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Y2 Cancer > Invasion - Regulation of Cell Migration > Flashcards

Invasion - Regulation of Cell Migration Flashcards

1
Q

What is the sequence of steps that lead to tumour formation and spread

A
  1. Homeostasis
  2. Genetic Alterations
  3. Hyper-proliferation
  4. De-differentiation
  5. Invasion
  6. Metastasis
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2
Q

Describe the epithelial tissue in the homeostasis stage of tumour progression

A

In homeostatic epithelial tissue there is a layer of cells tightly attached to each other lying on a basement membrane
Beneath is a stroma consisting of blood vessels and supportive tissues

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3
Q

What is the consequence of genetic alterations in tumour progression

A

If there are a cumulation of genetic alterations, there may be hyperproliferation of some cells – this leads to the formation of a benign tumour

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4
Q

Explain the de-differentiation stage of tumour progression

A

Progression from a benign to malignant tumour involves the cells de-differentiating (losing their identity and function as epithelial cells)

disassembling cell-cell contacts
losing polarity

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5
Q

Explain the invasion stage of tumour progression

A

Malignant cells invade the basement membrane, requires:
Cleavage of ECM proteins
Increase motility

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6
Q

Describe metastatic cells under the microscope

A

Cell migrate much faster
No attachment to neighbours
Movement in every direction, over each other
Do not stop by contact inhibition

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7
Q

Describe the sequential events of metastasis

A
  1. Epithelial cells in primary tumours are tightly bound together
  2. Metastatic tumour cells become mobile mesenchyme-type cells and enter the bloodstream
  3. Metastatic blood cells then 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 and form a new tumour
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8
Q

How are tumour cells profiled

A

Tumour cells are inoculated in a mouse, and they form a primary tumour. Growth factors can then be used to stimulate cell migration

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9
Q

How is the extraction of both the primary tumour cells, and the more invasive cells compared with regards to their expression profile ≈

A

By measuring mRNA levels

It is found that there is upregulation of genes involved

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10
Q

Which genes are upregulated in comparison of expression profile of invasive cells vs primary tumours

A

Cytoskeleton regulation

Motility machinery

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11
Q

What are the stimuli for cell movement

A

organogenesis and morphogenesis
Wounding
Growth factors/chemoattractants
Dedifferentiation (tumours)

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12
Q

What are the factors involved in regulation of cell movement

A

Direction (polarity)
Contact-inhibition motility
Specialised structure formation (focal adhesion, lamellae, filopodium)

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13
Q

What are focal adhesions

A

Focal adhesions are the sites at which the cell attaches to proteins which make the ECM

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14
Q

Explain how ECM proteins cause cell attachment to the substratum

A

Filamentous actin lies beneath the membrane, and hooks the focal adhesions to the
cytoskeletons via integrins
On the intracellular side, integrins interact with various cytoskeletal proteins to form a plaque

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15
Q

What are filopodia and what do they do

A

Finger-like protrusions rich in actin

Protrude from the cell to sense where they want to attach, and direction of movement

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16
Q

Which structures in actin filaments attach to the substratum and what is the name given to them when they move back

A

Lamellipodia

Ruffles

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17
Q

What is vinuncilin

A

Proteins that overlie the protrutions of filopodia

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18
Q

Control is needed:

A

Within a cell to coordinate what is happening in different parts
To regulate adhesion/release of cell-ECM receptors
From outside to respond to external influences

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19
Q

What are the 2 types of cell motility

A

Hapoptatic motility - movement with no direction

Chemotactic movement - movement in which the cell senses a stimulus and goes towards it

Both involve changes in cell shape

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20
Q

How do cells regulate their shape changes

A

Regulation of actin cytoskeleton

  1. Signal (e.g. nutrient source) at one end
  2. F-actin at the other end disassembles
  3. Subunits diffuse to the signal side
  4. Reassembly of the subunits at the new site
  5. Movement facilitation
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21
Q

What structure can actin be found as in the cytoskeleton

A

Can be found as small soluble globular monomers (G-actin)
Or
in a large polymerized filamentous polymer (F-actin)

22
Q

How does actin facilitate movement

A
  1. Signal (e.g. nutrient source) at one end
  2. F-actin at the other end disassembles
  3. Subunits diffuse to the signal side
  4. Reassembly of the subunits at the new site
  5. Movement facilitation
23
Q

Describe the actin filament arrangement in the cell cortex

A

random gel-like arrangement to provide support to the plasma membrane

24
Q

Describe the actin filament arrangement in the stress fibres

A

anti-parallel arrangement, forming contractile bundles

25
Q

Describe the actin filament arrangement in the filopodium

A

tight parallel bundles

26
Q

What is remodelling of actin filaments driven by and what does actin dynamics refer to

A

Different actin binding proteins

The cycle between G-actin monomers

27
Q

Describe the G-actin monomers in solution and what is the solution to the problem it poses

A

Polymerises very quickly, because the lowest energetic state is as a filament (but you can’t just have loads of filaments in the cell)
The solution to this is to have sequestering proteins, which store the G-actin monomers until they are required.

