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eMCD - Can > Cancer 11: Invasion - regulation of cell migration > Flashcards

Cancer 11: Invasion - regulation of cell migration Flashcards

1
Q

2) What are the molecular mechanisms that regulate

A

microfilaments
regulation of actin dynamics
cytoskeletal proteins
signalling proteins

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2
Q

Describe the process of tumour progression

A
  1. homeostasis
  2. genetic alterations
  3. hyper - proliferation (due to mutation)
  4. de-differentiation
    - -> cells lose their identity
    - -> lose contact w each other
    - -> and lose polarity (no longer cuboidal epithelium)
  5. invasion
    - -> cells break down BM
    - -> acquire increased motility
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3
Q

Metastasis requires distinct and sequential events

give a general overview of these events

A

benign = cells still attached

  • -> then invades surrounding stroma
  • -> travel via circulation
  • -> invade new organ
  • -> forms a new tumour
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4
Q

compare between the 2different types of tumour cell migration/ motility ?

A

a) single cell
- Amoeboid (circular) or mesenchymal
- Require integrins + proteases

b) collective cell migration
- Group of cells detach + form clusters/cohorts or multicellular strands/sheets (where cells follow leader cell)

  • Require cadherins + gap junctions
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5
Q

note: Tumour cell metastasis mimic morphogenetic events

A

-

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6
Q

Comparison of expression profile of invasive cells Vs primary tumours

A

needle w EGF = haemotactic

–> invasive cells go up needle –>

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7
Q

What are main stimuli for cells to migrate ?

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

What is direction of movement of cells controlled by?

A

Direction controlled by polarity (directionality)

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9
Q

What controls Stop of movement of cells?

A

Stop of movement = controlled by contact-inhibition motility

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10
Q

How do cells actually move?

A

via specialised structures (focal adhesion, lamellae, filopodium)
–> allows them to move

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11
Q

Attachment of cells to substratum

allows them to move - how?

A
  • Focal adhesions hook onto ECM + provide holding for cell whilst move
  • Hooking mostly done by integrins
  • Focal adhesions are on terminal ends of actin filament
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12
Q

What are filopodia?

A
  • Finger-like protrusions rich in actin filaments
  • used for motility
  • important for sensing environment ( senses stimulus + site of attachment )
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13
Q

What are Lamellipodia ?

A

Sheet-like protrusions rich in actin filaments

- used for motility

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14
Q

Why is control need in cell movement?

A

a) to coordinate what is happening in different parts
b) to regulate adhesion/release of cell-extracellular matrix receptors

c) to respond to external influences from outside –
needs:
- -> sensors
- -> directionality

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15
Q

Compare between the 2 types of cell motility :

hapoptatic vs chemotatic

A

hapoptatic - cell roaming around
chemotatic - cells have a purpose

–> but same machinery

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16
Q

What are the processes of cell motility?

A

Cell motility (movement to R):

  • Extension: of cell body in direction of movement
  • Adhesion: led by lamellipodium, then filopodia hook onto ECM –> form new focal adhesion
  • Translocation: contraction of cell body –> bring back of cell forwards; needs energy
  • De-adhesion of previous focal adhesions
17
Q

describe how Actin filament polarity affects the cell movement.

A

actin filaments = made of polymers
- G actin –> soluble –> forms F actin (has polarity)
- in response to signs, e.g nutrients,
F actin on one side –> disassembles
and reassembles on the side with the signal –> allows polarity –> allows movement

18
Q

Describe the organization and structure of the Filament ?

A
  • Filopodia filled with bundles of parallel actin filaments
  • Stress fibres have antiparallel organisation – when contract, affect whole cell body; have focal adhesions on endings
  • Lamellipodia have branched + cross-linked filaments –> provides support to big membrane sheet
19
Q

describe the Remodelling of actin filaments.

