Cancer invasion and metastasis

Question 1

What % of cancer-related deaths are due to the primary tumour?

Answer 1

10%

Question 2

What are the steps of the invasion-metastasis cascade?

Answer 2

Primary tumour formation 
localized invasion 
intravasation 
transport through circulation 
arrest in microvessels of various organs
extravasation 
formation of micrometastases 
colonization- formation of macrometastases

Question 3

What is the basement membrane?

Answer 3

Specialised extracellular matrix which is essential for the structure of a organ, also important for separating organs from the surrounding stroma

Question 4

What is it called if a carcinoma is contained to the basement membrane?

Answer 4

The cancer is said to be benign if it is localised and contained

Question 5

What is intravasation?

Answer 5

The process of cancerous cells entering the blood and lymphatic vessels

Question 6

What interactions are thought to be essential for intravasation?

Answer 6

Interactions between the cancerous cells and macrophages and endothelial cells which make up vessel walls
interaction allows cancerous cells to enter the blood through the endothelial walls

Question 7

What is extravasation?

Answer 7

The process of cancerous cells escaping the vessels and entering tissue

Question 8

What is thought to facilitate extravasation?

Answer 8

Interaction between cancerous cells and macrophages

Question 9

What happens when cancerous cells first arrive in new tissue?

Answer 9

They are situated in the parenchyma of the tissue and form small clumps of cancer cells= micrometastasis

Question 10

Why is colonisation so difficult?

Answer 10

The cancerous cells are in a different environment to their native environment- dont receive the same signals etc

Question 11

What is metastatic inefficiency?

Answer 11

The general inefficiency of the invasion/metastasis process

few individual cells complete the whole process- many wont survive

Question 12

Why do cancer cells undergo an epithelial-to-mesenchymal transition?

Answer 12

Epithelial cells are firmly attached to one another and the basement membrane- they arent mobile cells
to be able to migrate these cells must change their phenotype

Question 13

What is lost in the EMT?

Answer 13

Cytokeratin expression
tight junction and adherence junctions involving E-cadherin
epithelial cell polarity
epithelial gene expression- e.g catenins

Question 14

What is gained in the EMT?

Answer 14

A fibroblast like shape
motility and invasiveness 
mesenchymal gene expression e.g fibronectin
protease secretion 
vimentin expression

Question 15

What is single cell migration?

Answer 15

The migration of cells independent of cell-cell interactions
cells migration is not dependent on its neighbours migration pattern

Question 16

What are the types of single cell migration?

Answer 16

Amoeboid like- round cell body with blebbing protrusions

Mesenchymal-like- elongated cell body with longer protrusions

Question 17

What are the types of collective cell migration?

Answer 17

Narrow linear strands- lead by one leader

Irregularly shaped sheets- multiple cells in diameter- lead by several leader cells

Question 18

What is migration plasticity?

Answer 18

When cancer cells can switch between different migration modes- individual to collective and vice versa

Question 19

Why is migration plasticity a problem when trying to block metastasis?

Answer 19

Blocking a single migration mode isn’t helpful when cancer cells can just switch to another

Question 20

Whats a new strategy for trying to block metastasis?

Answer 20

Targeting the master regulators which controls a cell’s ability to switch - hinder the cells ability to switch

Question 21

P53 affects what- as well as cell cycle control and apoptosis-?

Answer 21

Cell migration and invasiveness

Question 22

How does P53 oppose EMT?

Answer 22

P53 inhibits the loss of cell-cell junctions

BUT not the mutant form of P53

Question 23

What does mutant P53 promote?- what cancer is it associated with

Answer 23

An aggressive cancer phenotype -

mutant P53 is found in 50-75% of pancreatic ductal adenocarcinomas

Question 24

What model showed the difference between null P53 and mutant p53?

Answer 24

Transgenic mice model
cre-recombinase
1st mouse-stop codon upstream of a pancreas specific promoter and P53 floxed, (k-ras also under control of this promoter)
cre recognises the lox-p sites and removes whats in between
activation of ras and removal of p53
2nd mouse- p53 is not floxed
expression of ras and mutant p53

Question 25

What was the difference between the transgenic mice in terms of survival and liver metastasis?

Answer 25

Survival- no difference between the groups
Metastasis- null p53= no metastases
mutant p53= half of the mice showed liver metastases

Question 26

What can be concluded about mutant p53?

Answer 26

It drives the formation of metastases

Question 27

In terms of the mechanisms of cancer invasion- what part does mutant P53 have?

Answer 27

Mutant P53 promotes the recycling of integrins and growth factors
increased recycling= sustained downstream Akt signalling (positive regulator of cell cycle progression)- which drives cancer invasion and metastases