carcinogenesis Flashcards
external growth factors: recall the role of external growth factors in controlling cell division and list examples, explain why signaling pathways involving growth factors are often implicated in the uncontrolled division of cancerous cells
what does cell behaviour describe
way cells interact with their external environment and their reactions to this, particularly proliferative and motile responses of cells
2 types of external influences detected by cells
chemical, physical
examples of chemical external influences detected by cells
hormones, growth factors, ion concentrations, ECM, molecules on other cells, nutrients, dissolves gas concentrations
examples of physical external influences detected by cells
mechanical stresses, temperature, topography of ECM and other cells
what external factors can influence cell division in relation to cancer cell behaviour
growth factors, cell-cell adhesion, cell-ECM adhesion
what protrusion of a cell is important in cell motility
lamellipod of a polarised cell
describe cell-spreading process
energy required to modulate cell adhesion and cytoskeleton during spreading, (not passive, gravity-dependent event)
with cells with no contact to ECM substratum, what do they do instead of spreading
bleb, so undergo apoptosis
how does cell-ECM adhesion influence cell proliferation
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
why do cells with no cell-ECM adhesion have a much lower probability of proliferation
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
how does matrix type have effects on phenotype of cells
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
what do cells have on their cell surface, and what do they do to detect their environment
receptors which bind specifically to ECM molecules
attachment of cell-ECM adhesion molecules to cell
often linked, at cytoplasmic domains, to cytoskeleton (so have mechanical continuity between ECM and cell interior)
most important cell-ECM adhesion molecule receptor
integrin
structure of integrin
heterodimer complex of a and B subunits (>20 combinations)
how do integrins associate EC
by “head” regions
what do integin “leg” regions span
plasma membrane
what occurs at junction of integrin head regions
ligand-binding
what do a/B integrin subunits specifically bind to
short peptide sequence on ECM proteins
peptide sequence on ECM proteins that a5B1 integrin receptor binds to, and what it is found on
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)
what do integrin complexes cluster to form
focal adhesions (most) or hemidesmosomes (a6B4)
what are integrin cluster complexes involved in
signal transduction
what else can integrin receptors bind to
adhesion molecules on other cells
define outside-in integrin signalling
where ECM binding to an integrin complex stimulates the complex to produce an IC signal
2 conformations of integrin complexes
flexed (low affinity with legs bent, head pointing down) and extended (high affinity)
what does switching between conformations allow integrins to do
alter their ability to bind ligands and their signalling, causing cell-ECM adhesion and signals to be turned on and off
what can focal adhesions also sense in their ECM surroundings
mechanical properties
what does the amount of force generated at a focal adhesion depend on
force generated by cytoskeleton (F cell) and stiffness of ECM
2 functions of cytoplasmic proteins which integrins recruit
promote cell signalling, promote actin assembly
define inside-out integrin signalling
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
2 examples of inside-out signalling
inflammation, blood-clotting (switches on adhesion of circulating lymphocytes)
contact inhibition vs density-dependence
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)
pathway of ERK MAP kinase cascade for cyclin D expression
growth factor (density-dependence) binds to tyrosine kinase receptor -> adapter -> ras -> raf -> MEK -> ERK -> gene expression for proliferation in nucleus
what else is required for efficient stimulation of proliferation in nucleus
ECM (anchorage-dependence) binding
what pathway do integrin signalling complexes activate
similar pathways to growth factor receptor pathway e.g. ERK MAP kinase cascade
growth factor and integrin signalling complexes: individual activation vs combined activation
individually, activation of signalling pathway is weak and/or transient, but together, activation is strong and sustained (synergistic)
short-term contact interaction between cells
transient interactions between cells which do not form stable cell-cell junctions
long-term contact interaction between cells
stable interactions between cells which form stable cell-cell junctions
contact inhibition of locomotion between non-epithelial cells, preventing multi-layering of cells
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
long-term cell-cell contacts: types of cell-cell junctions
adherens (zonula - belt), desmosomes (macula - spot), tight junctions (zonula - belt), gap junctions (macula - spot)
what cells form layers using long-term cell-cell contacts
epithelial and endothelial cells
what cells form synapses using long-term cell-cell contacts
neurones
what cells typically form cell-cell junctions
those which form a monolayer
3 other features of cells which form a monolayer and cell-cell junctions
inactive MAPK, low proliferation (high p27KIP), Ca2+
what happens if Ca2+ is removed from monolayer cell-cell junction cells
no cell-cell junctions, so activated MAPK and high proliferation (low p27KIP)
effect of Ca2+ on cell-cell adhesion
increases, forming long-term cell-cell junctions and reducing proliferation
effect of adhesion blocking antibody on cell-cell adhesion
opposite effect of Ca2+, so reduced cell-cell junctions and increased proliferation
how does Ca2+ increase cell-cell adhesion and reduce proliferation
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)
what protein is involved in degradation of B-catenin, and what does this cause
APC gene-product, causing APC (adenomatous polypopsis coli; inherited colon cancer)
when is B-catenin sequestered
when bound to cadherin forming junctions at plasma membrane with other cells
what happens to B-catenin in normal cells, if junctions between cells is broken down
released into cytoplasm, where binds to active APC complex and is rapidly degraded
what happens to B-catenin in inherited colon cancer cells, if junctions between cells is broken down
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
what does clustering of cadherins after cell-cell contact alter
activation of small GTPases (e.g. Rac activated, Rho inhibited), influencing proliferation
how might location of receptor reduce capacity to promote proliferation
if growth factor receptor is associated with cell-cell junction
effects if cells lose behavioural restraints to become cancerous
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
2 consequences of cells losing contact inhibition of locomotion for progression of cancer
promote formation of solid tumours, become metastatic (invasion) by breaking through basement membrane
define proto-oncogene
normal cellular gene that, if mutated (becoming oncogene), promotes cancerous phenotypes due to uncontrolled proliferation
what does an proto-oncogene code for, and effect if mutated
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.
general examples of proto-oncogenes
receptors, signalling intermediates, signalling targets (e.g. transcription factors); normally affects both pathways of growth factor (density-dependent) and ECM (anchorage-dependent)
what are most human cancers
carcinomas (derived from epithelial cells)
how does a primary carcinoma cell metastasise
cell-cell adhesion downregulated (e.g. reduce cadherin levels), cells are motile, degradation of ECM occurs
what enzyme increases in metastatic cancer cells to migrate through basal lamina and interstitial ECM
matrix metaloproteinase (MMP)
what does degree of carcinoma cell-cell adhesion indicate
how differentiated primary tumour is, invasiveness, and prognosis
