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Year 2 - MCD - Cancer > 8: Invasion - Regulation of Cell Migration > Flashcards

8: Invasion - Regulation of Cell Migration Flashcards

1
Q

What are the molecular mechanisms that regulate motility?

A

microfilaments
regulation of actin dynamics
cytoskeletal proteins
signalling proteins

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2
Q

What are the steps that make a benign tumour go to malignant?

A

De-differentiation

  • disassembly of cell-cell contacts (don’t recognise neighbouring cells anymore)
  • loss of polarity

Invasion

  • increased motility
  • cleavage of ECM proteins
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3
Q

What are the 4 main steps in metastasis?

A
  1. epithelial cells in primary tumours are tightly bound toegether
  2. metastatic tumour cells become mesenchyme-type cells and enter the bloodstream.
  3. metastasic cells travel through the bloodstream to a new location in the body
  4. metastatic cells exit the circulation and invade a new organ
  5. Cancer cells lose their mesenchymal characteristics in the new tumour.
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4
Q

What are the types of tumour migration?

A

A. Individual

  • ameboid (mostly lymphoma, leukemia, SCLC)
  • mesenchymal (single cells)
  • mesenchymal (chains)
    e. g. glioblastoma, aplastic

B. Collective
(- clusters/cohorts -> 3-20 cells (in epithelial cancer and melanoma)
- multicellular strands/sheets (epithelial and vascular tumours)
- cadherins, contact between the neighbours, gap junctions

=> even with the same number of cells, there is a higher metastatic potential in clusters of cells than in single cells.

=> different signalling, different molecules. - proteases and integrins in both

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5
Q

Tumour cell metastasis - mimicking morphogenic events

A

a) 2D sheet
b) branching morphogenesis - mammary gland (has a leader cell)
c) vascular sprouting
d) multicellular 3D invasion
e) Border cells (e.g. ovary) - there are nurse cells around that are responsible for feeding
f) detached cluseter

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6
Q

In experiments on rodents, what was seen in terms of differences in cells of primary tumours and invasive cells?

A
  • invasive cells have a higher expression of genes for cytoskeleton regulation and motility machinery
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7
Q

What are stimuli for cells to move?

A
  • organogenesis and morphogenesis
  • wounding
  • growth factors/chemoattractants
  • dedifferentiation (tumours)
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8
Q

What determines where a cell will go?

A

Polarity / Directionality (due to factors like chemoattractants)

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9
Q

What determines when the cell should stop moving?

A

contact-inhibition motility

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10
Q

How does a cell move?

A

specialised structures e.g.:

  • focal adhesions
  • lamellae
  • filopodium
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11
Q

What are focal adhesions?

A
  • dynamic protein complexes through which the cytoskeleton of a cell connects to the ECM.
  • form mechanical links with (filamentous) actin inside the cell
  • filamentous actin hooks to focal adhesions
  • there is no enzymatic action on the ic side of integrins so a plaque of cytoskeletal proteins on the inside is responsible for the actions -> signalling port and connection to cytoskeleton
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12
Q

Filopodia

A
  • structures used for motility
  • Finger-like protrusions rich in actin filaments
  • “fingers”
  • contain filaments
  • sense surrounding of cells
  • are all over the cell
  • also at the bottom of the cells if they are attached
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13
Q

Lamellipodia

A
  • structures used for motility

- sheet-like protrusions rich in actin filaments / broad sheets of membrane

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14
Q

Cell movement control - why is it needed?

A
  • within a cell to coordinate what is happening in different parts (e.g. if cell is moving in one direction, on the other end the cell has to detach to allow for movement)
  • regulate adhesion/release of cell-extracellular matrix receptors
  • from outside to respond to external influences –
    sensors
    directionality
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15
Q

How is cell movement mediated?

A
  • change of cell shape
  • focal adhesions with ECM
    1. extension -> lamellipodium lands on ECM
    1. adhesion -> lamellipodium forms new (focal) adhesion on ECM
    1. Translocation - cell body moves
    1. De-adhesion (old adhesion on the opposite side of direction of movement detatches from ECM)

=> here also small GTPases like Rho and Raf play a role. Also there are different actin activities such as polymerisation, gel/sol transition and contraction)

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16
Q

Motility types

A

Hapoptatic: you just go for the sake of moving

Chemotatic: there is a purpose and direction to move, there is a stimulus that drives the cell to a particular location

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17
Q

What is the difference between G- and F-actin?

A
  • G: small, soluble subunits

- F: long, filamentous polymer

18
Q

How does actin change to allow for cell shape change?

A
  1. signal such as nutrient source
  2. disassembly of filaments and rapid diffusion of subunits
  3. reassembly of filaments at a new site (actin can polymerase to large units fast!)
19
Q

In what ways can actin filaments be remodelled?

A
  • constant flow between G and F-actin pool
  • proteins involved e.g. sequestering proteins, motor proteins that will contract, capping, cross linking, severing, nucleating

F-actin

  • severing
  • cross linking
  • capping
  • side binding
  • motor proteins
  • bundling

G-actin

  • nucleating
  • sequestering
20
Q

vinculin

A
  • one of the main components of the integration plaque
  • binds to filamentous actin
  • high concentration of forms fingers of the cell (filopodia)
21
Q

What is a key difference between stress fibers and filipodium?

