Metastasis - L5 Flashcards
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
6) COLONISATION
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
