Invasion And Metastasis Flashcards
(37 cards)
What is metastasis
A secondary tumour that grows separate from the primary and has arisen from detached transported cells
What are the two common hits in colorectal cancer?
APC gene (a tumour suppressor) by a germline mutation in FAP and a somatic mutation in sporadic CRC
Second hit is a somatic mutation to APC
After the initial two hits in CRC, what other mutations can occur after this?
In proto-oncogenes
- KRas
- Smad4
p53
What do the initial two hits in CRC cause?
Aberrant crypt foci and progression to early adenoma
What are the steps in metastasis?
Growth of primary tumour
Local invasion
Transport to different sites
Thrive at a new site
How can cancer cells be transported to different sites?
Intravasation
Transport through circulation
Arrest in microvessels of various organs
If metastasis is such an inefficient process, what makes it successful?
The huge number of cells
What steps do cells have to do in order to metastasis which makes it inefficient?
Intravasate into the vasculature and survive in the bloodstream
Arrive and arrest in secondary sites
Extravasate out of the vasculature into the secondary organ
80% get to this point
Form micrometastases - around 2% initiate growth
Persist to grow into micrometastases - 0.02% manage this
Give an example of what environmental changes can occur to allow metastasis
Tumour-associated macrophages promote breast cancer metastasis
-A paracrine loop between tumour cells and macrophages is required for tumour cell migration
How is cell-to-cell adhesion lost?
Changes in cadherins such as E-cadherin on the plasma membranes that hold cells together
How can E-cadherin be repressed?
Activation of repressors such as
- SNAIL
- SLUG
- ZEB1
- ZEB2
Which cancer is high expression of ZEB1 and 2 seen in?
Bladder cancer - leads to less E-cadherin
What is epithelial to mesenchymal transition?
When cells lose their polarity and cell-cell adhesion
Gain migratory and invasive properties to become mesenchymal stem cells
How can epithelial to mesenchymal transition be activated?
A number of signalling pathways including
- E-cadherin and catenins being repressed which are epithelial markers
- mesenchymal markers induced such as fibronectin and N-Catherine
What are the different types of migration modes cells need to have to metastasise?
Mesenchymal transition
Amoeboid transition
Collective migration
Which types of cancer cells use mesenchymal transition?
Fibrosarcoma
Glioblastoma
What happens to allow mesenchymal transition?
Activation of Rac at the leading end allowing formation of new contracts (integrin)
Inhibition of Rho leading to dissolution of adhesions at the other end
Contraction of actin and myosin to promote translocation of the cell
How is Rho activated in mesenchymal transition?
When a GDP nucleotide is converted to GTP by guanine nucleotide exchange factors
What is amoeboid motility?
When cancer cells squeeze through matrix barriers without the use of MMPs or integrin engagement
Which cells migrate using amoeboid motility?
Leukaemia and lymphoma
What is collective migration?
When a number of cells move together and so retain cell-to-cell adhesion
What must be changed about proteolysis of a cell in order to invade?
Remodelling of the extracellular matrix - must destruct the basement membrane
Increased proteolytic activity of the cells
What are some extracellular matrix degrading proteins?
Matrix metalloproteinases Serine proteases Adamlysin-related membrane proteases Bone-morphogenic protein (BMP)-1 type metalloproteinases Heparanases Cathepsins, cysteine proteases
Give some examples of serine proteases? (A category of extracellular matrix degrading proteins)
Plasminogen activating system
Plasmin
Serpins
Thrombin
