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Cancer > 11. Invasion - regulation of cell migration > Flashcards

11. Invasion - regulation of cell migration Flashcards

1
Q

What percentage of human tumours are derived from epithelial tissues?

A

80-90% (tight junctions and polarised, based on top of BM)

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2
Q

What happens to polarity in tumours?

A

Loss of polarisation

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3
Q

How do cells pass through the BM?

A
  • Secrete proteases to clip the BM

* Then make protrusions bu cleaving ECM proteins and invade the surrounding tissue

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4
Q

What are the 2 types of cell motility?

A
  • Individual (single cell)

* Collective (group of cells)

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5
Q

What do both types of motility require?

A
  • Integrins

* Proteases

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6
Q

Name 4 methods of migration for different tumour types, and give examples of these tumours

A
  • Amoeboid - lymphoma, leukaemia
  • Mesenchymal - fibrosarcoma, glioblastoma
  • Cluster/cohorts - epithelial, melanoma
  • Multicellular - epithelial, vascular
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7
Q 
Which cell migration types are the following found in:
• Integrins
• Proteases (clears ECM for tracks)
• Cadherins
• Gap junctions
A
  • Integrins - all
  • Proteases - all
  • Cadherins - collective
  • Gap junctions - collective
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8
Q

Describe which physiological event tumour cell invasion mimics

A

• Morphogenetic events
• Normally if a confluent monolayer is scraped, cells sense the space and migrate together to close the gap (healing)
- collective migration
• Tumour cells demonstrate this but it is not organised
• Contact inhibition is ineffective in tumour cells, and growth is faster

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9
Q

How does the cytoskeleton of a cell change morphology when it is stimulated to migrate?

A
  • Actin-based cytoskeleton moves towards apex

* Microtubule cytoskeleton moves basally

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10
Q

How are cells attached to the ECM?

A
  • Focal adhesions
  • Cytoskeleton is engaged
  • Hooking onto ECM by dimer integrin receptors - transmembrane proteins with a short cytoplasmic tail (no enzymatic activity)
  • Integrins have docking places for cytoskeletal proteins - form a plaque/complex of proteins which mediates the interaction with actin fibres
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11
Q

What are filopodia?

A
  • Finger-like protrusions rich in actin filaments
  • Sense the environment, telling the cell where they should attach
  • Coordinate movement
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12
Q

What is vinculin?

A
  • Actin-binding protein

* Bundling protein

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13
Q

What are lamellipodia?

A
  • Sheet-like protrusions rich in actin filaments
  • Project to the front of the cell in the same direction as the movement of the cell
  • The sheets then ruffle back so the cell can move
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14
Q

What is hapoptatic motility?

A

Directional motility or outgrowth of cells with no purpose

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15
Q

What is chemotactic motility?

A

Movement in response to a chemical stimulus

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16
Q

What are the steps of cell movement?

A
  • Extension - lamellipod
  • Adhesion - focal adhesion
  • Translocation - back of cell contracts to move the cell forward
  • De-adhesion - old adhesions left behind

Cell moves one step at a time

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17
Q

Are actin monomers polarised?

A

Yes - different structures on each end ( + and - )

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18
Q

There is a complex regulation between what states of actin?

A

Monomer (small soluble subunits) and large filamentous polymer

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19
Q

What happens to the general actin arrangement when a signal reaches the cell (causing a change in polarity)?

A
  • Rapid disassembly of the filaments
  • Rapid diffusion of the actin monomers
  • Reassembly at the side of the cell that is going to the source
  • Repolarisation of cell
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20
Q

What form and arrangement is actin in, in the filopodium?

A
  • Filamentous form

* Parallel arrangement

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21
Q

How are stress fibres organised?

A
  • Anti-parallel organisation of the filaments

* Necessary for contraction

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22
Q

At what structures do stress fibres end?

A

Focal adhesions

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23
Q

How are the fibres arranged in the lamellipodia?

A
  • No direct fibres
  • Branched and cross-linked fibres, like a net
  • Provide support to the big sheet of membrane
24
Q

What is the rate-limiting step in the organisation of the cytoskeleton?

A
  • Nucleation
  • Requires a lot of energy
  • Arp (actin-related proteins) help monomers to form a trimer, to initiate polymerisation
  • The arp-2,3 complex binds to the minus end of the actin filament to form a trimer
  • Once this step happens, filaments can form
25
Q

Describe the step in the organisation of the cytoskeleton following nucleation?

A

Elongation
• Different classes of proteins assist:
• e.g. profilin binds to G-actin (monomeric) and drags it to the actin filament
• e.g. thymosin binds to actin and inhibits the polymerisation process (acts like a brake)

26
Q

Describe the step in the organisation of the cytoskeleton following elongation?

