Intro To Metastasis

Question 1

Difference between malignant and benign neoplasms

Answer 1

Benign - well differentiated, non invasive, genomically stable, encapsulated, low mitotic rate
Malignant- undifferentiated, invasive, genomically unstable, non ecapsulated, high division rate

Question 2

Define metastasis

Answer 2

When a tumour cell leaves the primary tumour, travels to a distant site and establishes a secondary tumour

Question 3

Why is metastasis common?

Answer 3

Millions of tumour cells shed daily into circulation, depending on tumour
Metastatic cells can have dormant phase

Question 4

Describe the metastasis process

Answer 4

Tumour cell breaks off primary tumour and enters ECM
MMPs secreted to degrade ECM and allow movement through BM and into vasculature
EMT signals facilitate motility and intravasation
Cells travel in blood vessels- survival and dormancy at distant sites
Tumour cells enter tissues through junctions due to weak adhesion of tumour cells to endothelial cells
Open pathway created for other tumour cells
Colonisation of new tissue

Question 5

MMP function in normal cells

Answer 5

MMPs cleave portion of ECM
Modify interaction between cellular adhesion molecules and ECM components
ECM cleavage used to free up space, modify signalling molecules

Question 6

What molecule of ECM is especially disregulated in metastasis?

Answer 6

E cadherin
Anchors cell to surrounding cells and stabilises cytoskeleton.
In cancer cells cleavage of e cadherin by MMPs is increased = cells are free to move

Question 7

What are lytic enzymes and how are they classified?

Answer 7

Enzymes which break down ECM
Can be:
Serine-
Cysteine-
Aspartyl- proteases
Or MMPs

Question 8

Serine proteases in ECM degradation

Answer 8

Plasmin
Plasminogen activators
Cathepsin G

Question 9

What is plasmin

Answer 9

Protease that degrades fibronectin and laminin

Involved in angiogenesis

Question 10

Plasminogen activators

Answer 10

What Urokinase plasminogen activator (uPA) is bound to surface of tumour cells
Following plasminogen activation there is tissue invasion
PA inhibitor proteins (PAI1/2) are upregulated in metastatic cancer
Inhibitors could be used as anticancer agents

Question 11

Influence of integrins in metastasis

Answer 11

Affect MMP activity

MMPs need to be activated by integrins

Question 12

Change of cadherin expression in cancer

Answer 12

Switch from e cadherin to n-cadherin ( more embryonic)
This is epithelial mesenchymal transition
This switch leads to increased tumour cell invasion

Question 13

4 factors determining destination sites for metastatic tumours

Answer 13

Venous drainage blood flow - blood supply
Chemotaxis- the organ produces factors that attract tumour cells
Compatible adhesion sites on endothelial surface
Appropriate GFs and ECM environment

Question 14

Contribution of inflammation to metastasis

Answer 14

Tumour cell expression of chemokine receptors
Chemokines induce directed chemotaxis in nearby responsive cells
Chemokines normally regulate leukocyte recirculation and trafficking to sites of inflammation
Allow tumour cells to reach sites of metastasis