Flashcards in Metastasis - L5 Deck (37):
What is metastasis ?
it is the spread of cancer from the organ of origin to one that is not directly connected to it
- it is the process that seriously causes damage
- happens in most cancers if they are left untreated
- it is frequently the life threatening part of getting cancer
What does EMT stand for?
epithelial mesenchymal transition
What are most tumours?
most tumours are epithelial and are connected by cell-cell junctions= E-cadherin junctions
What separates the epithelial cells from the stromal cells ?
basement membrane - laminin is the key protein present in this
What are examples of proteins that connect cells together?
claudin, occluding and JAM
- claudin is down regulated in breast cancer
What happens when E-cadherin is lost?
it is a key step in the progression of cancer because the cells are no longer connected and therefore they can go off and do their own thing
What is EMT?
it is the loss of epithelial characteristics and acquisition of mesenchymal ones (lose association, polarity)
- it is a gene reprogramming event that cancer cells go through before they acquire characteristics to go off and invade the body
- cells end up under the control of new transcription factors= mesenchymal set of associated transcription factors, these induce expression of hundreds of these cells, producing cells that are more motile, lack polarity so they move around
How is E-cadherin lost ?
lost by promoter methylation (epigenetic process-the methyl groups prevent transcription factors binding), repression, mutation
In EMT the cells are under control of new transcription factors. What does this cause?
- changes in cell morphology and gene expression
- enhanced stem cell like traits, invasiveness and motility e.g. immune to chemotherapy and are able to differentiate into many cell types
- synthesis/secretion of enzymes to modify the stroma- degrade matrix of stroma
- increased resistance to apoptosis
How is EMT induced?
By stromal factors
- hypoxia, low pH, low glucose, alterations in extracellular matrix, liberation of previously bound growth factors from ECM
What are the transcription factors associated with EMT?
Snail, Slug and Twist - they are associated with mesenchymal phenotype
- high levels of these transcription factors means a reduced survival rate because it makes the tumour more aggressive as it can metastasise
What is the step-wise nature of metastasis ?
1) LOCAL INVASION= of basement membrane, it needs to be degraded to prevent separation of epithelial cells from their surroundings
2) INTRAVASATION= cells invade into blood- cells interact with all different factors
3) SYSTEMIC DISTRIBUTION= travel through blood stream and lymph nodes- this strongly influences where the cancer ends up
4) EXTRAVASATION= cells leave blood vessels
5) MICROMETASTATIC FORMATION= at new site but they are undetectable
How does the condition of the basement affect surgical resection ?
if the basement membrane is intact then it is unlikely that distant metastases will occur
whereas if the basement is lost then months after the surgery it is likely that the patient will suffer metastatic relapse
In local invasion the basement membrane is degraded. How are MMPs linked to this ?
when MMP3 were forcibly expressed in mouse mammary cells it was sufficient to induce carcinogenesis followed by metastasis
MMP inhibitors failed in clinic because they are vital for normal functions such as cartilage remodelling
How does intravasation occur ?
Cancer cells escape basement membrane
MMP proteins degradation and signalling effects cause the endothelial cells lining blood vessels to separate
cancer cells use many other cells to carry out this process because they are able to reprogram other cells to do what they want e.g they can reprogramme macrophages reprogramme the endothelial cells
= paracellular intravasation
What happens in transcellular intravasation ?
the cancer cells just go through the endothelial cell
What is the "seed and soil" hypothesis ?
by stephan paget
= metastasizing cancer cells (seed) find a compatible home only in certain especially hospitable tissues (soil)
How is organ tropism determined?
- characteristics of metastatic target organ
- intrinsic characteristics of cancer cells
- systemic impact of the primary tumour
- blood flow pattern
The specific dissemination is based upon the primary origin of the cancer cells
How does extravasation occur ?
cancer cells express many different plasma membrane proteins that recognise signals on the endothelial cells lining blood vessels
it gradually binds more and more factors and becomes stickier until it sticks there
cancer cells have to contain the correct reprogramming mechanisms to then migrate through the gap between the endothelial cells
What does the presence of micrometastases indicate?
it correlates with poor prognosis - reduced chance of survival
What is clonal evolution of cancers?
tumours are made up of cells acquiring mutations as cells continually divide
- each new mutation gives rise to a new subpopulation of tumour cells
- so when you look at a tumour you get different cells with different genotypes
What are the common problems of studying diet and associating it to cancers?
- questionnaires aren't very reliable
- difficult to carry out a proper placebo component
- difficult to ensure high adherence from people
- how do you know how long to carry out the experiment
- unsure whether cell lines are good models
- confounding factors= if a person eats a lot of one food are they more likely eat other foods
What % of cancers are thought to be preventable by lifestyle changes ?
What dietary factor has been associated with increased risk of breast cancer ?
the more calories of animal fat consumed, increases your chances of developing breast cancer
What dietary factor has been negatively correlated with breast cancer risk ?
consumption of plant proteins
is it the consumption of plant protein or the the reduction in animal fat consumption
What is the Liver X receptor ?
its a transcription factor
binds and senses cholesterol metabolites
anti-proliferative in every cancer line studies
activity is dependent upon the amount of circulating cholesterol
What other structures are similar to cholesterol ?
stigmasterol = plant phytosterol
What does the slight difference in 22(R) hydroxycholesterol structure mean ?
it means it cannot signal through LXR and it is therefore a strong antagonist
What does stigmasterol do to LXR?
it represses them - preventing cholesterol metabolites activating them
What can 22 (R) hydroxycholesterol inhibit and what does SULT2B do?
-can inhibit cyp11a1
- removes LXR ligand so it cant signal through this receptor
What are the opposing effects of 22(R) hydroxycholesterol and stigmasterol ?
22- binds to receptors and drives gene expression
stig- binds and represses gene expression
What is link between breast cancer and high HMGCR and low SULT2B?
it causes reduces chances of survival because these tumours contain lots of oxysterols which can act on LXR
What do dietary phytosterols do ?
They reduce chemoresistance, metastasis and stem cells
What happens if hydroxycholesterol and phytosterols are given in combination ?
they counteract the relationship between LXR and cholesterol metabolites
What do LXR induce in the presence of cholesterol and phytosterols ?
cholesterol= chemotherapy resistance, stem cell like properties and metastasis
What is the link between Vitamin D3 and prostate cancer ?
D3 is anti-proliferative in prostate cancer cells
it cooperates with p53 to control cell cycle progression
vit d reduces prostate cancer
Areas which receive less sunlight demonstrate a higher incidence of prostate cancer