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Year 2: MCD > Cancer 11: Invasion regulation of cell migration > Flashcards

Cancer 11: Invasion regulation of cell migration Flashcards

1
Q

How does detachment from primary tumour and migration occur?

A

1)

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2
Q

What are the molecular mechanisms that regulate motility?

A
  • microfilaments
  • regulation of actin dynamics
  • cytoskeleton proteins
  • signalling proteins
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3
Q

What are the steps in tumour progression?

A

1) homeostasis - cells attached to each other on top of a basement membrane
2) genetic alterations
3) hyperproliferation
4) de-differentiation: 1. Disassembly of cell-cell contacts 2. loss of polarity (lose their shape)
5) invasion: 1. increased motility 2. cleavage ECM proteins

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4
Q

Describe the process of metastasis

A

Epithelial cells in primary tumours are tightly bound together

Metastatic tumour cells become mobile mesenchyme-type cells and enter the bloodstream.

Metastatic cells then travel through the blood stream to a new location in the body

Metastatic cells exit the circulation and invade a new organ

Cancer cells lose their mesenchymal characteristics and form a new tumour

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5
Q

What are the different types of tumour cell migration

A

1) Individual cells can migrate
2) Collective cell migration

Ameoboid - round structures (lymphoma, leukaemia)
Mesenchymal (single/chain cells) - (fibrosarcoma, anaplastic tumours)
Cluster/cohorts - epithelial cancer
Multicellular strands/sheets - epithelial cancer

All require cadherins and gap junctions integrins and proteases. Cadherins and gap junctions for the cluster and multicellular strands

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6
Q

Tumour cell metastasis mimic morphogenetic events

A

All invasive tumours have a leader cells push and degrade the ECM,

  • 2D sheets
  • vascular sprouting
  • border cells
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7
Q

Compare the expression profile of invasive cells and a primary tumour?

A

Invasive cells have upregulated of genes involved in:

  • cytoskeleton regulation
  • motility machinery
  • higher EGF receptors (makes sense because they move towards the GF)
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8
Q

What stimulus cause cell movement?

A
  • organogenesis
  • morphogenesis
  • GF/chemoattractants
  • dedifferentiation

Cell movement = changing cell shape

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9
Q

When do cells stops moving?

A

Contact-inhibition

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10
Q

Where do cells go?

A

Directionality (polarity) - they form a mesenchymal shape?

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11
Q

How do cells move?

A

Through specialised structures (focal adhesion, lamellae, filopodium)

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12
Q

What are the cells attached to?

A

Attachment to substratum (ECM proteins)

Focal adhesions
Filamentous actin attach to these FA so that they are anchored to move.

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13
Q

What structures are used for motility?

A

Filopodia - finger-like protrusions rich in actin filaments

  • Actin
  • Vinculin

Lamellipodia - sheet-like protrusions rich in actin filaments

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14
Q

Describe the control of cell movement

A

Control is needed:
- within a cell to coordinate what is happening in different parts
- regulate adhesion/release of cell-extracellular matrix receptors. This ensure they can move in one direction
- from outside to respond to external influences –
sensors
directionality (where to go)

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15
Q

Describe all the steps of motility (the way they move)?

A

Think about rock climbing

  • Form a FA
  • Extension: Laemellipodium (the cell moves forward feeling for a new FA) During this stage you get all the different actin filament processes - disassembly, nucleation, branching, severing, capping and bundling. Polymerisation
  • Adhesion: Form a new FA - attachment of ECM. Gel/sol transition also occurs.
  • Translocation: The cell body contracts and moves towards the new FA
  • De-adhesion: The old FA at the back is released.
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16
Q

Describe all the steps of motility (the way they move)?

A

Think about rock climbing

  • Form a FA
  • Laemellipodium
  • Form a new FA
  • The cell body contracts and moves towards the new FA
  • The old FA at the back is released.
17
Q

What are the main cytoskeletal structures that give shape to the cell?

A

Actin filaments: G-actin –> F-actin

The filaments have a polarity - plus and minus end.

If there is a signal such as a nutrient source the cell will dissemble filaments and reassembly the filaments at the new site moving the cell towards the signal. See slide 16 for diagram

18
Q

Describe the organisation of the filaments in lamellipodium and filapodium. Remodelling of actin filaments.

A

Slide 17-18

The cell can assemble a variety of structures

19
Q

What is nucleation?

A

This is a how a single monomer of actin becomes a filament. This requires energy.

Arp2 and 3 proteins form a complex where an actin monomer can bind forming a trimer. This is basis from which elongation can begin.

This favoured at the minus end of the filament. The plus end is where the monomers add onto.

20
Q

What is elongation?

A

Profilin helps elongation

Thyrmosin blocks elongation

21
Q

What is capping?

A

A capping protein will bind to the plus and minus end blocking elongation.

22
Q

What is severing?

A

The severing protein will destabilise the filaments and break it down.

After severing there are three options for the filament
- Barbed end capping
- annealing
Growth from pre-existing end

23
Q

What is cross-linking and bundling?

A

Bundles filaments togther
fascin, fimbrin and alpha-actinin all bundle the actin filaments together. They are connected parallel to each other.

Spectrin
filamin
dystrophin

24
Q

Cooperation of actin functions to organise filaments

A

slide 24

25
Q

What is the gel-sol transition by actin filament severing?

A

Gel (rigid) and sol (can flow)

The severing protein clips the filaments so it can flow.

26
Q

What is the gel-sol transition by actin filament severing?

A

Gel (rigid) and sol (can flow(

The severing protein clips the filaments so it can flow.

27
Q

What actin formations are required for the production of lamellae protrusion?

A

Polymerisation, disassembly, branching and capping.

This structure pulls the membrane forward.

See slides for diagrams

28
Q

What actin formations are required for the production of filopodia?

A

Actin polymerization, bundling and crosslinking.

See slides for diagrams

29
Q

See slide 31

A

31

30
Q

What mechanism regulates 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

31
Q

Participation of small GTPases on cell migration?

A

Extension: Rac modulates actin polymerization and branching

Adhesion: Rac and Rho modulates FA and assembly

Translocation: Rho controls the contraction of the cell

De-adhesions: Rho controls de-adhesion

Cdc42 - filopodia, polarized motility and actin polymerization.

Year 2: MCD (40 decks)

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