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Year 2 Collin > Cancer 11 - Invasion - regulation of cell migration > Flashcards

Cancer 11 - Invasion - regulation of cell migration Flashcards

1
Q

How do tumours progress (stages)

A
  1. Homeostasis
  2. Genetic alterations
  3. Hyper-proliferaion
  4. De-differentiation
  5. Invasion
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2
Q

In the de-differentiation stage of tumour progression, what things happen

A
  1. Cell-cell contacts disassemble

2. Loss of polarity of the cell

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3
Q

In the invasion stage of tumour progression, what things happen

A
  1. Increased motility

2. Cleavage of ECM proteins (e.g. via MMPs)

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4
Q

What 4 molecular mechanisms regulate motility

A
  1. Microfilaments
  2. Regulation of actin dynamics
  3. Cytoskeletal proteins
  4. Signalling proteins
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5
Q

What are the 2 types of tumour migration/motility

A
  1. Single cell migration - amoeboid (circular) or mesenchymal - requires integrins and proteases
  2. Collective cell migration - requires cadherins and gap junctions - groups of cells detach and forms clusters/cohorts or multicellular sheets - cells follow leader cell
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6
Q

Tumour cell metastasis mimics morphogenetic events. Give an example of this

A

e.g. collective cell migration in vascular sprouting

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7
Q

Give 2 differences between invasive cells and primary tumours

A

Invasive cells have an up regulation of cytoskeleton regulation and motility machinery

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8
Q

What gives invasive cells stimuli to move

A
  1. Organogenesis and morphogenesis
  2. Wounding
  3. GFs/chemoattractants
  4. Dedifferentiation
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9
Q

What controls the direction of invasive cells to go?

A

Polarity

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10
Q

What signals invasive cells to stop moving

A

Contact-inhibition motility

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11
Q

How do invasive cells move?

A

Through specialised structures (focal adhesion, lamellae, filopodium)

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12
Q

What hooks cells onto substratum whilst they move?

A

Focal adhesions (on the terminal end of actin filaments)

Integrin does most of the hooking

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13
Q

What are filopodia and how are they linked into bundles

A

Finger like protrusions containing many actin filaments that are cross linked into bundles by actin binding proteins (e.g. fascin and fimbrin, vinculin)

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14
Q

What is a lamellopodia

A

Sheet like membrane rich with actin filaments - they project to the front then ruffle back when the cell moves to allow movement

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15
Q

Control of cell movement occurs within the cell to coordinate what is happening in different parts; but also outside the cell. Why is this control needed?

A

Within cell - To regulate adhesion/release of cell/ECM receptors.

Outside cell - to respond to external influences (requires sensors)

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16
Q

Describe the 2 types of motility

cell movement involves cell changing shape

A
  1. Haptotaxis - no purpose

2. Chemotaxis - purpose (e.g. responding to GF)

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17
Q

Describe the 4 phases involved in cell motility

A
  1. Extension - of cell body in direction of movement
  2. Adhesion - led by lamellipodium, then filopodia hook onto ECM - forming new focal adhesion
  3. Translocation - contraction of cell body - bring back of cell forwards - needs energy
  4. De-adhesion of previous focal adhesions
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18
Q

Explain actin filament polarity

A

G-actin (small soluble units) and F-actin (large, twisted, filamentous polymer)

  1. Signal reaches cell (e.g. nutrient source)
  2. Filaments rapidly disassembled and monomers rapidly diffuse across cell –> reform at the end of the cell towards the site of the signal
  3. Cell repolarises moving towards the nutrient signal
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19
Q

What filament organisation do stress fibres have?

A

Antiparallel filament organisation - affect whole cell body when contract to produce force

Stress fibres have focal adhesions on their ends

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20
Q

What filament organisation do filopodia have?

A

Parallel filament organisation

21
Q

What filament organisation do lamellipodium have?

