17. metastasis Flashcards
name the process by which tumour cells exit the blood stream?
extravastation
describe the basic structure of intestinal tissue
- epithelial cells absorb things from the gut
- there is muscle and connective tissue under this
- these cells are embedded within capillaries and blood supply
- under this is a layer of epithelial cells which sit on the basement membrane and proliferate out from this
- it is organised and regular
where is a tumour most likely to arise in the gut?
in the epithelial layer
made the two types of adhesion molecule that cells use
cadherins and intergrins
what type of adhesion molecules are used for cell to cell adhesions?
cadherins
what type of adhesion molecules are used to cell to ECM adhesions?
intergrins
what type of signalling in the soft agar assay has been disrupted which means normal cells can no longer proliferate?
intergrin
what type of signalling in the focus formation assay has been disrupted which allows cells to grow regardless of contact with other cells?
cadherin
cells that are adhered to a basement membrane, for example tissue culture plastic, have intergrin signalling. what expression is induced in these cells? and how does this change when cells are in suspension?
cyclin A
cells do not express cyclin A when in suspension
expression of what is elevated when cells are in suspension and there is no intergrin signalling? and what happens to this when cells are reattached to a membrane?
p27
levels rapidly decrease once cell is attached to the membrane
there is a link between intergrin signalling and what?
cell cycle machinery
what are the relative sizes of the intra- and extra-cellular portions of intergrins and cadherins?
large extra-cellular domain and a small intra-cellular domain
when intergrins interact with ECM, what happens in the cytosol of cells?
intergrins interact with actin filaments and signalling molecules
intergrins are heterodimeric proteins, describe the possible subunits and comment on the combinations
- there are 15 alpha subunits and 8 beta subunits
- different combinations of these dictate the proteins that they bind on the outside of the cell, and this binding dictates whether or not there will be intra-cellular signalling
name a molecule that is a key player in intergrin signalling and what outcomes does it modulate? (3)
ILK - intergrin like kinase
- it modulates cyclin D levels and proliferation
- it can modulate the pro-proliferation, pro-survival signal ALK
- cell motility
what happens if ILK is over expressed?
it becomes oncogenic, the more ILK the more malignant the tumour
when you deregulate ILK, you compromise you ability to withstand cancer
what is responsible for cells being able to recognise their neighbours and why is this useful?
cadherins
if they can sense their neighbours then they know not to proliferate into that cell
what do cadherins need in order to bind other cadherins?
calcium
cadherins are calcium sensing
mammary gland tumour cells were introduced into mice in a non-breast location. these were either p53 KO or p53 and cadherin KO, what was observed in each case? what does this show?
p53 KO cells are not sufficient enough to cause tumours
p53 and cadherin KO cells proliferate and metastasise and spread throughout the body and are selective in where they go
this shows that KO cadherin allows expansion and metastasis
how can injected tumour cells be traced in a mouse?
loads them with an enzyme that can create bioluminescence when given the appropriate substrate
there are links between cadherins and actin. what does actin control?
cell shape and motility
cadherin signalling can results in the formation of three things, what are they?
- stress fibres
- lamellipodia
- filopodia
how does the cadherin structure cause changes in the actin structure?
by regulating a family of small GTPases
when the cadherin complex inhibits Rho what does this lead to?
stress fibres form, preventing cells from being motile
when the cadherin complex activates Ras what does this lead to?
Lamellipodia check surroundings, if everything is ok and there is a monolayer of cells then cells do not proliferate
if not then they will proliferate to rectify it
when the cadherin signalling activates cdc42 what does this lead to?
Filopodia are more elongated than Lamellipodia but have the same function to check the environment and check that everything is ok
name three molecules that interact with cadherins and mediate its contact with actin filaments and which more directly contacts the actin filament and what does this mean?
p120 catenin
beta catenin
alpha catenin - alpha catenin directly contacts the actin filament, it can potentially make changes in the cytoskeleton that are independent of beta catenin and p120
which of the three molecules that interacts with cadherins are most directly associated with cancer?
beta catenin
what does beta catenin interact with?
it interacts with cadherins and alpha catenin
what is the homologue of beta catenin in Drosophila called? and describe the structure of this protein
armadillo
it has multiple repeats of alpha helices with turns throughout the protein, these are called armadillo repeats
what makes beta catenin good for binding other proteins?
- large surface area
what do the alpha helices and loop do in beta catenin?
alpha helices hold structure in place while the loops provide binding specificity
where is beta catenin found in normal cells?
at the membrane associated with active cadherins or in the cytosol being recruited to the membrane or degraded
where is beta catenin additionally found in cancer cells? and what type of cancer is this particularly important for?
in the nucleus
this is particularly important for the development of tumourogenesis in colon cancer
what does FAP stand for?
Familial Adenomatous Polyposis
what two forms can colon cancer come in?
familial and sporadic