8: Regulation of Cell Motility (Invasion) Flashcards
Explain the different steps in tumor Progession
When do benign Tumors turn to malignant tumors?
- Homeostasis (normal cells)
- Genetic alteration
- Hyper-proliferation
–> Benign
- De-differentiation
- dissasembly of cell-cell contacts
- loss of polarity
- Invasion
- increase motility
- cleavage of ECM proteins and basemsent membranes –> Metastisis
What are the two main types of tumor cell migration?
How do they differ?
-
Individual cell migration
- Ameoboid cells
- Mesenchymal (single) cells
- Mesenchymal(chain) cells
-
Collective cell migration
- Cluster cohorts
- Multicellular strands/sheaths
Which factors are needed in individual cell migration?
Individual cell migration requires
- integrins and proteases for Basememnt membrane cleavage
What factors are needed in Cluser/multicellular cell migration of tumors?
- Integrins and proteases to cleave basement membrane
- Gap junctions and cadherins for coordination of movements
What are the characteristics of tumor cell metastisis?
They mimic normal morpholigical movements
- as seen in angiogenesis
- branching morphogenseis like in mamillary gland
- etc.
How does migration of a tumor differ from normal cell migration?
Often they try to mimic morphological cell movement but are different in
- deattaches from another (no cell-cell junctions and signaling)
- grow randomly + unorgansied
- fast growth
How does the Gen profile of migrating tumor cells differn from those that don’t migrate?
Often:
- upregulation in cytoskeleton regulation
- and machinery
–> Normally they don’t have more oncogenic mutations but are just more mobile (EGF mouse experiment)
When does a cell move?
Normally due to external stimuli like
- organogenesis and morphogenesis
- wounding
- growth factors/chemoattractants
But can also happen in oncogenesis
- dedifferentiation (tumor formation)
What are focal adhesions?
They are connections between the cell and the extracellular matrix through integrins
- Extracellularly: integrins bind to extracellular ligands
- Intracellularly: multiproteins assemble (Plaque) and are connected to the actin cytoskeleton
What is the role of focal adhesions?
Important in signaling of movement
- anchor the cell
- Signaling: inform the cell about the composition of the ECM –> influence behaviour of cell
What are filopodia?
Finger like projections of cell membrane made of actin filaments, involved in cell motility
Explain the structure of Fillopodia
They are organised in
- straight, crosslinked actin filaments
- fomed by
- Polerymerisation
- Bundling of actin filaments
- Crosslinking of the filaments
What are Lamellipodia?
Shee-like pertrusions of cell membrane, rich in actin filaments needed for cell motility
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What are the four steps that repetitively happen in cell movement?
- Extention
- Lamellipodia and Fillopodia grow into direction of movement
- Adhesion
- New adhesions (focal adhesions) with ECM+ Basement membrane found
- Translocation
- Cell body is moves in the direction of the movement, via contraction of actin filaments on the side opposite of movement
- De-adhesion of old adhesion
How does the overall cell shape change in a migrating cell compated to a normal cell?
It will become a polerised (in shape) cell
What are stress fibres?
What is their role in cell migration?
Antiparralel strucztures actin filaments needed in cell migration
–> contraction of the cell
What is the first and rate limiting step in actin assembly?
What happens durin this step
Nucleation
- Attachment of actin to the inner cell membrane
- Arp proteins form a complex and bind actin monomers to create a nucleated actin filament
- Actin monomers bind to Arp-complex
Which proteins are important in the nucleation of actin filaments (other than G actin itself?)
Arp complexes
After initial formation of a actin trimer, what is the next step in actin filament formation?
Which protein is neede for it?
Elongation
- Controlled by
- +: profilin
- inhibited by thymosin
What happens after the Elongation of actin monomers to form an actin filament?
Capping
- further elongation inhibited
- done by proteins like: (also Arp protein involved)
After capping of Actin filaments, what is the next step?
Why is it importantn?
Severing
- enables quicker break down and reassembly of actin filaments (because chunks of actin are available, not jut monomeres)
What ar the possible fates of single severed actin filaments?
- De-polymerisation and monomer recylcling
- Annealing to other parts
- Elongation (at (+)Barbed-end with profilin actin filaments)
What is the next step after formation of a fully functional indivudual actin filament?
Cross-linking and bundling of strands
- functional dependant, many proteins can cross link e.g.
- Bundling
- Buckling if needed for contraction
Explain the role and the protein involved in actin branching
Branching forms a stable network of actin filaments
–> needed in formation for Lemelipodia
- 70° angle used
Mediated by the Arp complex
What happens during the Gel-Sol transition of actin filaments?
Why does it happen?
A process of severing
- a few actin filaments are cleaved to allow movement (sol-phase) from steady gel phase
Which cytoskeletal changes occur during Extention of the cell during movement?
Cell polymerisation is needed and all processes happen to deassambly/re-assembly actin filaments(e..g for lamellae protrusion)
- Disassembly
- Nucleation
- Branching
- Severing
- Capping
- Bundling
Which cytoskeletal changes occur durin lamellae portrusion?
Polymerization, disassembly, branching, capping
Which cytoskeletal processes occur during Filopodia bulding?
- Polimerization
- Bundling
- Crosslinkin
Which proteins regulate the cytoskeleton?
Name indivudual ones that controll
Overall: Rho proteins
- Folopodia: Cdc42
- Lamellipodia: Rac
- Stress fibres: Rho
How do Rho proteins get activated?
activated by
- receptor tyrosine kinase
- adhesion receptors
- signal transduction pathways.
–> Cause GTP binding and therefore acivation (quick indactivation via phosphorylation)
How do Rho proteins controll the cytoskeleton?
- They set of a set of intracellular messenger systems and activate actin bindin proteins
- Lead to actin polerization/organisation
- Arp2/3 in nucleation
- Cofilin, Profilin
- etc.
Explain the role of Rac in cell migration and movement
Needed in the
- Adhesion
- and Extention phase of cell migration
- controlles lamellipodia and therefore needed for
- focal adhesion assembly
- actin polimerizsation and branching
Explain the role of Rho (specific protein, not family) in cell migration and movement
Controlls stress fibres therefore needed in
- Adhesion
- Translocation
- De-adhstion of cell
Via
- tension and contraction of filamnents
