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Cancer > 7. External factors controlling division and behaviour of normal and cancerous cells > Flashcards

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

1
Q

What is the term ‘cell behaviour’ used to describe?

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 external influences do cells detect?

A 
Chemical influences
• hormones
• growth factors
• ion concentration
• ECM (density, composition)
• molecules on other cells
• nutrients
• dissolved gas concentrations

Physical influences
• mechanical stresses
• temperature
• topography of the ECM

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3
Q

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

A
  • Growth factors
  • Cell-cell adhesion
  • Cell-ECM adhesion
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4
Q

How does a cell change when it is moved from a suspension to a culture surface?

A
  • Spherical => spreads
  • Gains motility as it acquires a polarity (guided by lamellipodia and filopodia)
  • Energy required to modulate cell adhesion and the cytoskeleton during spreading (not gravity dependent)
  • When the culture is turned upside down, the cells will stills spread
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5
Q

What is blebbing and when can it happen?

A
  • Cell detaches its cytoskeleton from the membrane
  • Causes membrane to swell into spherical bubbles
  • Can happen if there is a cell on top of another, so it has no contact with the ECM substratum
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6
Q

What is necessary for a cell to be able to respond to growth factors (in terms of ECM)?

A
  • Cells have to be adhered to matrix in order to respond to external GFs => proliferation
  • Cell has to be able to fully spread out as well
  • ‘Anchorage dependence’
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7
Q

How does cell survival differ in suspension and attachment to ECM?

A
  • Suspension - do not significantly synthesise protein or DNA (no S phase)
  • ECM - combined with spreading, allows protein synthesis and proliferation to occur
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8
Q

How is the cell attached to the ECM?

A
  • Cells have receptors which bind specifically to ECM molecules
  • Linkage at cytoplasmic domains allows mechanical continuity between cell interior and ECM
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9
Q

Describe the results in a test where mammary epithelial cells were mixed with gels made up of 2 type of ECM?

A

Interstitial matrix (type 1 collagen)
• cells cluster together (loose and undifferentiated)
• hormones present in culture but no effect on the cells
• not secretory cells

Basal lamina matrix gel

  • cells form a spherical cyst (hollow ball)
  • these organoids switch on the production of milk proteins
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10
Q

Describe the structure of integrins

A

(one of the groups of cell-ECM adhesion complexes)
• Heterodimer complexes of alpha and beta subunits
• Associate extracellularly by their ‘head’ region
• Beta unit has a slightly longrr cytoplasmic tail
• Lingand-binding (to ECM) occurs at the junction of the ‘head’ regions
• Most are linked to the actin cytoskeleton via actin-binding proteins

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11
Q

What is the most important ECM receptor?

A

Integrin

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12
Q

How many different known combinations of integrin are there?

A
  • 20 combinations

* About 10 alpha chains and 8 beta chains known

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13
Q

What do integrins recognise?

A

• Each combination specifically binds a particular, short, peptide sequence within a matrix molecule
• Such peptide sequences can be found in more than one ECM molecule
e.g. a5b1 receptor binds to arg-gly-asp (RGD), found in fibronectin, vitronectin, fibrinogen etc.

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14
Q

Are integrins rigid or flexible?

A
  • Flexible
  • Can adopt different combinations (folded, intermediate or extended)
  • Important for its function
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15
Q

What is the only integrin that we know of that isn’t associated with the actin cytoskeleton?

A

a6b4 integrin complex found in epithelial hemidesmosomes, linked to the cytokeratin (intermediate filament) network

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16
Q

What types of clusters do integrins form and what are they involved in?

A
  • Focal adhesions (most)
  • Hemidesmosomes (a6b4)
  • Involved in signal transduction
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17
Q

Apart from epithelial cells, what other cells can integrins bind to (and via which protein)?

A
  • White blood cells - PECAM-1 (CD31)

* Endothelial cells in inflammation - ICAM-1

18
Q

What are focal adhesions?

A
  • Large, dynamic protein complexes through which the cytoskeleton of a cell connects to the ECM
  • Found at the ends of bundles of filamentous actin (microfilaments of the cytoskeleton)
19
Q

What is outside-in signalling?

A
  • Cell binds to the matrix via the integrin
  • Stimulates an intracellular signal
  • Cell can receive information about its surroundings from this
  • Composition of ECM determines which integrin complexes bind and which signals it receives
  • This can alter the phenotype of the cell
  • However, not all cells express the same integrins
20
Q

How do focal adhesions sense the mechanical properties of their surroundings, and how do molecules take advantage of different forces?

A

• Amount of force generated at focal adhesions depends on:
- the force generated by the cytoskeleton (F cell)
- stiffness of the ECM
• Some of the ECM can be coiled, and when it is stretched, it is exposed to allow other molecules to bind for specific function

21
Q

Do integrins have any enzymatic activity and how do they signal?

A

• No enzymatic activity
• Therefore, when integrins cluster, they recruit:
- signalling molecules
- molecules that associate with the actin cytoskeleton

22
Q

How do integrins change configuration when switched on and off?

A
  • On - extended

* Off - flexed/bent

23
Q

What is inside-out signalling and when is it used?

