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MCD Cancer > External Factors controlling Division and Behaviour of Normal and Cancerous cells > Flashcards

External Factors controlling Division and Behaviour of Normal and Cancerous cells Flashcards

1
Q

what does cell behaviour mean?

A

describes the way in which cells interact with their external environment and their reactions to this, particularly to proliferative and motile responses of the cell.

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2
Q

what are the 2 types for external influences on a cell?

A

o Chemical – i.e. hormones or growth factor.

o Physical – i.e. mechanical stress or temperature.

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3
Q

what are the main external influences on a cell in terms of proliferative effects?

A

growth factors
cell-cell adhesion
cell-ECM adhesion.

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4
Q

what will a normal cell do on a culture surface (representative of ECM)?

A

spread on a culture surface
acquire motility and polarity
will have direction

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5
Q

when will a cell have a greater chance of spreading?

A

when it is spread over in the area of adhesion

more likley to enter S phase and proliferate

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6
Q

what may happen to the cell if it doesn’t bind to enough ECM?

A

may apoptose

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7
Q

what happens when the cell is not attached to the ECM i.e. suspended?

what does this show?

A

does not significantly synthesis DNA or protein

the binding of the ECM and spreading is essential in order to be able to respond to the Growth Factor

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8
Q

what is the concept of the cell requiring the ECM for survival called?

A

Anchorage Dependency

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9
Q

what enables the interaction between cell and ECM?

A

Cells have receptors on their surface for ECM molecules
These receptors link to the cell’s cytoplasm and therefore give it mechanical continuity between the ECM and cytoskeleton

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10
Q

what can bind the ECM to the cytoplasm?

A

integrins

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11
Q

what is the structure of integrin?

A
  • heterodimers of alpha and beta sub-units
  • associate at the head (extracellular) region
  • 10 alpha and 8 beta subunits create >20 combination
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12
Q

what do integrins do to connect the cytoplasm to the ECM?

A

o They recognise short, specific peptide sequences and each combination of subunits of an integrin binds to a specific sequence.

the same sequence may be found in multiple types of ECM molecule

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13
Q

how does integrin attach to the actin cytoskeleton?

A

via actin proteins

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14
Q

what do integrins form when they cluster?

A

focal adhesions (most) or hemi-desmosomes

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15
Q

which integrin is found in most epithelial hemi-desmosomes?

A

alpha6beta4

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16
Q

example of an integrin and the sequence is recognises

A

alpha5beta1 fibronectin receptor recognises arg-gly-asp (RGD) sequence

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17
Q

what are integrin clusters involved in?

A

signal transduction

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18
Q

what are the 2 types of signalling that integrin is involved in?

A

“Outside-in” integrin signalling

“Inside-out” integrin signalling

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19
Q

what is “Outside-in” integrin signalling ?

A

ECM receptors can act to transduce signals inside the cell when stimulated.

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20
Q

what is “Inside-out” integrin signalling?

A

signals generated inside the cell can act on the integrin to alter the affinity of it.

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21
Q

what occurs in outside-in signalling?

A

cell can receive information about its surroundings from its adhesion to the ECM (info about its composition) which can alter the phenotype of the cell.

There will be conformational change in the cell.

Focal adhesions can sense mechanical properties of the environment

assembly

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22
Q

example of how cells recognise their surrounding ECM (its composition) and affects their phenotype

A

mammary epithelium does not differentiate to secretory cells in Type 1 collagen but in basal lamina ECM, it does organise and differentiate.

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23
Q

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

A

 The force generated by the cytoskeleton (F cell).

 The stiffness of the ECM.

24
Q

what happens in inside-out signalling?

A

The inside signals flex the receptor outwards so it has more affinity for the ligands binding.
(bent–> low affinity, extended–> high affinity)

Integrins recruit cytoplasmic proteins which can promote signalling and actin assembly.

25
Q

why do cells stop proliferating in a monolayer?

A

there is a high density of cells in a monolayer which all compete for growth factors

they stop proliferating as the growth factors are used up

“density-dependency of cell division” i.e. contact inhibition

26
Q

what is the competing theory of why cells stop proliferating in a monolayer?

A

that when cells meet each other in a mono-layer, they stop proliferating due to the contact of the cells.

27
Q

what signals are required for the proliferation of cells?

A

cross-talk between the ECM (anchorage-dependency) and the growth factor signalling (density dependency)

28
Q

what is the anchorage dependency mechanism?

A

GF receptors AND integrin signalling can each activate identical signalling pathways (e.g. MAPK, MAPKK, etc.).

In order to respond to these signals, the cell must be bound to ECM

29
Q

what is the importance of the synergistic relationship between both the anchorage-dependency and density dependency signals in activating the proliferative pathway?

