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eMCD - Can > Cancer 7: External factors controlling division and behavior > Flashcards

Cancer 7: External factors controlling division and behavior Flashcards

1
Q

Define 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 are some EXTERNAL chemical influence detected by cells ?

A

Chemical:- hormones, growth factors, ion concs, ECM, molecules on other cells, nutrients and dissolved gas (O2/CO2) concs.

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3
Q

What are some EXTERNAL physical influence detected by cells ?

A

Physical:- mechanical stresses, temperature, the topography or “layout” of the ECM and other cells

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4
Q

What are 3 Important (regarding cancer cells) external factors influencing cell division?

A
  • GFs
  • cell-cell adhesion
  • cell-ECM adhesion
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5
Q

What is Cell spreading needed for?

A
  • Cell spreading needed for cell survival + growth, otherwise cell in single spot dies by apoptosis
  • -> provides polarity + motility
  • -> cell can spread, survive + grows

–>cell front = lamellipod

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6
Q

Why do cancer cells need to be attached to ECM?

A
  • In suspension (no spread), cells don’t significantly synthesise protein/DNA
  • Cells must be attached to ECM to begin protein synthesis + proliferation (DNA synthesis)

– ECM attachment may be needed for cell survival
(Anchorage dependence)

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7
Q

give an example showing how phenotype of cell = depends on environment

A

phenotype of cell = depends on environment

e.g Cultured Mammary Epithelium

A) in interstitial matrix (type 1 collagen), mammary epithelium does not differentiate to secretory cells;

(B) in basal lamina (basement membrane) matrix, mammary cells organise into “organoids” and produce milk proteins.

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8
Q

A cell can receive information about its surroundings from its adhesion to ECM

How do they do that?

A

Cells have receptors on their cell surface which bind specifically to ECM molecules

these molecule = often linked, to their cytoplasmic domains, to the cytoskeleton

this arrangement means that there is mechanical continuity between ECM and the cell interior

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9
Q

What are integrins ?

A

integrin = heterodimer complexes of a and b subunits that associate extracellularly by their “head” regions (ligand binding occurs here)

the “leg” region –> spans the plasma memb
–> relatively short cytosolic domains

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10
Q

What is the significance of integrins?

A

integrins –> Recognise short, specific peptide sequences

  • Integrin complexes cluster to form focal adhesions (mostly) or hemidesmosomes (in a6b4)

–> These clusters = involved in signal transduction

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11
Q
  • Most integrins linked to _____________ (via actin-binding proteins)
A
  • Most integrins linked to actin cytoskeleton (via actin-binding proteins)
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12
Q 
note:
ECM receptors (e.g. integrins) can act to transduce signals
A

-

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13
Q

How can cell-ECM adhesion, and signals, can be switched on and off?

A
  • Integrin complexes can adopt “flexed” OR “extended” molecular confirmations.

Switching between these confirmations affects their ability to bind their ligands, and their signalling

–> allows it to be switched on/off

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14
Q

How can a Cell receive environmental information from its adhesion to ECM?

A

o E.g. composition of ECM determines which integrin complexes bind + which signals it receives –> this can alter cell phenotype

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15
Q

The amount of force that is generated at a focal adhesion depends on what 2 things?

A
  • force generated by the cytoskeleton (F cell)

- stiffness of the ECM

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16
Q

Upon binding certain ECM molecules, what happens to the integrins?

A
  • causes opening of legs of integrin –> exposes binding sites for recruitment of cytoplasmic signalling molecules

integrin recruits cytoplasmic proteins + form clusters –> which in turn recruits actin cytoskeleton + signalling molecules (e.g FAK) –> which promotes signalling + actin assembly/interaction

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17
Q

describe the concept of Inside-Out Integrin Signalling:

A

Inside-Out Integrin Signalling:

  • Signal generated intracellularly (e.g. due to hormone binding to receptor) can act on an integrin complex to alter affinity (for ECM binding) of the integrin

o E.g. in inflammation or clotting, switching on adhesion of circulating leukocytes

-

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18
Q

bent confirmation of integrin = low/high affinity

extended confirmation of integrin = low/high affinity

a) what causes this switch in conformation

A

bent confirmation of intern = low affinity

extended confirmation of intern = high affinity
–> allows cytoplasmic signalling molecules to bind

a) signals from inside the cell –> promotes switch in conformation

19
Q

what is meant by density dependence of cell division

A

When cells in culture form a confluent monolayer, they cease proliferating and slow down many other metabolic activities –> competition for external growth factors and not cell-cell contact responsible:-

aka Density-dependence of cell division.

higher cell density = less cell proliferation

20
Q

ERK MAP Kinase cascade:

A

GF binding to receptor tyrosine kinase –>causes phosphorylation which recruits RAS –> initiates cascade –> causes MAPK activation –> acts on nucleus –> cause proliferation

21
Q

What are the 2 signals needed for efficient stimulation of proliferation of tissue cells?

A

signals from:

1) Growth factor (density dependence)
2) ECM (anchorage dependence)

22
Q

Describe the mechanism of anchorage dependence.

A

o GF receptors + integrin signalling complexes both activate identical signalling pathways (e.g. MAPK)

o Individually –> activation weak and/or transient

o Together –> activation strong + sustained

o The separate signalling pathways –> act synergistically –> to stimulate proliferation

23
Q

in terms of contact interaction btw cells, what is meant by :

a) Short term
b) Long term

A

short-term: transient interactions between cells which do not form stable cell-cell junctions

long term: stable interactions resulting in formation of cell-cell junctions

24
Q

What is the significance of contact inhibition of locomotion?

