Cancer 9: external factors controlling division Flashcards
WHat is cell behaviour?
Term used to describe the way cell interact with external environement and their local environement-particulalry proliferation and motility
What are the 2 form of external influences that cells can detect?
Chemical-hormones, GF, ions, ecm, molecules, nutrients-
Physical-mechanical stress, temperature, topography of ECM
in cancer the main one are GF, cell cell adhesion and cell-memrbane adhesion
How do cells adhere in culture?
Spreads out using lamellipods-polarised as a motile cell
spreading isinitial contact
definitly not a gravity dependent event-cytoskeleton related
If a cell sticks ontop of another one-doesnt spread
as spread more likely to replicate on culure
in agar-low S rate chance
(with presence of GF)
=> ECM is required for division
What is the relation between ECM and cell proliferatio?
Suspension-not make protein or DNA
require ECM and spreading to being the proper process
ECM is required for survival-can undergo apoptosis if bad ECM
WHat is the relation between ECM and cell differentiation?
cell phenotype can be determined by composition of the matrix
just collagen-form loose ball of cells (even epithilial cells)
With a basal lamina-form a lumen and organise themselves in oragnoids (and produce the right proteins)-mammary glands produce milk)
How do cells attatch and signall through the ECM? What is the main exemple?
Cell have receptors on their surface to bind ECM
Have cytoplasmic domain and extracellular (connect to cytoskeleton-link bewteen ECM and cell interior
Most well understood-Intergins
heterodimer of a and B chain-associate in head region-where binds ECM-to short AA sequence-like-arg-gly-asp (RGD)
Short cytosolic region
About 20 combinations of integrins
Bind the AA sequence find in some matrix moelcule-some can bind many, some only one
Focal adhesions are clusters of integrins
Hemidesmosomes are also clusters
ICAM and VCAM also bind integrins
How does the ECM signall the cell? Describe how?
ECM receprtors like intergins transfer the signal
Integrins can be flexed or extended (head down or up)
When binds to matrix-transduce a signal through to the cell=with recruited proteins (like focal adhesion kinase)
ECM/integrins direct what the signal-
amount of roce generated b focal adhesion can activate specific proteins
Internal signals also activate integrins to make them “sticky”-head up-and only after that signal can it bind ECM and recruit signalling proteisn
depending on the cell it can be constantly high affinity
Why do cell in culture formin a monolayer stop proliferating?
Either cell to cell contact tell them to stop-no more space–cell to cell inhbition
But also idea that its because of the competition for GF-not enough for everyone to divide-density dependence of cell division
How do GF and ECM combine to lead to proliferation?
No need for detail
But TKR-through MEKKK pathway-signal nucleus
Integrins can also activate the same pathway
But inidivudally its weak
need booth for strong and stable activation
What are the 2 outcomes of cells contact?
short term-transient interactions bewteem cells which do not become stable cell-cell junction
Long term-stable interaction-uses cell-cell junctions
Most non epithelilial cells collide they dont form junctions and actually try and move around from one another-contact inhbition of locomotion
epithelial cells are specialised in cell junction-dont repel
What are the types of epithelial cell-cell jucntion
Either as belts or discrete spots
Tight junctions
GAp junctions
Desmosomes-adhesion belt+fical contact-adherens junction
What happens when epithalial cells touch in culture? What happens when you remove Ca?
They spread along the junction point and actually take more space than sum of each cell-
When remove Ca-cant form junction-cell near but not joined-high proliferation
re-add Ca-stop proliferation
What are adherens?And cadherins? What is a main player
On each cell-bind each other- (on different cells)-Cadherins is the ca dependent form
intra cellular: Cadherin bind Bcatenin-binds acatenin which binds actin filament
B-catenin degradation mutation leads to multiple polyp in colon
when cells bind- a and B catenin is inside
If adherens of the cells around bound to another cell/junctions breakdown-cytoplastic b-catenin is very quickly degraded by APC complex
When not degraded-> B catenin is pro-proliferative. Degradation is how cell-cell contact inhbits proliferation
But in some cancer, APC complex inactive-becomes part of TF complex (LEF1)-leads to prolifeation
What adhesion associated signalling pawthways are associated with proliferation
Adherins and B-catenin
Cultersing of cadherins after contact can activate GTPases (RAC uo, Rho down)
Some GF receptors are associated with cell to cell junction-reduce capactity to promoter proliferation
WHat happens when cell lose ability to talk to each other?
proliferate uncontrollably-no density dependence
Less ahderent and mutlilayer-lose contact inhbition of locomotion and acnhorage dependent
Epithelia breakdown cell-cell
not hayflick limited-> cancer
this is a lot of cacer
