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Invasion- Regulation of Cell Migration Flashcards

1
Q

what are the 5 stages of tumour progression?

A 
o Homeostasis.
o Genetic alterations.
o Hyper-proliferation.
o De-differentiation
o Invasion (benign become malignant)
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2
Q

what happens generally in de-differentiation?

A

Disassembly of cell-cell contacts.

Loss of cell polarity.

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3
Q

what happens generally in invasion?

A

 Increased motility.

 Cleavage of ECM proteins.

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4
Q

what are the two types of cell migration?

A

 Individual cell migration

 Collective cell migration

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5
Q

name examples of cells that migrate as individual cells

A 
o Amoeboid – e.g. lymphomas.
o Mesenchymal (single) – e.g. Fibrosarcoma.
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6
Q

what are the types of collectives

name example of cells that migrate as collective cells

A 
o Mesenchymal (chains)
 e.g. Fibrosarcoma

o Cluster/cohorts –
e.g. Epithelial cancers.

o Multicellular strands/sheets –
e.g. Epithelial cancers.

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7
Q

why does collective cell migration still have some cell-cell junctions present?

A

 Collective cell migration requires more coordination to metastasise and so still has some cell-cell junctions

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8
Q

which type of cell migration has a higher malignancy potential?

A

collective migration compared to the same number of individual cells

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9
Q

what does tumour cell metastasis, i.e. migration, mimic?

A

normal morphogenic events like branching morphogenesis in the mammary glands or migration of primary glial cells to repair a scratch wound or vascular sprouting

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10
Q

what does tumour cell metastasis compare to normal cell migration?

A

no clear migration front (unorganised and rapid) and no sense of direction

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11
Q

what genes does EGF have an regulatory effect on?

A

o Cytoskeleton regulation.
o Motility machinery.

these induce migration

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12
Q

what are the normal stimuli for migration for a cell?

A

o Organogenesis and morphogenesis
o Wounding
o Growth factor/Chemoattractants
o De-differentiation.

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13
Q

how is direction of travel of the cell determined?

A

through polarity

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14
Q

how is termination of migration determined?

A

contact-inhibition when neighbouring cells are recognised and no space is left

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15
Q

how is migration of the cell facilitated?

A

using specialised structures:

  • focal adhesions
  • lamellae
  • filopodium
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16
Q

what must the cell attach to, to carry out migration?

A

attach to the ECM via integrins

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17
Q

what are filopodia?

A

finger-like projections rich in actin filaments.

A bundle of parallel filaments.

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18
Q

what are lamellipodia?

A

sheet-like protrusions rich in actin filaments.

Branched and crosslinked filaments.

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19
Q

what is the purpose of controlling the process of motility?

A

o Coordinate happenings inside the cell itself.
o Regulate adhesion/release of cell-ECM.
o To respond to external influences.

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20
Q

what are the two types of motility?

A

haptotaxis and chemotaxis

Haptotaxis: directional motility or outgrowth of cells

Chemotaxis: gradient developed in soluble fluid

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21
Q

what are the 4 steps of cell migration?

A

1) extension
2) adhesion
3) translocation
4) de-adhesion

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22
Q

what happens in extension?

A

focal adhesions exist

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23
Q

what happens in adhesion?

A

lamellipodium formed and new focal adhesions are created

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24
Q

what happens in translocation?

