L6 - Invasion and Metastasis I Flashcards

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1
Q

The uncontrolable growth of cancer cells at a specific site is known as …

A

Primary cell mass

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2
Q

How many deaths does the primary cell mass causes

A

10%

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3
Q

What is responsible for the other 90% of deaths

A

When the cancer spreads to secondary - distal sites - this is known as metastasis

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4
Q

Stages of the invasion-metastasis cascade

A

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

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5
Q

Is the secodnary organ that a cancer cell ends up at random?

A

No

Cells from different cancers are able to migrate to specific organs

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6
Q

What organs does breast cancer tend to metastasise to

A

Lung
Brain
Bone

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7
Q

What are cancers from epithelial cells known as

A

Carcinomas

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8
Q

Why are carcinomas initially known as benign

A

BEcause surrounded by basement membrane - confines the cancer to a specific environment

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9
Q

When does a benign tumour become dangerous?

A

When the basement membrane has been breached

Cancer cells are then able to invade into the surrounding stroma

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10
Q

how can breaching of the basement membrane be visualised in vitro

A

Using a breast cancer organoid

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11
Q

What is important to allow intravasation

A

Interaction between the cancer cells and macrophages and the endothelial cells

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12
Q

Describe what live cell imaging has shown regarding the cancer cells interactions with macrophasges

A

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

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13
Q

Why is live cell imaging of the intravasation interactions hard to get

A

Since frequency of these events occuring is v low

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14
Q

Extravastion occurs when …

A

Cells become physically trapped within the small vessels of organs

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15
Q

What must occur during extravasation

A

Cells must escape the vessel and penetrate the surrounding organs

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16
Q

What interaction fascilitates the extravasation

A

interaction with macrophages

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17
Q

How can confocal microscopy allow us to visualise extravasation

A

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

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18
Q

How do micrometastases form

A

Once cells arrive at the secondary site they form little clumps
Can remain like this for several years

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19
Q

What is growth of a micrometastasis known as

A

Colonisaion

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20
Q

Why is colonisation the most difficult step of invasion-metastasis

A

Since foreign tissue doesnt provide the support that cancer cells had in their primary tumours

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21
Q

The fact that their is a low prob of a cell completing all of the steps of the cascade is known as …

A

Metastatic inefficiency

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22
Q

What s the first step of the cascade

What does it involve

Describe this

What is this process known as

A

Localised cell invasion

Major phenotypic changes - since the organisation of epithelial cells is normally incompatible with motility

EMT

23
Q

What does the EMT involve

A

Loss of E characteristics

Gain of M characteristics

24
Q

Examples of some charactertistics that are lost during the EMT

A

Cytokeratin expression
Tight junctions and adherence junctions involving E-Cadherin
Epithelial cell polarity
Epithelial gene expression program (e.g. catenin)

25
Q

Examples of some characterstics that are gained during the EMT

A
Fibroblast like shape 
Motility and invasive potential 
Mesenchymal gene expression (fibronectin)
Protease secretion (MMPs)
Vimentin expression
26
Q

How can we visualise the EMT occuring

A

Immuno staining for various E and M characteristics

Can see changes occuring

27
Q

Describe how invasion and E-cadherin expression was monitored in vivo

What were the conclusions

A

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

28
Q

What is further evidence from platelets regarding the importance of the EMT

A

In circulation cancer cells interact with platelets
Causes more EMT
Fascilitates extravasation

29
Q

At the end of metastasis what transition is required

Why

A

MET required

To allow micrometastases to form macrometastases
Need to gain cell contact to allow survival

30
Q

Historically what was though of the EMT

How has this changed

A

Binary process - cell is either mesenchymal or it is epithelial

Now thought to be a gradual process with numerous intermediate states

31
Q

What do these intermediate states confer

A

Specialist properties

32
Q

When is a cell more suited to proliferate

A

When fully epithelial

33
Q

When is a cell better suited to invade

A

When fully mesenchymal

34
Q

When is a cell better suited to metastasise

A

When it is a hybrid

35
Q

What three things is EMT also involved in

A

Cancer stem cells
Chemoresistance
immunotherapy resistance

36
Q

How is EMT involved in cancer stemness

A

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

37
Q

How is EMT involved in chemoresistance

A

EMT contributes to resitance to chemotherapy

Can target to overcome chemoresitance

38
Q

How is EMT involved in resistance to immunotherapies

A

Epithelial tumours are more suseptible to immunotherpay

So would be better to treat cance rif we could inhibit EMT and render the cells epithelial

39
Q

What are the three TFs involved in the EMT

A

SNAIL
TWIST
ZEB

40
Q

What is SNAIL improtant in

A

Breast cancer metastasis to the lung

41
Q

What are both Zeb1 and 2 ivolved in promoting

A

Cell migration and invasion in breast and colorectal cancers

42
Q

What is Zeb1 expression required for

A

Efficient invasion and metastasis n a mouse pancreatic cancer model

43
Q

What are EMT TFs turned on in response to

A

Pleotropic signals

44
Q

What is the net effect of the EMT TFs

A

Inhibition of E genes

Expression of M genes

45
Q

The fact that cancer cells can migrate into the stroma in a variety of ways means

A

Cancer cells can adapt and adopt different morphologies and migration characteristics depending on their environment

46
Q

Characteristics of single cell migration

A

Lack of cell interaction during migration
Uncordinated (different cells do different things)
Can dispay different phenotypes

47
Q

Describe the different phenotypes that can be seen by single cells migrating

A

Ameoboid-like - round cells with short or blebbing protrusions

Mesenchymal-like - elongated body and longer protrusions

48
Q

Characteristics of collective cell migration

A

Retention of adhesions

49
Q

How do cells move during collective migration

A

As one linear strand or as a broad sheet

50
Q

What properties does the leader cell have

A

Mesenchymal characteristics

Likely to be an intermediate phenotype

51
Q

Can cancer cells switch their methods of migration?

A

YES

This is known as plasticity

52
Q

Give some examples of migrational plasticity

A

Can go single Collective
OR
Transition between the different modes of singe cell migration

53
Q

What is the chanllenge when designing treatments for anti-metastats wrt cell migration

A

Targetting the determinants of a single migration mode unlikley to block metastasis

54
Q

So what is the overall strategy when designing treatments to prevent metastasis (wrt migration)

A

Target the master regulators controlling plasticity

This will hinder the ability of cells to switch between the migration modes