A
  1. Nucleation: (occurs at -ve end for +ve end to have polymerization)
    = rate-limiting step in organisation of cytoskeleton/actin,
    –> high energy needed
    - Arp = actin-related proteins, like actin

–> Arp 2 + Arp3 = resembles actin structure –> helps actin monomers form initial trimers –>initiates polymerization –> eventually form filaments

  1. Elongation:
  • Profilin binds G-actin –> brings it to actin filament
  • Thymosin binds G-actin, but doesn’t bring to filaments –> inhibits polymerisation
  • Sequestering: b4-thymosin, ADF/cofilin (doesn’t inhibit polymerization)
  1. Capping: capping proteins regulate elongation of actin filament: (capping protein = blocks polymerization)
    - At + end: Cap Z, Gelsolin, Fragmin/severin; At – end: Tropomodulin, Arp complex
    - When blocked at front by capping proteins –> causes shortening/disassembly of filament at back
  2. Severing: regulate filament size, filaments may grow + shrink
    - Severing proteins:

o Gelsolin, ADF/cofilin, fragmin/severin

  • Gelsolin also is capping protein; function determined by regulation e.g. post-translational modification or signalling protein

after being cut 3 pathways

  • continue elongation
  • annealing –> join fragments back together
  • capping cut end ( to prevent elongation)
  1. Cross-linking + bundling of newly formed filaments:
    - e.g Fascin bundles filaments together
  • Fimbrin does same but at longer distances
  • Spectrin, filamin, dystrophin cross-link multiple filaments at particular angles;
    6. Branching:
  • Branching in lamella occurs at particular angles (70 °)
  • Arp2/3 complex = responsible for branching appearance of filaments in lamella as cells move forward
  • Thus, Arp2 does both nucleation + filament elongation/angling
  1. Gel-sol transition by actin filament severing:
    - Cross-linking proteins hold cytoskeleton to make rigid mesh/scaffold
  • to release + protrude to memb –> they need cytoplasm to flow (gel status –> sol status)
  • Can severe filaments (not cross-linking proteins) to allow cytoplasm flow in parts of cell to allow expansion of membranek
20
Q

how does cooperation of actin help in generating filaments?

A
  • Profilin-(G)actin binds plus end for elongation
  • When filaments broken down, cell can glue pieces back together (annealing)
  • Or short filament can grow new separate fibre
21
Q

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

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

A

e) Alzheimer (neurodegenerative)

22
Q

Participation of different actin activities during cell movement

i.f list the various stages

A
  • disassembly
  • nucleation
  • branching
  • severing
  • capping
  • bundling
23
Q

What is lamallae protrusion?

A
  • controlled by polymerization + formation of branched filaments
  • -> allows sheer of memb to be protruded
  • -> movement of monomer to the front
  • -> allows incorporation of new filaments
24
Q

what do you need to form the filopodia?

A

you need

  • actin polymerisation
  • bundling
  • crosslinking
25
Q

describe the regulation of cytoskeleton by small G proteins.

A
  • Rho subfamily of small GTPases belongs to the Ras super-family

–> Family members: Rac, Rho, Cdc42 best known

  • Participate in a variety of cytoskeletal processes.
  • These proteins are activated by: receptor tyrosine kinase/ adhesion receptors / signal transduction pathways.
  • Expression = up-regulated in different human tumours.
26
Q

How do small GTPases participate on cell migration?

A
  • Deadhesion is action of Rho, so if block Rho –> block movement
  • Lamellipodium controlled by Rac
  • Focal adhesion controlled by Rac + Rho
  • Contraction + deadhesion controlled by Rho
27
Q

types of tumour cell migration

A
  • ameoboid –> round
    mesenchymal –>
  • cluster / cohorts –> synchronise motility
  • multicellular strands/ sheets –>
  • -> integrins + protease = found in all types of cell migration
  • -> cahejrins + gap junctions = found in cluster cohorts + multicellular strands - which mediates cell to cell contact
28
Q

note: compared to wound healing, migration in tumour = faster + more dysregulated

A

-

29
Q

What are 3 structures used for motility?

A

Lamellipodia

filopodia

Attachment of cells to substratum

30
Q

what are the 4 signalling mechanisms that regulate 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

31
Q

note:

Rho activation –> formed stress fibres
Rac –> forms lamellipodia
CDC42 –> forms filopodia

A

-

32
Q
  • actin polymerisation + branching of lamellipodium = controlled by _____
  • focal adhesion + assembly = controlled by _____
  • contraction = controlled by ____
  • detachment at back = controlled by ____
  • formation of filopodia + polarisatied motility + actin polymoeration = controlled by ______
A
  • actin polymerisation + branching of lamellipodium = controlled by Rac
  • focal adhesion + assembly = controlled by rac + rho
  • contraction = controlled by rho
  • detachment at back = controlled by rho
  • formation of filopodia + polarisatied motility + actin polymoeration = controlled by cdc 42

eMCD - Can (15 decks)

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