28
Q

What are capping and severing proteins

A

Stop signals which prevent further growth.

Severing proteins act like scissors, and various proteins regulate how the filaments are arranged

29
Q

Draw a diagram that illustrates the remodelling of actin filaments

A

(refer to notes)

30
Q

What is nucleation in actin filament remodelling

A

Rate limiting step in actin dynamics

Formation of trimers to initate polymerisation

31
Q

Explain what occurs in nucleation during actin filament remodelling

A

Arp 2 + 3 (actin-related proteins) are similar to actin, and form a complex on which trimers of actin can attach (on the minus end)
Elongation of the filament can then occur from the Arp2/3 complex

32
Q

Explain what occurs in the elongation stage of actin filament remodelling

A

Profilin binds to the monomers and helps to elongate the filament.
Thymosin is a sequestering protein which prevents polymerisation.
There is a balance between these two proteins to regulate filament growth, as
profilin competes with thymosin for binding to actin monomers and promote
assembly.

33
Q

Explain what occurs in the branching stage of actin filament remodelling

A

branched filaments form a precise 70 degree angle.
Arp complex binds to the
ide of the filament, providing nucleation at a different site

34
Q

What do capping proteins do

A

Prevents further growth of the filament

Can be used to regulate directionality of growth

35
Q

Which proteins are in the plus end of capping proteins

A

Cap Z
Gelsolin
Fragmin
Severin

36
Q

Which proteins are in the minus end of capping proteins

A

Tropomodulin

Arp complex

37
Q

What are the two types of cross-linking and bundling

A
  1. Actin filaments and alpha-actinin, which forms a contractile bundle, which a loose packing allowing myosin-II to enter the bundle
  2. Actin filaments and fimbrin, which forms parallel bundling with tight packing
38
Q

What is the role of severing during action filament remodelling

A

Prevents low rate of growth/shrinking of very long filaments

39
Q

Give examples of severing proteins

A

Gelsolin
AF/Cofilin
Fragmin/severin

40
Q

What do membrane connections allow the cell to do

A

Sense surfaces and suitable environments for protrusions

41
Q

What do membrane connections involve

A

Transmembrane protein, and a intracellular plaque which is attached to the cytoskeleton
Connections are then mediated by cell-cell and cell-ECM receptors

42
Q

Give examples of proteins that membrane connections involve

A 
Talin
Alpha-catenin
Spectrin
Ezrin
All of these proteins are perturbed (Changed, or truncated) in cancer
43
Q

Which actin activities occur in cell movement

A 
Disassembly
Nucleation
Branching
Severing
Capping
Bundling
44
Q

Give an example of participation of action in cell movement and what actin activities does it involve

A

Lamellae protrusion

Involves polymerisation, disassembly, branching and capping.

45
Q

What are the signalling mechanisms that regulate the actin cytoskeleton

A

Ion flux changes (i.e. intracellular calcium)

Phosphoinositide signalling (phospholipid binding)

Kinases/phosphatases (phosphorylation cytoskeletal proteins)

Signalling cascades via small GTPases

46
Q

Explain how ion flux changes regulate the actin cytoskeleton

A

Gelsolin severing is Ca2+ dependent, as this exposes the fast depolymerising end

Alpha-actinin crosslinks actin filaments, and this is decreased in high Ca2+ levels

47
Q

Explain how signalling cascades via small GTPases regulates the actin cytoskeleton

A 
Uses Rho (subfamily from Ras) to participate in cytoskeletal processes
Activated by receptor tyrosine kinase, adhesion receptors and signal transduction pathways
48
Q

What are filopodia, lamellae and stress fibres activated by

A

Filopodia - Cdc42
Lamellae - Rac
Stress fibres - Rho

49
Q

What do the G-proteins )GTP-ases) of the Ras super family cdc42, Rac, and Rho activate

A

Filopodia - Cdc42
Lamellae - Rac
Stress fibres - Rho

50
Q

What occurs during protrusion in lamellar protrusion

A

Net filament assembly at the leading edge, and net filament disassembly behind the leading edge.

51
Q

What do filopodia involve

A

Polymerisation / growth
Bundling
Fimbrin cross-linking

Y2 Cancer (16 decks)

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