A

Capping
• Capping proteins regulate the elongation process
• Binds to the end of the filament and prevents monomers from being added
• Once adding is blocked, a disassembly process results in the shortening of the filament

27
Q

Name the capping proteins

A

+ end
• Cap Z
• Gelsolin
• Fragmin

  • end
    • Tropomodulin
    • Arp complex
28
Q

What is ‘severing’ in the organisation of the cytoskeleton?

A
  • Regulation of filament size
  • The unsevered actin filament grows and shrinks
  • Severing proteins chop the filament up
  • This counter-intuitively generates more ends so the filaments grow rapidly
29
Q

Name the severing proteins

A
  • Gelsolin
  • ADF/cofilin
  • Fragmin/severin
30
Q

What does fascin do?

A

Bind filaments together at a particular distance

31
Q

What does fimbrin do?

A

Bind filaments at a long distance from one another, together

32
Q

What is alpha-actinin?

A

A dimer, which binds filaments

33
Q

What does spectrin, filamin and dystrophin do?

A
  • Cross-link the filaments in particular angles

* Dystrophin helps attach filaments to the plasma membrane

34
Q

Which cross-linking protein is mutated in muscular diseases?

A

Dystrophin

35
Q

For motor proteins coming in, what does this depend on?

A
  • Way in which the proteins are bundling

* Distance of the filaments (if too close, motor proteins can’t come in)

36
Q

Wha happens if there are 2 shorter separate filaments connecting to the same longer filament, and they move towards each other?

A

Buckling

37
Q

What is the precise angle of cross-linking proteins in the lamellar?

A

70º

38
Q

Which protein is responsible for the branching appearance of filaments as the cells move forward in the lamellar?

A

Arp-2 complex

39
Q

What does the Arp-2 complex do once it binds to the sides of the filament at 70º?

A

Nucleates (forming a trimer of G-actin) and elongates (branches)

40
Q

What happens to the rigid cell cortex when the cell needs to move and project?

A
  • Must be broken - allows the cell membrane to flow forward
  • Called ‘gel-sol’ transition
  • Gel is a rigid structure of the actin cytoskeleton - cross-linking proteins hold the filaments as a mesh here
  • Gel mesh is broken down if the membrane pushes through - severing
  • Actin cross-linking proteins are still present - just no mesh
  • Allows a sol that can flow - cytoplasm can move to another area
41
Q

What is Wiskott-Aldrich Syndrome (WAS)?

A
  • Immune cells impaired as they cannot remodel cytoskeleton
  • Cannot phagocytose
  • Immunodeficiency, eczema, autoimmunity
42
Q

What is Bullous Pemphigoid?

A
  • Autoimmune skin disease
  • Breakdown between skin cells and their BM
  • Due to antibody damage
43
Q

How do the filaments organise themselves in:
• Lamellipodium extension
• Focal adhesion formation

A

Extension
• Lot of actin polymerisation

Focal adhesion formation
• Assembling
• Nucleation
• Elongation
• Capping
• Severing
• Branching
• Bundling
44
Q

What happens if the cells don’t contract at the back and detach to move it forward?

A

Cell will rip apart

45
Q

Where in the filopodia does elongation occur?

A

Only at the tip - keeps chain localised and thin

46
Q

What are the 4 signalling mechanisms that regulate the actin cytoskeleton?

A
  • Ion flux changes
  • Phosphoinositide signalling (phospholipid binding)
  • Kinases/phosphatases - phosphorylation of cytoskeleton proteins
  • Signalling cascades via small GTPases - master regulators
47
Q

Which super-family do the Rho subfamily of small GTPases belong to?

A

Ras super-family

48
Q

Describe the control of the actin cytoskeleton by small G proteins?

A
  • Activation - GDP => GTP
  • Small G proteins bind to effectors
  • Effectors are the messengers that carry out actions
  • Proteins inactivated by hydrolysis of GTP => GDP
49
Q

What are the best know proteins in the Rho family?

A
  • Cdc42
  • Rac
  • Rho
50
Q

What happens when CDC42, RAC and RHO are activated?

A
  • Cdc42 - induces filopodia
  • Rac - induces lamellipodia, expansion and flattening of the cell
  • Rho - induces stress fibres
51
Q

What does Rac protein activate and induce?

A
  • Activates WAVE and Arp-2/3

* Induces polymerisation

52
Q

What does activated Cdc42 activate?

A
  • WASP
  • This regulates Arp-2/3
  • Branching out to activate many proteins
  • Mutated in Wiskott-Aldrich Syndrome
53
Q

Which Rho family proteins does focal adhesion assembly involve?

A

Rac and Rho

54
Q

Which Rho family proteins does contraction to retract the cell involve?

A

Mostly Rho

55
Q

What happens to the cell in contraction if Rho is blocked?

A

Cell may rip apart as it’s involved in detatchment

56
Q

Which processes of filopodia does Cdc42 control?

A
  • Exploratory processes

* Driving polarised motility and actin polymerisation

57
Q

Does lamellipodia or filopodia occur first?

A

Filopodia, as it tests where the cell is going

Cancer (15 decks)

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