carcinogenesis

Question 1

what does cell behaviour describe

Answer 1

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

Question 2

2 types of external influences detected by cells

Answer 2

chemical, physical

Question 3

examples of chemical external influences detected by cells

Answer 3

hormones, growth factors, ion concentrations, ECM, molecules on other cells, nutrients, dissolves gas concentrations

Question 4

examples of physical external influences detected by cells

Answer 4

mechanical stresses, temperature, topography of ECM and other cells

Question 5

what external factors can influence cell division in relation to cancer cell behaviour

Answer 5

growth factors, cell-cell adhesion, cell-ECM adhesion

Question 6

what protrusion of a cell is important in cell motility

Answer 6

lamellipod of a polarised cell

Question 7

describe cell-spreading process

Answer 7

energy required to modulate cell adhesion and cytoskeleton during spreading, (not passive, gravity-dependent event)

Question 8

with cells with no contact to ECM substratum, what do they do instead of spreading

Answer 8

bleb, so undergo apoptosis

Question 9

how does cell-ECM adhesion influence cell proliferation

Answer 9

if cell is suspended with no cell-ECM adhesion, has a much lower probability of entering S phase (proliferation); if on a small adhesive patch, higher chance, and if on a big adhesive patch, highest chance of proliferation; to do with arrangement and area of adhesive contact, not amount

Question 10

why do cells with no cell-ECM adhesion have a much lower probability of proliferation

Answer 10

cells require binding to ECM (and degree of spreading) to be fully competent for responding to soluble growth factors (anchorage dependence), allowing protein synthesis and proliferation

Question 11

how does matrix type have effects on phenotype of cells

Answer 11

if matrix type is similar/same to that as found in body (e.g. epithelial cells on basal lamina matrix), they organise themselves and differentiate for their function, suggesting cells sense the composition of their environment from adhesion to ECM; if the matrix type is different, they do not differentiate

Question 12

what do cells have on their cell surface, and what do they do to detect their environment

Answer 12

receptors which bind specifically to ECM molecules

Question 13

attachment of cell-ECM adhesion molecules to cell

Answer 13

often linked, at cytoplasmic domains, to cytoskeleton (so have mechanical continuity between ECM and cell interior)

Question 14

most important cell-ECM adhesion molecule receptor

Answer 14

integrin

Question 15

structure of integrin

Answer 15

heterodimer complex of a and B subunits (>20 combinations)

Question 16

how do integrins associate EC

Answer 16

by “head” regions

Question 17

what do integin “leg” regions span

Answer 17

plasma membrane

Question 18

what occurs at junction of integrin head regions

Answer 18

ligand-binding

Question 19

what do a/B integrin subunits specifically bind to

Answer 19

short peptide sequence on ECM proteins

Question 20

peptide sequence on ECM proteins that a5B1 integrin receptor binds to, and what it is found on

Answer 20

RGD, which is found on more than one ECM molecule (binding depends on sequence of peptides around it, and accessibility e.g. due to folding)

Question 21

what do integrin complexes cluster to form

Answer 21

focal adhesions (most) or hemidesmosomes (a6B4)

Question 22

what are integrin cluster complexes involved in

Answer 22

signal transduction

Question 23

what else can integrin receptors bind to

Answer 23

adhesion molecules on other cells

Question 24

define outside-in integrin signalling

Answer 24

where ECM binding to an integrin complex stimulates the complex to produce an IC signal

Question 25

2 conformations of integrin complexes

Answer 25

flexed (low affinity with legs bent, head pointing down) and extended (high affinity)

Question 26

what does switching between conformations allow integrins to do

Answer 26

alter their ability to bind ligands and their signalling, causing cell-ECM adhesion and signals to be turned on and off

Question 27

what can focal adhesions also sense in their ECM surroundings

Answer 27

mechanical properties

Question 28

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

Answer 28

force generated by cytoskeleton (F cell) and stiffness of ECM

Question 29

2 functions of cytoplasmic proteins which integrins recruit

Answer 29

promote cell signalling, promote actin assembly

Question 30

define inside-out integrin signalling

Answer 30

where a signal is generated inside cell (e.g. due to hormone binding to another receptor), which acts on integrin complex and alters its affinity to ECM binding

Question 31

2 examples of inside-out signalling

Answer 31

inflammation, blood-clotting (switches on adhesion of circulating lymphocytes)

Question 32

contact inhibition vs density-dependence

Answer 32

contact inhibition: when cells are in culture and form a confluent monolayer, they cease proliferating; however it is competition of external growth factors, and not cell-cell contact, that stops proliferation (density-dependence)

Question 33

pathway of ERK MAP kinase cascade for cyclin D expression

Answer 33

growth factor (density-dependence) binds to tyrosine kinase receptor -> adapter -> ras -> raf -> MEK -> ERK -> gene expression for proliferation in nucleus

Question 34

what else is required for efficient stimulation of proliferation in nucleus

Answer 34

ECM (anchorage-dependence) binding

Question 35

what pathway do integrin signalling complexes activate

Answer 35

similar pathways to growth factor receptor pathway e.g. ERK MAP kinase cascade

Question 36

growth factor and integrin signalling complexes: individual activation vs combined activation