A
  • stress fibres have antiparallel fibers

- filopodia have parallel filaments

22
Q

Nucleation of actin

A
  • key limiting factor in the transition form g to filamentous actin pool is the initial step of nucleation
  • in order for polymerisation to occur you need nucleation of 3 monomers together (this is not very stable)
  • proteins called nucdelators are needed
  • Arp2 and Arp 3 resemble actin but they are not actin
  • > bind to monomer -> polymerisation starts
  • > facilitate rapid nucleation to start polymerisation.
  • Arp2 and Arp3 are the minus end. Elongation is at the plus end.
23
Q

What is the limiting step in actin dynamics? (g -> f)

A

formation of trimers to initiate polymerization

24
Q

Elongation of actin

A
  • after you have the trimer, elongation is needed
  • requires 2 types of protein:
    • profilin
    • thymosin
  • thymosin binds to actin and hold it for itself
  • profilin facilitates rapid incorporation of actin
  • profilin competes with thymidine for binding to actin monomers and promotes assembly

beta-4-thymosinf and ADF/cofilin are sequestering (the second one does not inhibit polymerisation)

25
Q

Capping of actin

A

=> they tell the filament to stop growing (breakdown from the other end unless capped there too?)

At positive ends:

  • capZ
  • Gelsolin
  • Fragmin / Severin

At negative ends:

  • Tropomodulin
  • Arp complex (for nucleation and capping)
26
Q

Severing of actin

A
  • in the unsecured population actin filaments grow and shrink relatively slowly
  • in severed population actin filaments grow and shrink more rapidly
  • coordination between capping and severing
  • severing proteins:
    gelsolin (also in capping)
    ADF/cofilin
    fragmin/severin (also in capping)
27
Q

Cross linking and bundling of actin

A
  • involves different proteins
  • give the actin a variety of shapes
  • numerous proteins involved e.g.
    fascin (highly mutated in melanoma)
    fimbrin
    alpha-actinin (dimer that cross links filaments)
    spectrin (fundamental in epithelial cells to stabilise cortical structures)
    filamin (cross links at different angles -> mesh inside cells)
    dystrophin ( cytoskeletal protein that links filaments to the plasma membrane)
    villin
    vinculin
28
Q

Some proteins are involved in different functions e.g. gelsolin + framing/severin are both involved in capping but also in Severin. How does this work?

A
  • depends on the way it is regulated and the stimulus

- multitasking of these proteins

29
Q

Cooperate of actin functions to generate filaments

A
  • coordination of the functions
  • work as a team so that the cell can change its shape
  • bundling proteins hold filaments together
  • myosin can help contract the cells
30
Q

what are the 3 options for severed filaments?

A
    • end / barbed end is capped
  • re-annealing (proteins join together small filaments)
  • growth (promote growth by pre-existing ends (rather than nucleation from scratch)
31
Q

Branching of actin

A
  • branching protein: Arp complex (also in nucleation and capping)
  • branching is at precisely at 70 degrees
  • then polymerises again to make a short branch
32
Q

Gel-sol transition by actin severing

A
  • the network maintains some level of rigidity of the membrane and cytosol
  • you clip the filaments at particular sites (not everywhere)
  • > there are cross linked filaments that are not all connected to each other
gel = rigid
sol = can flow
33
Q

Which one of these diseases is not caused by deregulation of actin cytoskeleton?

High blood pressure
Wiskott-Aldrich Syndrome – WAS (immunodeficiency, eczma, autoimmunity)
Duchenne Muscular Dystrophy (muscle wasting)
Bullous Pemphigoid (autoimmune disease)
Alzheimer (neurodegenerative)

A

e)

all the other diseases are involved in deregulation in the actin cytoskeleton.

34
Q

Lamellae protrusion

A
  • Polymerization, disassembly, branching, capping
  • spacial, temporal and moleucular regulation
    ( see slide 29)
35
Q

Filopodia formation

A

INITIATION + PROTRUSION + RETRACTION

  • actin polymerisation
  • bundling
  • cross-linking
  • fast elongation
  • disassembly is via retracting back to the body
36
Q

Cell shape and cytoskeleton organisation

A

Formation of different structures e.g.

  • bristles
  • microvilli
  • stereo cilia
  • filopodia
  • lamellipodia

=> different proteins involved

37
Q

Signalling mechanisms that regulate the actin cytoskeleton

A

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

38
Q

Control of actin cytoskeleton by small G proteins

A
  • Rho subfamily of small GTPases belongs to the Ras super-family: Family members: Rac, Rho, Cdc42 best known
  • phosphorylation actiivates, dephosphorylation de-activates
  • Participate in a variety of cytoskeletal processes.
  • These proteins are activated by receptor tyrosine kinase, adhesion receptors and signal transduction pathways.
  • Expression levels up-regulated in different human tumours.
39
Q

What structures are the different members of the Rho family responsible for?

A
  • Cdc42: master of filipodia, 5x the length
  • Rac: forms lamellipodia, large lamellae ‘‘pancakes’’
  • Rho: stress fibers, tension, contraction
40
Q

How does signalling from small GTPases regulate actin cytoskeleton and motility?

A

actin binding proteins regulated by Rac/Cdc42

Year 2 - MCD - Cancer (15 decks)

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