Kate Angel 1

Question 1

Why is the ability of a cancer to metastasis clinically relevant?

Answer 1

Only 10% of deaths from cancer are due to growth of the primary tumour
With the remainder of the deaths being due to cancerous growths detected in sites which are remote from the primary tumour

Question 2

What are metastases?

Answer 2

Tumour growths composed of cancer cells which have left the primary tumour from the blood or lymphatic circulation (the majority is through blood)

Question 3

Are all cancers equally likely to metastasise?

Answer 3

No some cancers such as melanomas are highly invasive while others such as basal cell carcinomas very rarely metastasise

Question 4

What is a microcolony or micrometastasis?

Answer 4

One or only a few cells

Question 5

What is the invasion-metastasis cascade?

Answer 5

In situ carcinoma breaches the basement membrane
Intravasate into the blood microvessels or lymphatics
Cells enter the circulation
Cancer cells become trapped in the microvessels in other organs
Cells Extravasate into tissue
Formation of a dormant micrometastasis
Some micrometastasis will colonize the tissue to from macrometastasis

Question 6

What are the two phases of the invasion-metastasis cascade?

Answer 6

Phase 1: Physical distribution of cells fro mthe primary tumour to distant tissues/organs
Phase 2: Colonisation where the disseminated cancer cells adapt to the microenvironment if the new tissue/organ

Question 7

How efficient is the Invasion-Metastasis cascade?

Answer 7

It is highly inefficient with a low chance that any cell leaving the primary tumour will found a distant metastasis
20% of cells are lost during extravasation and 96% attrition from micrometastasis formation and 99.3% attrition for metastatic colonization

Question 8

How does the basement membrane play a role in cancer?

Answer 8

Tumours begin on the epithelial side of the basement membrane, some carcinomas gain the ability to breach this membrane while others loose the membrane encasing the tumour
Loss of the basement membrane enclosing a carcinoma correlating with the probability of developing metastatic disease

Question 9

What happens to cancer cells after the breach the basement membrane?

Answer 9

They reach the stroma where they have direct access to blood vessels and lymphatics and access to plentiful nutrients
Cancer cells or stromal cells recruited by the cancer cells secrete proteases such as MMP9, MMP2
This allows ECM degradation and penetration of blood vessels

Question 10

How do cancer cells intravastate into the circulation?

Answer 10

Often require help from other cells to enter into the blood vessel lumen
The invasiveness and capacity of the cells to intravasate is stimulated by EGF from macrophages
This often results in visualisation of three cells in contact (cancer cell, endothelial cell and macrophage) which facilitates intravasion

Question 11

What is the difference between para and trans cellular intravasation?

Answer 11

In paracellular intravasation MMP-1 remodels endothelial junctions and TNFalpha secreted by macrophages inducing the retraction of endothelial cell junctions allowing migration though the produced gaps
In transcellular intravasation however there is vast remodelling of the endothelial cytoskeleton and membrane creating a pore in the cell for the cancer cell to move through

Question 12

Why is being in the blood lumen a hazardous place for cancer cells?

Answer 12

The detachment from a solid substrate can induce apoptosis
Stromal cells could be essential for the cancer cells survival, these are not present in the circulation
The sheer forces in small blood vessels can tear cancer cells apart

Question 13

What are microthrombi and how do they play a role in cancer cell survival?

Answer 13

Cancer cells can recruit platelets and red blood cells to clump around them
These can protect the cancer cell from damage in small blood vessels
Stop recognition and killing of the cancer cells by NK and lymphocytes
Platelets may expediate metastasis through their ability to bind to the vessel wall

Question 14

How do cancer cells travel in the circulation?

Answer 14

They must follow the traditional route of mammalian circulation meaning that they must reach the lungs, here many of the cells are too large to fit through the pulmonary capillaries and they can get stuck

Question 15

What are the different ways in which tumour cells can pass through the lung circulation?

Answer 15

Arterial-venous shunts

Question 16

What are the organ specific barriers to metastatic infilitration?

Answer 16

The blood-brain barrier
The traditional capillary as seen in the lung
The leaky capillary of the bone marrow sinusoid

Question 17

How do cancer cells extravasate from the circulation?

Answer 17

Typically occurs in small blood vessels or capillaries where the cells get trapped due to their size
Or due to stable attachments to endothelial cells to facilitate extravasation

Question 18

What are the two different mechanisms of extravasation?

Answer 18

The cancer cell can push through the vessel wall through use of factors such as ANGPL4 which disrupt endothelial junctions or the cancer cell leaving a gap through which the cell can move
Cancer cells can also proliferate in the lumen of the blood vessel causing it to rupture allowing it to come into contact with the endothelial cell basement membrane which the cancer cell will eventually break through

Question 19

What are the in vitro techniques for studying cancer cell transendothelial migration?

Answer 19

There are transwall assays where the endothelial cells are grown on a transwell and the number of cells which move through these cells in response to a chemo attractant is measured
Three-dimensional models can be used these are technically challenging and involve growing cells in or on ECM it also provides more accurate data