A

• Signal generated inside the cell (due to hormone binding to receptor)
• Affinity of integrin is altered - extended conformation
e.g. inflammation, blood clotting, adhesion of circulating leukocytes
• Allows cells to be able to stick when necessary e.g. over-adhesion of platelets could cause clots
(• Ligand binding can then cause a further change to the molecule)

24
Q

When normal tissues cells are plated in a culture dish, when do they stop proliferating and why??

A

Once the culture surface area is covered, forming a confluent monolayer
• Contact inhibition
• Competition for external growth factors

25
Q

How does density affect cell proliferation?

A
  • Cells can still divide at a high density
  • However, the higher the density, the lower the rate of proliferation
  • Cell-cell contact is not responsible … density-dependence is
26
Q

Describe the ERK MAP kinase cascade?

A

Cascade required for cyclin D expression
• GF binds to receptor tyrosine kinase
• Causes adaptor molecule to bind and recruit Ras protein
• Ras activates RAF
=> MEK
=> ERK
(various levels of MAP-kinases)
• These can influence gene expression and stimulate proliferation
• GF is not enough, as cells need to be bound to matrix

27
Q

Outline the mechanism of anchorage dependence coinciding with GF signals

A
  • Integrin signalling complexes and GF receptors can activate identical signalling pathways e.g. MAPK, in different ways
  • Individually, this is weak/transient
  • Together, activation is strong and sustained
  • The separate signalling pathways act synergistically
28
Q

ECM influence on the cell is associated with ‘anchorage dependence’, as GF influence is associated with…

A

Density dependence

29
Q

How does the time of contact interaction between cells have an affect?

A

Short-term
• transient interactions between cells => do not form stable cell-cell junctions
• when most cells collide, they actually repel one another by paralysing motility at the contact site
• this promotes the formation of a motile front at another site and movement in the opposite direction (contact inhibition of locomotion)
• responsible for preventing multi-layering of cells

Long term
• stable interactions resulting in formation of cell-cell junctions (adherens, desmosomes, tight, gap)
• true of epithelial cells forming layers, and neurones forming synapses

30
Q

What are the 2 ways cell-cell junctions are arranged?

A
  • Zonula - continuous belts

* Macula - discrete spots

31
Q

Give an example of when contact-induced spreading is used

A
  • Contact between epithelial cells leads to the mutual induction of spreading
  • Done so the total spread area of the contact cell is greater than the sum of the 2 separated cells
  • Results in a stable monolayer
32
Q

What are cell-cell junctions dependent on, and what happens if they don’t form?

A
  • Calcium needed for formation
  • If not, MAPK is activated
  • p27KIP1 is decreased
  • This leads to high proliferation
33
Q

What happens is calcium is added once MAPK is activated?

A
  • MAPK is deactivated
  • p27KIP1 is increased
  • Low proliferation
34
Q

What can you use to actively block adhesion?

A
  • Add adhesion blocking antibodies instead of calcium

* They would bind to the cell adhesion molecules

35
Q

What is cadherin and what is it associated with intracellularly?

A
  • Calcium-dependent, homophilic cell adhesion molecules

* Cytoplasmic tail is associated with beta-catenin, alpha-catenin and the actin cytoskeleton (in order)

36
Q

What is APC and how can it cause colon cancer?

A

• APC = adenomatous polyposis coli
- tumour suppressor gene
• It is a protein involved in the degradation of the junction-associated molecule: beta-catenin
• If mutated, it reduces the degradation of beta-catenin
• In the cytoplasm, it binds with LEF-1, enters the nucleus and alters cell proliferation
• If degradation is reduced, this leads to cell proliferation

37
Q

How can beta-catenin be important in a mechanism for contact inhibition?

A
  • When bound to cadherin at the membrane, beta-catenin is not available for LEF-1
  • Therefore, its nuclear effects of proliferation aren’t achieved
38
Q

What effect does the clustering of cadherins, after cell-cell contact, have on GTPases?

A

Alters their activation

e.g. Rac activation, Rho inhibition => proliferation influenced

39
Q

Under certain conditions, cells can lose their behavioural restraints. What does this involve?

A

• Uncontrollable proliferation
• Less adherent and will multiplayer (lose contact inhibition of locomotion and anchorage dependence)
- touch for prolonged periods of time
- promotes formation of solid tumours
• Epithelial breakdown cell-cell contacts
• Not Hayflick limited, express telomerase i.e. cancer

40
Q

If a mutant gene forms products that are constitutively active, what does this mean for upstream signals?

A
  • Pathway is always switched on
  • Upstream signals e.g. GFs and integrin complex signalling, is not needed
  • Density dependence and anchorage dependence is lost
  • Allows cell to proliferate without any limitations
41
Q

How does a primary carcinoma cell metastasise?

A
  • Cell-cell adhesion down-regulated
  • Cell must be motile
  • Degradation of ECM - matrix metalloproteinase (MMP) levels increase in order to migrate through basal lamina and interstitial ECM
  • Cells can break away and travel to other sites, to form a secondary tumour
42
Q

What can be used as an indicator of tumour differentiation, and how does this affect its likeliness to spread?

A
  • Degree of cell-cell adhesion
  • Indicates its invasiveness and prognosis
  • Less differentiated
  • More likely to spread

Cancer (15 decks)

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