L6 - Invasion and Metastasis I Flashcards
The uncontrolable growth of cancer cells at a specific site is known as …
Primary cell mass
How many deaths does the primary cell mass causes
10%
What is responsible for the other 90% of deaths
When the cancer spreads to secondary - distal sites - this is known as metastasis
Stages of the invasion-metastasis cascade
Primary tumour formation
Localised invasion
Intravasation
Transport in the circulation or lymphatic systems
Arrest in microvessels of various organs
Extravasation
Formation of a micrometastases
Colonisation and formation of a macro metastasis
Is the secodnary organ that a cancer cell ends up at random?
No
Cells from different cancers are able to migrate to specific organs
What organs does breast cancer tend to metastasise to
Lung
Brain
Bone
What are cancers from epithelial cells known as
Carcinomas
Why are carcinomas initially known as benign
BEcause surrounded by basement membrane - confines the cancer to a specific environment
When does a benign tumour become dangerous?
When the basement membrane has been breached
Cancer cells are then able to invade into the surrounding stroma
how can breaching of the basement membrane be visualised in vitro
Using a breast cancer organoid
What is important to allow intravasation
Interaction between the cancer cells and macrophages and the endothelial cells
Describe what live cell imaging has shown regarding the cancer cells interactions with macrophasges
Tumour cells come close to and interact with macrophages
Close to the endothelial wall
After this has occured the tumour cells are able to invade through the wall of the vessel
Why is live cell imaging of the intravasation interactions hard to get
Since frequency of these events occuring is v low
Extravastion occurs when …
Cells become physically trapped within the small vessels of organs
What must occur during extravasation
Cells must escape the vessel and penetrate the surrounding organs
What interaction fascilitates the extravasation
interaction with macrophages
How can confocal microscopy allow us to visualise extravasation
Two focal planes
Above and below the wall of the vessel
Can see a cell vanish from one focal plane and appear in another as that cell crosses the wall
How do micrometastases form
Once cells arrive at the secondary site they form little clumps
Can remain like this for several years
What is growth of a micrometastasis known as
Colonisaion
Why is colonisation the most difficult step of invasion-metastasis
Since foreign tissue doesnt provide the support that cancer cells had in their primary tumours
The fact that their is a low prob of a cell completing all of the steps of the cascade is known as …
Metastatic inefficiency
What s the first step of the cascade
What does it involve
Describe this
What is this process known as
Localised cell invasion
Major phenotypic changes - since the organisation of epithelial cells is normally incompatible with motility
EMT
What does the EMT involve
Loss of E characteristics
Gain of M characteristics
Examples of some charactertistics that are lost during the EMT
Cytokeratin expression
Tight junctions and adherence junctions involving E-Cadherin
Epithelial cell polarity
Epithelial gene expression program (e.g. catenin)
Examples of some characterstics that are gained during the EMT
Fibroblast like shape Motility and invasive potential Mesenchymal gene expression (fibronectin) Protease secretion (MMPs) Vimentin expression
How can we visualise the EMT occuring
Immuno staining for various E and M characteristics
Can see changes occuring
Describe how invasion and E-cadherin expression was monitored in vivo
What were the conclusions
Breast cancer cells expressing fluroro-E-cadherin and cancer cells marked with YFP
As a cell migrates away this can be seen to be associated with the loss of CAM E-CAD
What is further evidence from platelets regarding the importance of the EMT
In circulation cancer cells interact with platelets
Causes more EMT
Fascilitates extravasation
At the end of metastasis what transition is required
Why
MET required
To allow micrometastases to form macrometastases
Need to gain cell contact to allow survival
Historically what was though of the EMT
How has this changed
Binary process - cell is either mesenchymal or it is epithelial
Now thought to be a gradual process with numerous intermediate states
What do these intermediate states confer
Specialist properties
When is a cell more suited to proliferate
When fully epithelial
When is a cell better suited to invade
When fully mesenchymal
When is a cell better suited to metastasise
When it is a hybrid
What three things is EMT also involved in
Cancer stem cells
Chemoresistance
immunotherapy resistance
How is EMT involved in cancer stemness
Small fraction of the cell within the tumour
Tumour initiating potential and the abiluty to give rise to a varietn of cell types
Activation of EMT linked to the acquisition of stem cell like properties
How is EMT involved in chemoresistance
EMT contributes to resitance to chemotherapy
Can target to overcome chemoresitance
How is EMT involved in resistance to immunotherapies
Epithelial tumours are more suseptible to immunotherpay
So would be better to treat cance rif we could inhibit EMT and render the cells epithelial
What are the three TFs involved in the EMT
SNAIL
TWIST
ZEB
What is SNAIL improtant in
Breast cancer metastasis to the lung
What are both Zeb1 and 2 ivolved in promoting
Cell migration and invasion in breast and colorectal cancers
What is Zeb1 expression required for
Efficient invasion and metastasis n a mouse pancreatic cancer model
What are EMT TFs turned on in response to
Pleotropic signals
What is the net effect of the EMT TFs
Inhibition of E genes
Expression of M genes
The fact that cancer cells can migrate into the stroma in a variety of ways means
Cancer cells can adapt and adopt different morphologies and migration characteristics depending on their environment
Characteristics of single cell migration
Lack of cell interaction during migration
Uncordinated (different cells do different things)
Can dispay different phenotypes
Describe the different phenotypes that can be seen by single cells migrating
Ameoboid-like - round cells with short or blebbing protrusions
Mesenchymal-like - elongated body and longer protrusions
Characteristics of collective cell migration
Retention of adhesions
How do cells move during collective migration
As one linear strand or as a broad sheet
What properties does the leader cell have
Mesenchymal characteristics
Likely to be an intermediate phenotype
Can cancer cells switch their methods of migration?
YES
This is known as plasticity
Give some examples of migrational plasticity
Can go single Collective
OR
Transition between the different modes of singe cell migration
What is the chanllenge when designing treatments for anti-metastats wrt cell migration
Targetting the determinants of a single migration mode unlikley to block metastasis
So what is the overall strategy when designing treatments to prevent metastasis (wrt migration)
Target the master regulators controlling plasticity
This will hinder the ability of cells to switch between the migration modes