A

individually, the activation is weak but when both GF and ECM anchorage activate the pathways, the activation is strong and sustained.

30
Q

what are the types of contact interactions between cells?

A

short term and long term

31
Q

what is a short term contact interaction?

A

transient interactions between cells that do NOT form stable cell-cell junctions
– i.e. cells bumping

32
Q

what type of cells form short term contact interactions?

A

Non-epithelial cells

33
Q

what do non-epithelial cells do when they collide? what is this called?

A

when they collide they actually repel each other by paralysing motility at the contact site and promoting formation of a motile front at another site

this is contact inhibition of locomotion
– prevents multi-layering of cells

34
Q

what prevents multi-layer of cells in normal cells?

A

contact inhibition of locomotion

35
Q

what are long term contact interactions?

A

stable interactions resulting in formation of cell-cell junctions

36
Q

which cells form long term contact interactions?

A

Epithelial
endothelial
neuronal cells

37
Q

what type of cell-cell junctions are formed in long term contact interactions?

A

adherens

desmosomes

38
Q

how are junctions arranged in epithelia?

A
  • continuous belts (zonula)

- discrete spots (Macula).

39
Q

how does the absence or presence of cell-cell adhesion affect proliferation?

A

there are ca2+ dependent junctions

  • when there is no/low ca2+ or presence of adhesion- blocking antibody there will be NO cell-cell junction
  • this results in:
    1) the activation of the MAPK pathway
    2) decreased p27KIP Cdk inhibitor
    3) high proliferation

therefore the existence of cell-cell junctions promotes stability of the cells and low proliferation

40
Q

what is the effect of the presence of calcium on proliferation?

A

cell-cell junctions formed
inactivated MAPK
increased p27KIP1
low proliferation

41
Q

name the ca2+ dependent adhesion molecule

A

cadherin (homophilic)

42
Q

what is the linking molecule of cadherin?

A

beta catenin

remember cadherin is a Ca2+ dependent junction that does not promote proliferation when present

43
Q

what is the significantce of beta catenin in adenomatous polyposis coli (APC)?

A

APC gene product is a protein that breaks down beta catenin

beta catenin is a proto-oncogene

44
Q

where is beta catenin found?

A

normally bound to the cadherin in on plasma membrane connecting it to the actin cytoskeleton
- can pass to cytoplasm

45
Q

what can beta-catenin do in the cytoplasm?

A

o Rapidly degrade when bound to APC.
o When at a high enough free concentration, can bind to LEF-1 in the nucleus and alter gene transcription.
o Re-bind back onto cadherin (cannot have nuclear effects).

therefore beta catenin is involved in cell-cell adhesion via cadherin and in gene expression

46
Q

when can beta-catenin have gene expression influences?

A

if beta-catenin levels rise due to:

  • inhibition of degradation (low APC)
  • loss of cadherin-mediated adhesion

they form the LEF-1/catenin complex which can enter the nucleus and alter gene expression –> proliferation of cells

47
Q

what is the effect of cadherin clustering after cell-cell contact ?

A

alters the activation of small GTPases

Rac is activated, Rho is inhibited.

this influences proliferation

48
Q

what are the effect on cells when behavioural constraints are lost?

A

o Proliferate uncontrollably – no density-dependency.
o Less adherent, will multilayer – lose contact-inhibition and anchorage dependency.
o Epithelial breakdown of cell-cell contacts.
o Not Hayflick limited so express telomerase.

49
Q

what does the loss of contact inhibition of location promote the growth of?

A

promote formation of solid tumours AND promote local invasion.

50
Q

what effect does mutation in gene encoding signalling pathways have?

A

An encoded protein may be constitutively active so the pathway is ALWAYS ON.

This short-circuits the proliferation activating pathways (anchorage dependence+ density dependence)

51
Q

what are oncogenes?

A

mutant genes which promote uncontrolled proliferation.

52
Q

what are proto-oncogenes?

A

normal genes corresponding to the oncogene

have normal regulatory functions

53
Q

which proto-oncogene is mutated in about 30% of all cancers?

A

Ras

54
Q

examples of proto-oncogenes

A 
EGFR
Ras
c-Raf
c-Jun
beta catenin
55
Q

what type of cancers are most human cancers?

A

carcinomas i.e. of epithelial origin

56
Q

what is the overall mechanism of metastasis?

A

o Cell-cell adhesion broken down-regulated.
o Cells must be motile.
o Degradation of ECM (via MMPs) to migrate.

57
Q

what does the degree of cell-cell adhesion indicate about a primary tumour?

A

how differentiated the primary tumour is and indicates its invasiveness and the prognosis.

MCD Cancer (17 decks)

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