A
  • it is responsible for preventing multilayering of cells in culture and in vivo.
    i. e Cells making contact-repel one another to prevent multilayering.
25
Q

give examples of long term cell-cell contacts

A

E.g. adherens junctions, desmosomes, tight + gap junctions (tissues 1)
–> Arranged as continuous belts (zonulae) or discrete spots (maculae)

  • E.g. in epithelial + endothelial cells –> form layers
    and neurones –> form synapses
26
Q

describe what happens in contact induced spreading of epithelial cells

A

Contact btw epithelial cells –> causes mutual induction of
spreading,

so that total spread area of the contacted cells =
greater than sum of the two separated cells.

–> This could result in a stable monolayer.

27
Q

What is the effect of cell-cell adhesion on cell proliferation with:

a) increased Ca2+
b) reduced adhesion blocking antibody
c) reduced Ca2+
d) increased adhesion blocking antibody

A

increased Ca2+ / reduced adhesion blocking antibody:

formation of cell-cell junction –> MAPK activity is reduced –> there is increase in Increased P27KIP1 (inhibits proliferation)
–> low proliferation

reduce Ca2+ / increased adhesion blocking antibody :

increased cell-cell junction
–> increase in MAPK activity –> decrease in P27KIP1 –> high proliferation

28
Q

Describe te molecular organisation of adherents junctions .

A
  • Involve cadherin
  • -> binds to identical molecule
  • -> Ca2+ dependent
  • Cytoplasmic tail = associated with beta-Catenin, alpha-catenin + actin
29
Q

Adenomatous polyposis coli (APC)

A

genetic disorder where colon massively produces too much tissue –> thousands of polyps

  • APC gene product = protein that causes –> degradation of B catenin (molecule involved in cell-cell junction)
30
Q

What happens in the

a) absence of APC
b) presence of APC

on B-Catenin

A

APC absent –> no rapid degradation of B catenin
–> binds to LEF-1 –> complex enters the nucleus –> increases gene expression –> to cause cell proliferation

APC present –> B catenin –> rapidly degraded

when bound to cadherin at the membrane –>
b-catenin = not available for LEF-1 binding and nuclear effects

31
Q

What other adhesion-associated signalling pathways can influence contact-induced inhibition of proliferation?

A
  • Clustering of cadherins after cell-cell contact alters activation of small GTPases

o e.g. Rac activated, Rho inhibited: affects proliferation.

  • Some GF receptors associated with cell-cell junctions –> reduces capacity to promote proliferation.
32
Q

What happens when cells lose their behavior restraints? (e.g due to cancer)

A

Cells:

  • proliferate uncontrollably (lose density dependence of proliferation)
  • less adherent and will multilayer (lose contact inhibition of locomotion and anchorage dependence)
  • epithelia breakdown cell-cell contacts
  • Not Hayflick limited, express telomerase –> unlimited number of divisions
33
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

helps in invasion properties of cancer cells

34
Q

Note:
Many components of signal trannduction = proto-oncogenes:

e.g. receptors, signalling intermediates + targets (e.g. transcription factors)

A

-

35
Q

Define oncogene

A

Oncogene:

mutant gene which promotes uncontrolled cell proliferation

36
Q

Define Proto-oncogene

A

Proto-oncogene:

normal cellular gene corresponding to the oncogene

–> Ras = common proto-oncogene that commonly mutates –> to cause cancer

37
Q

How does a primary carcinoma cell metastasise?

A
  • cell-cell adhesion must be down-regulated (e.g. cadherin levels reduced)

o Less differentiated –> more likely to spread

  • Cells need to be motile
- ECM degradation must occur
MEtrix metaloproteinase (MMP) levels increased to migrate through basement membrane + interstitial ECM
38
Q

o Degree of carcinoma cell-cell adhesion = indicator of:

A

o Degree of carcinoma cell-cell adhesion = indicator of:

  • how differentiated primary tumour is,
  • its invasiveness,
  • prognosis
39
Q

What difference might you observe in a cell in contract / no contact w the ECM?

A

no contact with ECM = blebbing

contact with ECM = less blebbing

40
Q

how would cells in

a) agar
b) small adhesive patch
c) large adhesive patch

differ in proliferation
in terms of cell spreading?

d) what does this experiment show?

A

Cells in agar –> low probability of entering S phase (cant proliferate)

Cells on small adhesive patch –> some degree of proliferation

Cells on large adhesive patch –> that could fully spread –> almost all enters S phase (can proliferate a lot )

d) what does this experiment show?
- shows that cells need to be bound to ECM to be fully competent for responding to soluble GFs

41
Q

What is the RGD Motif?

A

peptide sequence

a5b1 fibronectin receptor binds arg-gly-asp

42
Q

What is outside-in signalling?

A

outside-in signalling = cell binds to matrix –> generates signal within the cell

–> so composition of matrix determines with integrin complex bind + which signals it receives

–> this is one of the ways the matrix can influences / alters the phenotype of the cell

43
Q

What is inside out signalling?

A
  • signals from inside the cell –> can act on integrin complex to change its confirmation –> increase activity

–> important in inflammation / blood clotting /switching on adhesion of circulating leucocytes (as in blood clotting)

44
Q

Note: uncontrolled proliferation of tissues cells (cancer cells) –> doesn’t require GF or anchorage in order to proliferate

A

-

eMCD - Can (15 decks)

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