Metastasis

Question 1

Tumours often arises in what kind of tissue?

Answer 1

epithelial

Question 2

What tissue layer is beneath epithelial layer?

Answer 2

Connective tissue

Question 3

What is the connective tissue made of?

Answer 3

Fibroblasts, secreted growth factors

Question 4

What is beneath the connective tissue layer?

Answer 4

Another epithelial layer followed by Capillaries

Question 5

The basement membrane is the layer that epithelial cells sits on is made of what?

Answer 5

ECM

Question 6

Cells form interactions with extracellular proteins via what?

Answer 6

Integrins (claps)

Question 7

Cell-cell interactions are made via what?

Answer 7

Cadherins

Question 8

What happens to cyclin A expression when integrin signalling is disrupted?

Answer 8

Cyclin A can be produced without anchorage

The affect on p27 is the reverse

Question 9

Describe integrin?

Answer 9

Heterodimeric TM protein with large extracellular domain and small intracellular domain

Question 10

How many alpha and beta subunits exist for integrin?

Answer 10

15 alpha
8 beta
can exist in many conformations - affect what it can interact with in the ECM

Question 11

Give examples of proteins that integrins interact with?

Answer 11

actin and signalling molecules (e.g. ILK, FAK)

Question 12

What pathways can ILK (integrin linked kinase) mediate?

Answer 12

cyclin D expression, AKT pathway, cadherin signalling and actin cytoskeleton

Question 13

What ion is cadherin sensitive to?

Answer 13

Ca2+, gives cadherin rigidity

Question 14

Do cadherins respond to extracellular or intracellular Ca2+?

Answer 14

Extracellular

Question 15

What does cadherin rigidity allow?

Answer 15

Interaction cadherins on neighbouring cells

Question 16

Cadherin interactions are anti-proliferative. True or False?

Answer 16

True

Question 17

What is the most common cadherin?

Answer 17

E-cadherin

Question 18

Is cadherin a tumour suppressor or oncogene?

Answer 18

Tumour suppressor

Question 19

What binds the intracellular part of cadherin?

Answer 19

beta catenin
alpha catenin
p120 catenin

Question 20

Which GTPases are p120 able to bind to?

Answer 20

RhoA
Rac
cdc42

Question 21

What is the function of RhoA?

Answer 21

form stress fibres - associated with increased motility

Question 22

What is the function of Rac?

Answer 22

Causes formation of lamellipodia

Question 23

What is the function of cdc42?

Answer 23

Causes formation of filopodia

Question 24

What do lamellipodia and filopodia cause generally?

Answer 24

check local environment and retract when they encounter cells

Question 25

Describe structure of beta-catenin.

Answer 25

Many alpha helical turns (armadillo repeats)

Question 26

Where can beta catenin be found in the cell?

Answer 26

Membrane bound or cytoplasmic

Question 27

What happens to cytoplasmic beta catenin?

Answer 27

Gets degraded via APC and GSK3

Question 28

What is familial adenomatous polyposis?

Answer 28

APC mutations (present in 80% of colon cancers) and gives rise to polyps and can form cancer

Question 29

Where is the beta catenin binding site in APC?

Answer 29

N terminal - cancerous mutations occur here

Question 30

Why does beta catenin have a NLS?

Answer 30

When beta catenin is not bound to cadherin in healthy cells it indicates a lack of cell-cell interaction and hence that proliferation is required to build monolayer

Question 31

What does beta catenin interact with the nucleus?

Answer 31

TCF/LEF

Question 32

What is TCF/LEF?

Answer 32

TF with no DNA binding site (only transactivation domain)

Question 33

What does TCF/LEF/beta-catenin express?

Answer 33

D cyclins, c-MYC, MMPs

Question 34

what is the affect of wnt signalling on beta catenin?

Answer 34

stabilises beta catenin

Question 35

Intracellular cadherin truncations result in what?

Answer 35

Higher concentrations of Cytoplasmic beta

Question 36

What is the affect of ILK on GSK3?

Answer 36

ILK inhibits GSK3 - how integrin and cadherin signalling links

Question 37

What is EMT?

Answer 37

epithelial mesenchymal transition - cells losing E-cadherin - occurs in development and cancer progression

Question 38

What are metallomatrix proteins?

Answer 38

MMP are required for movement through ECM - proteases that cleave substrates at hydrophobic residues

Question 39

What activates MMP expression?

Answer 39

beta catenin/TCF/LEF

Question 40

Where are MMP produced?

Answer 40

RER then shuttled to surface

Question 41

Some MMPs are TM with cytoplasmic tails. True or False?

Answer 41

True - however most are secreted

Question 42

MMPs have the different accessory domains but the same what?

Answer 42

catalytic fold

Question 43

Name an accessory domains in MMP?

Answer 43

Haemopexin - recruits substrate

Question 44

What is the catalytic domain motif that coordinates a zinc ion?

Answer 44

HEXGHXXGXXH

Question 45

What is the prodomain of an MMP?

Answer 45

PRCGXPD motif - cysteine binds to a zinc ion and blocks catalytic site inactivating it

Question 46

Different MMPs have different substrates but all cleave what type of protein?

Answer 46

ECM proteins | e.g. collagen, gelatine, elastin

Question 47

What residues do MMP cleave at?

Answer 47

V M F I L - these are common and so proteins get cleaved into small peptides that don't hinder cell movement

Question 48

Are MMP's potential drug targets?

Answer 48

Yes - if hinder cell mobility is reduced hence restricting metastasis

Question 49

What is the seed soil theory?

Answer 49

Primary tumour locations are associated with specific secondary locations

Question 50

Give an example of a seed and soil.

Answer 50

Lung --> brain

Question 51

What does secretion of IL-11 do?

Answer 51

causes osteoclast activation to make room for tumour colonisation in bones

Question 52

Secreting lysyl oxidase has what affect on osteoclast?

Answer 52

Causes lysine in collagen to form aldehydes which favours osteoclast

Question 53

Why are exosomes relevant to cancer?

Answer 53

Vesicles used by cancer to prepare sites of metastasis. Exosomes target integrins and deliver cargo that favour metastatic colonisation