Cancer 9 Flashcards
define cell behavior?
- the way in which cells interact with their external environment and their reaction to this, particularly proliferative and motile responses of cells
what external influences are detected by cells?
Chemical
- hormones, growth factors, ion concentrations, ECM, molecules on
other cells, nutrients, and dissolved gas concentrations
Physical
- mechanical stresses, temperature, the topography or ‘layout’ of the
ECM and other cells
what external factors can influence cell division?
all of them might but specifically =
- growth factors
- cell-cell adhesion
- cell ECM adhesion
how do cells behaviour in a culture?
- we can understand this by looking at isolated cells in culture
- when the cell is placed on the culture it settles down due to gravity
- It will then spread across the culture medium and it will usually obtain some polarity
- the front of the cell is the motile part
- this process is not passive it requires energy to modulate cell adhesion and cytoskeleton spreading
how does cell - ECM adhesion affect proliferation?
- experiments were undertaken where different sized adhesive patches were created upon a nonadhesive background
- these cells were compared with suspended cells in agar
- a comparison of a degree in proliferation in the different conditions was measured
- when the cells were in suspension there was a very small probability of cells entering S phase
- when the cells were in the small adhesive patch, a small number of cells reached S phase
- when the cells were put into large adhesive patches almost all reached S phase
why is the arrangement not amount of the adhesion areas important?
- most cells stick to fibronectin
- if you have a small defined patch of fibronectin and put a cell on it the cell will stick but it cannot spread
- if you take the same amount of fibronectin and distribute it over a number of small spots it will spread, survive and grow
- so it is not the amount of adhesive space that is important
- instead, it is the arrangement
what happens if the cell does not adhere to the matrix?
the cell will undergo apoptosis
how can cell phenotype be determined by the composition of the matrix?
- if you place the cells in different types of matrices the cells arrange themselves in different ways
- for example
- if you place the cells in type 1 collagen gel they form a loose form of cells
- if you place the same type of cells in basal lamina matrix gel they organize themselves into organoids
- furthermore, they start to differentiate and produce milk proteins
what are cell ECM adhesion molecules?
what does this suggest?
- cells have receptors on their cell surface which binds specifically to ECM molecules
- These molecules are often linked, at their cytoplasmic domains, to the cytoskeleton
- this means there is mechanical continuity between the ECM and the cell interior
what is the structure of integrins?
- Integrins are heterodimer complexes consisting of alpha and beta subunits
- They bind to the ECM via their heads
- each of the tail regions spans the plasma membrane
- There are about 10 alpha and 8 beta subunits that form more than 20 known combinations
what is the function of integrins?
- each integrin combination binds to a short, specific peptide sequence
- such peptide sequences are often found in more than one ECM molecule
- Intracellularly, the integrins are linked, via actin=binding proteins, to the actin cytoskeleton
- Integrin complexes cluster to form local adhesions (most) or hemidesmosomes
- these clusters are involved in signal transduction
- this allows the integrins to interpret the matrix composition of the environment
how many molecules do integrins bind to?
- integrins are promiscuous
- Some integrins bind to more than one ECM molecule
- Some only bind to a single ECM molecule
- Many integrins are also designed to bind to specific adhesion molecules on other cells
what conformational changes occur during integrin signalling?
- The integrin on the left is in the low affinity state
- the integrin can be switched on to become a high affinity state by an inside out signal
what does ligand binding do to the integrin?
- The ligand-binding causes a change in conformation
- The legs separate and cytoplasmic signaling molecules can then bind and that binding will then allow signaling to take place
what are signals to and from ECM receptors called?
- the signals to the ECM receptor is outside IN
- the signals from the ECM receptor is inside OUT
how does an INSIDE out signal affect the conformity of the integrin?
- A signal generated inside the cell can act on an integrin complex to alter the affinity of an integrin
- the integrin complex might originally be folded over meaning they have low affinity to the matrix molecules so don’t stick very well
- There are signals generated within the cell that makes them unfold and go into a high-affinity conformation and become sticky
why is the conformity of integrins important in blood clotting and the immune system?
- Platelets have integrins on their surface but they are inactive so that the platelet doesn’t stick to everything
- when you do need to activate the platelets the inside out signals will be activated so they become high affinity and start to stick
how does outside IN signalling affect the conformation of the integrin?
- A cell can receive information about its surroundings from its adhesion to ECM
- This can alter the phenotype and conformation of the cells
- The legs separate and cytoplasmic signaling molecules can then bind and that binding will then allow signaling to take place
what is it called when there is not enough growth factor for a high density of cells?
- density dependence of cell division
how does signalling control the proliferation of tissues?
- Growth factors trigger the ERK cascade and cause cell division
- there is cross-talk between ECM and growth factor signaling
- the signaling from the ECM and growth factor come together to produce proliferation
what is contact-induced spreading of epithelial cells?
- When the cells made contact, there was a mutual induction of spreading
- They would form stable junctions between the cells
- this is called contact-induced spreading of epithelial cells
- this allows epithelial cells to form a coherent epithelium
what is the molecular organization of adherens junctions?
- adherens junctions control the formation of other types of junctions
- it consists of a cadherin (calcium dependent, homophilic cell adhesion molecule) which binds to similar molecules on the adjacent cell
- Intracellularly it binds to β =catenin, which is associated with α =catenin, which, in turn, links to the actin cytoskeleton
what is adenomatous polyposis coli?
- APC is an inherited form of colon cancer there are familial forms
- The APC gene- product is a protein that is involved in the degradation of beta-catenin
what might happen to epithelial cells if they lose contact inhibition?
- Cancerous cell lose contact inhibition of locomotion and they will pile up on each other
give examples of oncogenes and proto- oncogenes?
what happens to anchorage dependence and density dependence in cancer?
- In cancer you have usually lost anchorage dependence (ECM binding) and 60 density dependence (growth factor)
- A normal cell would not be able to proliferate if it loses both these signals
- However, a cancer cell doesn’t require either of these signals because the growth signal has been permanently turned on
- The pathways has been ‘short=circuited’
what is the difference in proliferation of cancer between benign and malignant tumours?
- Benign = there is too much proliferation but it is contained in one place
- Malignant = the cells are usually more poorly differentiated and they invade surrounding tissues
