboid (round), mesenchymal (elongated)
Collective migration - clusters, multi-cellular strands
Different types of adhesion receptors in tumour cells?
Integrins/ proteases - found in ALL types of migration
Cadherins/ gap junctions - clusters and multi-cellular strands ONLY
