Lecture 11- Cancer invasion and metastasis

Question 1

Cancer Progression

Answer 1

• Cancer cells grow near the site where uncontrolled proliferation first began, resulting in the formation of the primary tumour mass.
• Only about 10% of cancer deaths are caused by primary tumours
• 90% of patients die because of cancer growths at sites (far) away from the site of the primary tumour  metastasis

Question 2

metastasis

Answer 2

• cancer is away from its original site

Question 3

Invasion metastasis cascade

Answer 3

1. primary tumour formation
2. localised invasion
3. intravasation (interaction with platelets, lymphocytes, and other blood components)
4. Transport through circulation
5. arrest in microvessels of various organs
6. Extravasation
7. formation of micrometastasis
8. colonisation- formation of a macrometastasis

Question 4

Localised invasion –

Answer 4

• Epithelial organs are surrounded by a specialised extracellular matrix called basement membrane, which separates the organs from the surrounding stroma
• Carcinomas are consider benign if they are contained within the basement membrane
• Cancer cells acquire the ability to breach the basement membrane and invade the nearby stroma (singly or in groups)
Can easily be studied in the lab in in vitro systems

Question 5

Intravasation –

Answer 5

• Intravasation process is less studied than localised invasion
• Studies suggest that the interaction with macrophages and endothelial cells enables breast cancer cells to invade through the endothelial walls in the lumen of the capillaries
• Individual cancer cells can than travel to other areas in the body
• The blood is an actively hostile environment for cancer cells  only a tiny proportion of circulating tumour cells are successful in founding new metastatic colonies
Tiny proportion of cancer cells can actually survive in the blood

Question 6

Extravasation-

Answer 6

cancer cells leave the BV and enter tissue
• Wandering cancer cells are physically trapped within small vessels
• Cancer cells must escape from these vessels and penetrate into the surrounding tissues  extravasation
• As in the case of intravasation, cancer cell/macrophage interaction has been shown to facilitate extravasation

Question 7

Formation of a micrometastasis

Answer 7

cancer cells arrive in new env and grow

Question 8

micrometastases

Answer 8

• Once cancer cells arrive in the parenchyma of a tissue, they form small clumps of cancer cells =

Question 9

Colonisation

Answer 9

• The growth of microscopic in macroscopic metastases

Question 10

Why is Colonisation the most difficult step of the cascade?

Answer 10

the foreign tissue environment does not provide the support that cancer cells had in their primary tumours

Question 11

• The probability of an individual cell to complete all the steps of the invasion-metastasis cascade is

Answer 11

very low&raquo_space; metastatic inefficiency

Question 12

What effect does a change in env have?

Answer 12

Different signals in gland vs bone – change in env reduces survival chances

Question 13

Localised invasion

Answer 13

First step of invasion cascade
Involves major changes to phenotype of cancer cells within the primary tumour
In order to migrate, epithelial cells need to undergo a drastic alteration -Epithelial to mesenchymal transition

Question 14

Characterisation

Answer 14

Characterized by loss of epithelial features and acquisition of mesenchymal features

Question 15

loss of Cytokeratin expression

Answer 15

Acquisition of fibroblast -like shape

Question 16

loss of tight junction and adherence junction involving E-cadherin

Answer 16

Acquisition of Motility and invasiveness

Question 17

Loss of epithelial cell polarity

Answer 17

Acquisition of mesenchymal gene expression

Question 18

Loss of Epithelial gene expression program

Answer 18

Acquisition of protease secretion

Question 19

Migration modes

Answer 19

1. Single
2. collective
3. Migration plasticity -Acquire migratory mode most efficient depending on their env

Question 20

Single cell migration:

Answer 20

• Lack of cell-cell interaction during migration
• Low correlation in the migration pattern between a cell and its neighbours
• Cells can display different phenotypes: in amoeboid-like = round cell body with short or blebbing protrusions, or mesenchymal-like = elongated cell body and longer protrusions

Question 21

Collective cell migration:

Answer 21

• Group of cells retaining cell-cell adhesions for long period of time
• Cells move either as narrow linear strands lead by one leader cell or as broad, irregularly shaped sheets, which are multiple cells in diameter and lead by several leader cells
• Leader cells acquire mesenchymal characteristics- Partial EMT

Question 22

Migration Plasticity

Answer 22

• Cancer cells have to ability to switch between migration modes  plasticity: different modes of single and collective cells migration + individual-to-collective & collective-to-individual transition
• Challenge for the design of anti-metastatic therapies  targeting the determinants of a single migration mode is unlikely to block metastasis
• Strategy  targeting master regulators controlling plasticity, to hinder the ability of the cells to switch between migration modes
Inhibitors can be designed to block pathway if single pathway induces

Question 23

P53

Answer 23

• The tumour suppressor p53 is lost or mutated in ~ half of all human cancers  expression of a transcriptionally inactive mutant p53
• Loss of p53 function influences cell cycle checkpoint controls and apoptosis
• BUT p53 also regulates other key stages of cancer progression, such as cell migration and invasion
• Expression of mutant p53 is not equivalent of p53 loss  mutant p53 can acquire new functions to drive cell migration, invasion and metastasis

Question 24

Loss of p53 function influences

Answer 24

Loss of p53 function influences cell cycle checkpoint controls and apoptosis

Question 25

p53 also regulates

Answer 25

other key stages of cancer progression, such as cell migration and invasion

Question 26

Expression of mutant p53

Answer 26

is not equivalent of p53 loss  mutant p53 can acquire new functions to drive cell migration, invasion and metastasis

Question 27

P53 WT

Answer 27

inhibits EMT and cell Migration
• p53 prevents the loss of cell-cell junctions, thus opposing EMT
• P53 inhibits the activity of a variety of pro-migratory proteins, resulting in a reduction in cell migration and invasion

Question 28

Mutant P53

Answer 28

promotes and aggressive caner phenotype
• p53 mutations are are found in 50-75% of pancreatic ductal adenocarcinomas (PDAC), following an initial activating mutation of K-Ras.(constituitively active)
• These mutations result in expression of a stable mutant (R175H), rather then p53 loss

Question 29

Evidence - experiment

Answer 29

• 2 transgenic mice
  P53 null K-Ras G12D activating mutation and loss of P53 in the pancreas
• Mutant P53
  K-Ras G12D activating mutation and expression of mutant P53 in the pancreas
• Pre recombinase technology

Question 30

Evidence - experiment Results

Answer 30

No p53 – none from metastasis
Mutant – more than Half metastasis

• Mutant p53 expression promotes the recycling of integrins and growth factor receptors from the endosomes to the plasma membrane
• The detail molecular mechanisms mediating this have not been elucidated yet
• The increased recycling sustains downstream Akt signalling, promoting cancer cell invasion and metastasis