A

Branched and cross linked filaments –> provides support to big membrane sheet

22
Q

What is the key process in the remodelling of actin filaments

A

Nucleation

23
Q

What is the limiting step in the actin remodelling dynamic

A

Nucleation - lots of energy needed

24
Q

What happens in nucleation

A
  1. Arp 2/3 protein complexes (Actin like proteins) cause actin monomers to form trimers —> eventually form filaments
  2. Arp proteins usually located at the minus end (so that the plus end is free to add monomers)
25
Q

What step happens after nucleation. What happens in this step

A

Elongation

  1. Profilin binds G-actin and brings it to filament (promotes assembly)
  2. Thymosin binds G-actin but inhibits polymerisation - doesn’t bring G actin to filament

Profilin and thymosin are competing

26
Q

What is sequestered in the elongation step

A

B4-thymosin

ADF/cofilin (these do not inhibit polymerisation)

27
Q

What steps follow elongation

A

Capping, then severing

Capping = capping proteins regulate elongation of actin filament (stop elongation when necessary)

Capping proteins at + end: CapZ, gelsolin, fragmin/severin

Capping proteins at - end: Tropomodulin, Arp complex

Severing = regulating filament size - severing filaments promotes growth as more ends are made

Severing proteins: gelsolin, ADF/cofilin, fragmin/severin

28
Q

Name a protein that is both a capping protein and a severing protein - its function being determined by regulation

A

Gelsolin

29
Q

Which end does profilin-(G) actin bind for elongation

A

Plus end

30
Q

When the filament is broken down, what are the 2 possible outcomes

A
  1. Cell glues filament pieces back together (annealing)

2. Short filament grows a new fibre

31
Q

What occurs after severing

A

Cross-linking (+ bundling of newly formed filaments)

  1. Fascin binds filaments at particular distances
  2. Fibrin binds filaments at longer distances
  3. Spectrin, filamin, dystrophin cross link multiple filaments at particular angles

Bundling occurs due to Vinculin - affects motor protein binding - if distance between filaments wide enough (enough distance), then motor protein enters (Eg myosin) - allows contraction

32
Q

What occurs after cross linking?

What is particular about this step

A

Branching

Occurs in the lamella at 70 degrees.

Arp2 complex causes branching appearance of filaments in lamella as cells move forward

33
Q

Which 2 things does the Arp2 complex do?

A

Nucleation

Filament elongation/angling

34
Q

Name a disease that is not caused by deregulation of the actin cytoskeleton

A

Alzheimers

35
Q

How can a gel-sol transition be achieved with the cytoskeleton

A

Cross linking proteins hold cytoskeleton - creates a scaffold/mesh

Severing actin filaments allows cytoplasm flow in parts of the cell

36
Q

Describe different uses of actin organisation in cell movement

A
  1. Polymerisation in lamellipodium extension
  2. Attachment to ECM at new adhesion
  3. Gel/sol transition on cortex at membrane going forward in translocation
  4. Detachment during de-adhesion
37
Q

Explain the actin organisation processes occurring in lamellar protrusion

A

Polymerisation, disassembly, branching, capping

Severing at back of lamellae, releases monomers which goes to front of cell –> F actin filament assembled at front and generates pushing force of cells to move forward

38
Q

Explain the actin organisation processes in filopodia

A

Polymerisation, bundling, cross-linking

Form bundles, then quickly elongate —> pushes membrane out in localised position

Once filopodia sense no more room to go forwards or no stimulus –> collapse of filament by attracting capping proteins —> retraction by eroding base

39
Q

What other cell types use bundling (a form of actin reorganisation)

A

Cilia, filopodia, microvilli, stereocilia

Branching - a different for of actin reorganisation - used in lamellipodia

40
Q

4 signalling mechanisms that regulate the actin cytoskeleton

A
  1. Ion flux changes (i.e. intracellular Ca)
  2. Phosphoinositide signalling (phospholipid binding)
  3. Kinases/phosphatases (phosphorylation cytoskeletal proteins)
  4. Signalling cascades via small GTPases
41
Q

Which superfamily does the Rho subfamily of small GTPases belong to

A

Ras super family

42
Q

Name some family members of the Ras superfamily

A

Rac - expansion + flattening of cell, lamellipodia

Rho - stress fibre formation

Cdc42 - promotes filopodia growth

Rac & Cdc42 also activates many other cytoskeletal proteins (involved in polymerisation and organisation)

43
Q

What does the Rho subfamily of small GTPases do

A

Activated by receptor tyrosine kinase, adhesion receptors and signal transduction pathways

Their expression is unregulated in different tumours

They participate in various cytoskeletal processes

44
Q

When is the Rho GTPase inactivated and how

A

Inactive when bound to GDP - inactivated by hydrolysis

45
Q

Which GTPase causes de-adhesion

A

Rho

46
Q

Lamellipodium is controlled by which GTPase

A

Rac

47
Q

Focal adhesion is controlled by which GTPases

A

Rac and Rho

48
Q

Contraction and de-adhesion is controlled by which GTPase

A

Rho

Year 2 Collin (114 decks)

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