Answer 36

individually, activation of signalling pathway is weak and/or transient, but together, activation is strong and sustained (synergistic)

Question 37

short-term contact interaction between cells

Answer 37

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

Question 38

long-term contact interaction between cells

Answer 38

stable interactions between cells which form stable cell-cell junctions

Question 39

contact inhibition of locomotion between non-epithelial cells, preventing multi-layering of cells

Answer 39

upon collision of non-epithelial cells, they do not form stable cell-cell contacts; instead they repel one another by paralysing motility at contact site, promoting formation of motile front at another site on cell, and moving in opposite direction; stable monolayer forms due to mutual induction of spreading, so that total spread area of contacted cells is greater than sum of 2 separated cells

Question 40

long-term cell-cell contacts: types of cell-cell junctions

Answer 40

adherens (zonula - belt), desmosomes (macula - spot), tight junctions (zonula - belt), gap junctions (macula - spot)

Question 41

what cells form layers using long-term cell-cell contacts

Answer 41

epithelial and endothelial cells

Question 42

what cells form synapses using long-term cell-cell contacts

Answer 42

neurones

Question 43

what cells typically form cell-cell junctions

Answer 43

those which form a monolayer

Question 44

3 other features of cells which form a monolayer and cell-cell junctions

Answer 44

inactive MAPK, low proliferation (high p27KIP), Ca2+

Question 45

what happens if Ca2+ is removed from monolayer cell-cell junction cells

Answer 45

no cell-cell junctions, so activated MAPK and high proliferation (low p27KIP)

Question 46

effect of Ca2+ on cell-cell adhesion

Answer 46

increases, forming long-term cell-cell junctions and reducing proliferation

Question 47

effect of adhesion blocking antibody on cell-cell adhesion

Answer 47

opposite effect of Ca2+, so reduced cell-cell junctions and increased proliferation

Question 48

how does Ca2+ increase cell-cell adhesion and reduce proliferation

Answer 48

cadherin (Ca2+ dependent cell adhesion molecule) binds to molecules on adjacent cells, and is connected to IC actin filament by B-catenin and a-catenin (downregulates signalling pathway for proliferation)

Question 49

what protein is involved in degradation of B-catenin, and what does this cause

Answer 49

APC gene-product, causing APC (adenomatous polypopsis coli; inherited colon cancer)

Question 50

when is B-catenin sequestered

Answer 50

when bound to cadherin forming junctions at plasma membrane with other cells

Question 51

what happens to B-catenin in normal cells, if junctions between cells is broken down

Answer 51

released into cytoplasm, where binds to active APC complex and is rapidly degraded

Question 52

what happens to B-catenin in inherited colon cancer cells, if junctions between cells is broken down

Answer 52

released into cytoplasm where APC complex is inactive, so binds to LEF-1 (transcription factor) and enters nucleus for gene transcription, leading to cell proliferation

Question 53

what does clustering of cadherins after cell-cell contact alter

Answer 53

activation of small GTPases (e.g. Rac activated, Rho inhibited), influencing proliferation

Question 54

how might location of receptor reduce capacity to promote proliferation

Answer 54

if growth factor receptor is associated with cell-cell junction

Question 55

effects if cells lose behavioural restraints to become cancerous

Answer 55

proliferate uncontrollably (lose density-dependence of proliferation), become less adherent and multilayer (lose contact inhibition of locomotion and anchorage-dependence), epithelia breakdown cell-cell contacts, no Hayflick limit and express telomerase

Question 56

2 consequences of cells losing contact inhibition of locomotion for progression of cancer

Answer 56

promote formation of solid tumours, become metastatic (invasion) by breaking through basement membrane

Question 57

define proto-oncogene

Answer 57

normal cellular gene that, if mutated (becoming oncogene), promotes cancerous phenotypes due to uncontrolled proliferation

Question 58

what does an proto-oncogene code for, and effect if mutated

Answer 58

component of signalling pathway, so if mutated protein is constitutively active, causing pathway to be permanently on, causing uncontrolled proliferation as a result of loss of growth factor dependence etc.

Question 59

general examples of proto-oncogenes

Answer 59

receptors, signalling intermediates, signalling targets (e.g. transcription factors); normally affects both pathways of growth factor (density-dependent) and ECM (anchorage-dependent)

Question 60

what are most human cancers

Answer 60

carcinomas (derived from epithelial cells)

Question 61

how does a primary carcinoma cell metastasise

Answer 61

cell-cell adhesion downregulated (e.g. reduce cadherin levels), cells are motile, degradation of ECM occurs

Question 62

what enzyme increases in metastatic cancer cells to migrate through basal lamina and interstitial ECM

Answer 62

matrix metaloproteinase (MMP)

Question 63

what does degree of carcinoma cell-cell adhesion indicate

Answer 63

how differentiated primary tumour is, invasiveness, and prognosis