The hallmarks of cancer

Question 1

What are the stages of the metastasis cascade

Answer 1

primary tumour
Localised invasion of surrounding tissue
Intravasation - invasion of cancer cells through the basal membrane into a blood vessel
Transport through circulation
Arrest in microvessels of various organs
Extravasation of surrounding tissues and form micrometastases followed by large ones.

Question 2

What is the basement membrane

Answer 2

A specialised extracellular matrix that surrounds the epithelia.

Question 3

When are carcinomas considered benign?

Answer 3

If they are contained within the basement membrane

Question 4

Do cancer cells acquire the ability to breach the basement membrane and invade nearby stroma singly or in groups?

Answer 4

Both

Question 5

How does intravasation occur

Answer 5

Studies suggest that the interation with macrophages and endothelial cells enables breast cancer cells to invade through the endothelial wall.

Question 6

What kind of an environment is the blood for cancer

Answer 6

Actively hostile - only a tiny proportion of circulating tumour cells are successful in founding new metastatic colonies.

Question 7

Does the location of the primary tumour have any influence on the area of metastasis

Answer 7

Yes - preferentially moves to specific organs depending on primary location - unsure why

Question 8

What are the three main sites of metastasis

Answer 8

Lungs, Bone, Brain

Question 9

What do the cancer cells do once they are trapped in one of the organs

Answer 9

Escape by extravasation
The opposite of intravasation
Again suggested to be by an interaction between cancer cells and macrophages

Question 10

What is colonisation

Answer 10

The growth of microscopic metasteses and is the most difficult step for a cancer as the foreign environment does not provide the support that the cancer cells had in their primary site.

Question 11

How does localised invasion occur?

Answer 11

Epithelial to mesenchymal transition (EMT)

Question 12

What is required for EMT to occur

Answer 12

Lose following features:
Expression of cytokeratin, E-cadherin, Epithelial polarity and epithelial gene expression
AQUIRE:
Fibroblast like shape, Mobility and invasiveness, Mesenchymal gene expression (Fibronectin), Protease secretion to degrade the surrounding basement membrane

Question 13

How do cancer cells move after leaving the primary tumour?

Answer 13

Display many modes of migration (able to adapt to different environmental conditions, assuming different morphologies and migration characteristics in order to stay mobile)

Question 14

What is single cell migration

Answer 14

Lack of cell-cell interation
Low correlation of the cell and its neighbours
Cells can display different phenotypes

Question 15

What are the different phenotypes of single migrating cells

Answer 15

1: Amoeboid like has a round cell body with short or blebbing protrusion
2: Mesenchymal like cell are elongated cell bodies and longer protrusions

Question 16

What is collective cell migration

Answer 16

Groups of cells retain cell-cell adhesions. They move as either a narrow linear strand or as broad irregular sheets.

Question 17

What is required of the leader cells of collective migrating cells

Answer 17

Mesenchymal characteristics - able to degrade the ECM around them

Question 18

What is migration plasticity

Answer 18

Cancer cells have the ability to switch between migration modes - which makes it challenging to design anti-metastatic pathways that target a single migratory mode.

Question 19

How do Anti-metastatic therapies target migrator modes

Answer 19

Target the master regulators that control and allow the cancerous cells to switch between the different modes of migration.

Question 20

Is mutant p53 expression the same as null p53

Answer 20

Not completely - mutant p53 can also acquire new functions to drive cell migration, invasion and metastasis

Question 21

What is the role of p53 in regard to EMT and cell migration

Answer 21

p53 prevents the loss of cell-cell junctions, opposing EMT.
It inhibits the activity of a variety of pro-migratory proteins, resulting in the reduction of cell migration and invasion.

Question 22

How does mutant p53 promote an aggressive cancer phenotype (pancreatic cancer as 50-75% of PDAC have p53 mutations, following the mutation of kras)

Answer 22

Results in the expression of a stable mutant (R175H) rather than the loss of p53 expression.

Question 23

What were the two mouse models for PDAC

Answer 23

LoxP mouse with a specific promoter found in the pancreas.
Stop codon for mutant k-ras is floxed as is p53. So when Cre recombinase is expressed: k-ras is expressed and the p53 is lost (in the pancreas)
2nd mouse
Same as previous but now a stop codon is floxed infront of the mutated p53.
This allows for the comparison of mice with no p53 or with mutant p53

Question 24

What was the result of p53 mutant expression vs no expression in the PDAC mouse

Answer 24

mutant p53: half the mice had metastases whereas the p53 null mice had no metastases.

Question 25

How does mutant p53 encourage metastases

Answer 25

It promotes the recycling of integrins and growth factor receptors from the endosome to the plasma membrane.
The increased recycling sustains downstream akt signalling, promoting cancer cell invasion and metastasis