A

the cell contracts via actin filaments and moves in a direction

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25
what happens in de-adhesion?
old focal adhesions are broken behind
26
what enables contraction of the cell?
the polymerisation of actin filaments
27
how does actin polymerisation help maintain a motion in the cell?
 Contraction of Filopodia and Lamellipodia can break old adhesions, allowing the cell to maintain a motion.
28
what is required to allow assembly and disassembly of actin filaments and therefore movement?
A signal to move could be a nutrient source Filaments can rapidly disassemble and then reassemble at a new site to move the cell towards this source
29
how is actin capable of carrying out different functions?
Actin filaments have a polarity- a plus and minus end- on which different proteins can bind. Depending on the proteins that bind, the actin filaments can carry out different functions.
30
from what is actin polymerised?
G-actin (small soluble subunits) into F-actin (large filamentous polymer) there is interconversion between the two so disassembly and assembly happens to travel in the necessary direction F-actin enables motility
31
what are the 3 ways in which actin filaments can organise themselves in order to enable motility?
- filopodia (parellel filaments) - lamellipodia (branched and cross linked filaments) - stress fibres (antiparallel, contractile structures)
32
what are the 7 steps of actin remodelling?
``` 1- nucleation 2- elongation 3- capping 4- severing 5- cross linking and bundling 6- branching 7- gel-sol transition ```
33
what is the significance of the nucleation step in remodelling?
it is the limiting step in actin dynamics
34
what occurs in nucleation?
Attachment of the actin to the cell inner membrane. | ARP proteins form a complex and bind to actin monomers to create a nucleated actin filament
35
what end of actin does ARP bind?
minus end
36
what are the 3 monomers required in nucleation?
actin Arp2 Arp3
37
what happens in elongation?
Profilin facilitates actin monomer binding to the actin filament
38
what reduces actin binding in elongation? how does it carry out its regulatory role?
Thymosin: reduces actin monomer binding by sequestering the free monomers so they are not available to bind to the actin filament. Profilin competes with thymosiin to bind to actin monomers
39
what is capping?
addition of a capping molecule (to + or – end) to limit elongation.
40
name some + end caps
Cap Z Gelsolin Fragmin/Severin
41
name some - end caps
Tropomodulin | Arp complex.
42
what is severing?
breaking up actin filaments (depolymerisation)
43
what is the effect of severing and not severing?
Unsevered actin filaments grow/shrink slowly. | Severed populations grow/shrink more rapidly.
44
what proteins are involved in severing?
gelsolin ADF/cofilin fragmin/severin.
45
what happens in cross-linking and bundling?
produces differing arrangements of actin filaments filaments can bundle or buckle and cause contraction
46
what are the proteins involved in cross-linking and bundling?
```  alpha-actinin.  Fimbrin.  Filamin.  Spectrin.  Villin.  Vinculin. ```
47
what is branching?
Arp complex enables branches off actin to come off at 70 degrees
48
what protein is involved in branching?
Arp complex
49
what are gel and sol branches? what are their differences?
Gels are rigid and have NOT been severed. Sols are not rigid (i.e. can flow) and HAVE been severed. actin is severed
50
where does filament remodelling happen during cell locomotion?
at focal adhesions which are the points of driving force for movement
51
what stage of migration does gel-sol transition occur?
in adhesion
52
what happens to monomers produced in disassembly in de-adhesion?
monomers are recycled back to the leading edge for assembly
53
what are the stage of filopodia action?
initiation- filaments start to be created protrusion- filament creation, elongation and bundling retraction- capping and disassembly
54
what are the 4 signalling mechanisms that regulate the cytoskeleton
1. Ion-flux changes – i.e. intracellular calcium. 2. Phosphoinositide signalling – i.e. phospholipid binding. 3. Kinases/phosphatases – i.e. phosphorylation of cytoskeletal proteins. 4. Signalling cascades via small GTPases. first 3 very similar to cell cycle regulation
55
what are the small GTPases involved in signalling cascades?
Rho, Rac, Cdc42 sub-families these affect proteins that eventually affect actin polymerisation belong to the Ras super family
56
what is Cdc42 involved in?
Filopodia production.
57
what is Rac involved in?
Lamellipodia production.
58
what is Rho involved in?
stress fibre production.
59
how is Rho activated?
when it is in a GTP bound state from a GDP bound state A phosphate is provided by GTP
60
which step of migration does Rac affect?
extension where lamellipodia are produced also adhesion
61
which step of migration does Rho affect?
stress fibres: adhesion and translocation where stress fibres are produced and tension is created for contraction of the cell also affects de-adhesion where old focal adhesions are broken
62
which GTPase affects extension?
Rac
63
which GTPase affects adhesion
Rac and Rho
64
which GTPase affects translocation?
Rho
65
which GTPase affects de-adhesion?
Rho
66
what effect does Cdc42 have?
on filopodia caused polarity and therefore actin polymerisation gives the cell direction involved in listeria motility
67
where is listeria found?
contaminated food and soil
68
what effect can listeria have on the pregnant?
In pregnant women, it can lead to infection and problems for the foetus including miscarriage. In the placenta, the lining of the maternal blood space is the syncytiotrophoblast where there are no clefts between the cells so the only way the listeria enters to the foetus is through the cytoplasm.
69
what protein does listeria depend on for motility?
ActA | 4 proline-rich repeat flanked by the same amino-acids seen in human zyxin
70
how does listeria gain motility in humans?
- ActA binds to VASP (only found in humans) - VASP binds to profilin and Arp complex - ActA binds to vinculin (cytoskeletal protein) mediating the attachment to the plasma membrane actin polymerisation then becomes the driving force for motility
71
what stabilises the filament in nucleation?
capping protein or Arp complex caps prevent further polymerisation
72
where do actin monomers add to the filament in elongation?
at the pointed end or barbed end (either end of the filament)
73
how can binding of monomers to either end of the filament differ?
Equilibrium differs for the 2 ends per whether actin binds ADP (favours loss) or ATP (favours addition). ATP hydrolysis to ADP within the filament. ATP more preferred ADP less preferred
74
what protein reduces free monomers polymerising?
beta-thymosin
75
how does profilin enhance monomers becoming filaments?
profilin enhances the normal rate of ADP replacement with ATP ATP is bound preferably and promotes polymerisation
76
which cross-linking proteins bind filaments together? - at angles - parallel
- angles (70 deg) by filamin | - parallel by alpha actinin
77
where do actin monomers bind to on listeria?
VASP on ActA
78
what protein ensure the comet tail of listeria is functional?
alpha actinin | maintains the structure of the comet tail and its polarised direction
79
how does listeria gain motility by infection?
ActA--> VASP on top--> actin binding : - Listeria enters the cell by binding to growth factor receptors with Lnlb - activation of many pathways including one that upregulates VASP production via CDC42 - Bacterial ActA recruits the human VASP upon phagocytosis and escape from a vacuole. - VASP aids binding of profilin and the Arp2/3 complex to the bacterial ActA. - Actin is bound onto the VASP and the comet trail begins to elongate. nb Cdc42 in filopodia nb profilin promotes polymerisation
80
what drug affects listeria's motility and how?
Cytochalasin - stabilises monomeric actin - interaction with PI-3k pathway prevents actin polymerisation - bacterium loses mobility

MCD Cancer (17 decks)

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