External factors controlling division and behaviour of normal and cancerous cells Flashcards

1
Q

What is cell behaviour?

A

The way cells interact with their external environment and their reactions to this, particularly proliferative and motile responses of cells.

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2
Q

What 2 classes of external influences are detected by cells?

A

Chemical

Physical

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3
Q

What chemical external influences are detected by cells?

A
Hormones
Growth factors
Ion concentrations
ECM
Molecules on other cells
Nutrients
Dissolved gas concentrations
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4
Q

What physical external influences are detected by cells?

A

Mechanical stresses
Temperature
Topography or ‘layout’ of the ECM and other cells

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5
Q

What external factors can influence cell division (in relation to cancer cell behaviour)?

A

Growth factors
Cell-cell adhesion
Cell-ECM adhesion

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6
Q

What is required for cell spreading to occur?

A

Energy is required to modulate cell adhesion and the cytoskeleton during spreading.
Not a passive, gravity-dependent event.

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7
Q

Why do cells need to be attached to ECM?

A

To begin protein synthesis and proliferation (DNA synthesis).
To be fully competent for responding to soluble growth factors.
Attachment to ECM may be required for cell survival, i.e. anchorage dependence.

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8
Q

Why is cell spreading important?

A

A degree of spreading is required for cells to begin protein synthesis and proliferation.

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9
Q

What are cell-ECM adhesion molecules?

A

Cells have receptors on their surface which bind specifically to ECM molecules- often linked at cytoplasmic domains to the cytoskeleton. This arrangement means that there is mechanical continuity between ECM and the cell interior.

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10
Q

What are integrins?

A

Heterodimer complexes of alpha and beta subunits that associate extracellularly by their ‘head’ regions and each ‘tail’ region spans the plasma membrane.

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11
Q

What are the most important ECM receptors?

A

Integrins

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12
Q

How many combinations of alpha/beta subunits in integrins are known?

A

More than 20.

Each combination specifically binds a particular peptide sequence.

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13
Q

What do integrins do?

A

Recognise short, specific peptide sequences.

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14
Q

What are most integrins linked to, and by what?

A

Linked via actin-binding proteins to the actin cytoskeleton.

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15
Q

What do integrin complexes cluster to form?

A

Focal adhesions (most) or hemidesmosomes (avb3)

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16
Q

What are clusters of integrin complexes involved in?

A

Signal transduction

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17
Q

How may integrins act as cell-cell adhesion molecules?

A

Integrins can bind to specific adhesion molecules on some cells.

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18
Q

What is ‘outside-in’ integrin signalling?

A

ECM receptors (e.g. integrins) can act to transduce signals. ECM binding to an integrin complex can stimulate the complex to produce a signal inside the cell.
A cell can receive information about its surroundings from its adhesion to ECM.
Allows cytoplasmic signalling molecules to bind.

19
Q

What does the composition of ECM determine in ‘outside-in’ signalling?

A

Which integrin complexes bind
Which signals it receives
Can alter phenotype of cell.

20
Q

What does the amount of force generated at a focal adhesion depend on?

A

Force generated by the cytoskeleton (F cell)

Stiffness of ECM

21
Q

What do cytoplasmic proteins recruited by integrins promote?

A

Signalling

Actin assembly

22
Q

What is ‘inside-out’ integrin signalling?

A

A signal generated inside the cell (hormone binds to receptor) can act on an integrin complex to alter the affinity (e.g. for ECM binding) of an integrin.
Switches from low to high affinity.

23
Q

When may ‘inside-out’ integrin signalling occur?

A

Inflammation
Blood clotting
Switching on adhesion of circulating leukocytes.

24
Q

What happens when cells in culture form a confluent monolayer?

A

They stop proliferating and slow down other metabolic activities.

25
Q

What is contact inhibition/ density-dependence of cell division?

A

At high density, cells compete for growth factors.
When a confluent monolayer forms, cells stop proliferating and other metabolism slows down.
Competition for external growth factors, not cell-cell contact, responsible.

26
Q

What is the mechanism of anchorage dependence?

A

Growth factor receptors and integrin signalling complexes can each activate identical signalling pathways (e.g. MAPK).
Individually, this action is weak and/or transient.
Together, activation is strong and sustained.
Separate signalling pathways act synergistically.

27
Q

What are short-term contact interactions between cells?

A

Transient interactions between cells which do not form stable cell-cell junctions.

28
Q

What are long-term contact interactions between cells?

A

Stable interactions resulting in formation of cell-cell junctions.

29
Q

What is contact inhibition of locomotion?

A

Cells making contact repel one another to prevent multilayering.

30
Q

How do non-epithelial cells repel one another when they collide?

A

Paralyse motility at the contact site, promoting the formation of a motile front at another site on the cell, and moving off in the opposite direction.

31
Q

What is contact inhibition of locomotion responsible for?

A

Preventing multilayering of cells in culture and in vivo.

32
Q

What types of cell-cell junctions exist in epithelia?

A
Continuous belts (zonula) 
Discrete spots (macula)
33
Q

What is contact-induced spreading of epithelial cells?

A

Contact between epithelial cells leads to the mutual induction of spreading, so that the total spread area of contacted cells is greater than that of the sum of the 2 separated cells.
This could result in a stable monolayer.

34
Q

What is the mechanism for contact inhibition of proliferation?

A

When bound to cadherin at the membrane, beta-catenin not available for LEF-1 binding and nuclear effects.
Normally, cytoplasmic beta-catenin rapidly degraded.
If beta-catenin cytoplasmic levels rise due to inhibition of degradation or loss of cadherin-mediated adhesion, beta-catenin/LEF-1 complex enters nucleus and influences gene expression, leading to proliferation.

35
Q

What may reduce the capacity of growth factor receptors to promote proliferation?

A

Association with cell-cell junctions.

36
Q

What happens if a cell accidentally gets stuck on top of another cell?

A

Top cell blebs as it has no contact with the ECM substratum- unable to spread.
Bottom cell begins to spread, and has less blebbing.

37
Q

Which integrin complex is not linked to the actin cytoskeleton?

A

a6b4, found in hemidesmosomes, linked to the cytokeratin (intermediate filament) network.

38
Q

What is the role of beta-catenin?

A

Links cell junction molecule to actin cytoskeleton
Acts as signalling molecule
Can alter cell proliferation

39
Q

What happens when cells lose their ‘social skills’ (behavioural restraints)?

A

Proliferate uncontrollably (lose density dependence of proliferation).
Are less adherent and will multilayer (lose contact inhibition of locomotion and anchorage dependence).
Epithelia breakdown cell-cell contacts.
Not Hayflick limited, express telomerase.
CANCER.

40
Q

Other than promoting the formation of solid tumours, what is an important consequence of loss of contact inhibition of locomotion for the progression of cancer?

A

Metastasis (spread through different tissue layers).

41
Q

Give examples of proto-oncogene types.

A
Receptors
Signalling intermediates
Signalling targets (e.g. transcription factors)
42
Q

How does a primary carcinoma cell metastasise?

A

Cell-cell adhesion down-regulated (e.g. cadherin levels reduced).
Cells are motile.
Degradation of ECM.
Matrix metalloproteinases increased to migrate through basal lamina and interstitial ECM.

43
Q

What does the degree of carcinoma cell-cell adhesion indicate?

A

How differentiated the primary tumour is.
Its invasiveness.
Prognosis.