Tumour Biology

Question 1

Define metastasis.

Answer 1

A tumour deposit that is discontinuous with the primary tumour.

Question 2

List the processes involved in the metastatic cascade.

Answer 2

1 - Detachment from primary tumour and invasion of extracellular matrix.

2 - Intravasation.

3 - Migration.

4 - Extravasation.

5 - Colonisation.

*The rest of the lecture goes through each of these points in order.

Question 3

What is the rate limiting step in metastasis?

Why might this be?

Answer 3

• Colonisation.
• This is because most metastatic cells die after extravasating because they are unlikely to be adapted to the new environment.

Question 4

What facilitates detachment of metastatic cells from the primary tumour?

Answer 4

Downregulation of adhesion molecules such as E-cadherin.

Question 5

In which cells are E-cadherins most common?

Answer 5

Epithelial cells.

Question 6

How does E-cadherin work?

Answer 6

• Two E-cadherin molecules on cell surfaces bind to a cell’s actin filament by binding to beta catenin on the actin filaments.
• E-cadherin molecules on other cell surfaces bind to other E-cadherin molecules, linking the actin filaments.

Question 7

What happens to beta catenin if E-cadherin is not present to bind to it?

Why is this important?

Answer 7

• It becomes free in the cytoplasm, triggering a failsafe response which clears beta catenin from the cell by way of the ubiquitin-proteasome system.
• This is important because free beta catenin is carcinogenic.

Question 8

What is APC?

Answer 8

A tumour suppressor gene which acts as a negative regulator of beta catenin.

Question 9

List 2 biological processes that are particularly common in the formation of colorectal cancer.

What is the common effect of these biological processes?

Answer 9

1 - E-cadherin is downregulated.

2 - APC is deleted, leading to the loss of its expression.

• These processes cause an increase in free beta catenin.

Question 10

How does free beta catenin increase risk of developing cancer?

Answer 10

It is able to translocate to the nucleus, where it is able to interact with transcription factors to drive the expression of genes that promote cell proliferation such as MYC.

Question 11

What are matrix metalloproteinases (MMPs)?

Answer 11

• Enzymes that are normally involved in tissue remodelling as part of wound healing.
• In the stroma surrounding cancer cells, these enzymes are often increased in expression.

Question 12

How are matrix metalloproteinases involved in metastasis?

Answer 12

• The developing cancer cells produce soluble factors that diffuse through the basement membrane.
• These factors activate the cells of the stroma.
• This increases production of matrix metalloproteinases.
• Matrix metalloproteinases allow the cancer to invade the basement membrane.

Question 13

How do benign tumours feel different from malignant tumours on palpation?

Why might this be?

Answer 13

• Benign tumours feel soft.
• Malignant tumours feel hard.
• This is because malignant tumour tissue contains many collagen-producing fibroblasts which secrete matrix metalloproteinases.

Question 14

Define dysplasia.

Answer 14

The presence of cells of an abnormal type within a tissue, which may signify a stage preceding the development of cancer.

Question 15

When do epithelial cells need to migrate?

How do epithelial cells migrate?

Answer 15

• During wound healing.

- They migrate by a process known as epithelial-mesenchyme transition.

Question 16

Briefly describe the process of epithelial-mesenchyme transition.

What is the clinical importance of this process?

Answer 16

• Epithelial cells adopt a mesenchymal phenotype.
• This phenotype allows the cells to migrate.
• Once migration has completed, the reverse process occurs (mesenchyme-epithelial transition).
• This is a potential target for cancer invasion (and therefore metastasis).

Question 17

Which transcription factors regulate epithelial-mesenchyme transition?

Answer 17

SLUG and SNAIL.

Question 18

Briefly describe the process of tumour extravasation.

Answer 18

• As tumour cells enter small capillaries, they slow due to size restriction.
• They then adhere through receptor-ligand interactions in a process similar to neutrophil extravasation.

Question 19

What is the seed and soil hypothesis?

Answer 19

A hypothesis to explain the non-random pattern of metastasis that says that the ability of a metastatic cancer cell to survive at a distant site is due to the characteristics of both the cancer cell and the environment that it invades.

Question 20

What is James Ewing’s opposing hypothesis to the seed and soil hypothesis?

Which hypothesis is correct?

Answer 20

• That metastasis occurs purely by anatomical and mechanical routes.
• Both theories are thought to be correct.

Question 21

Define metastatic niche.

Answer 21

The process of conditioning an environment to be conducive to metastasis by soluble factors that have been released systemically by the primary tumour.

Question 22

What are the advantages of glycolytic switch in cancers that are normoxic?

Answer 22

• Cancer cells become efficient users of glycolysis as they upregulate:

1 - Cell surface glucose transporters.

2 - Enzymes that metabolise glucose.

• Upregulation of glycolysis also enables tumour cells to outcompete normal cells for scarce glucose supply.
• This is made further by the relative resistance of cancer cells to a low of pH caused by an increase in lactate production.

Question 23

How are PET scans used to produce images of cancer?

Answer 23

PET uses a glucose analogue known as fluorodeoxyglucose, which, similar to glucose, is rapidly taken up by cancer cells.

Question 24

How is angiogenesis in cancerous tissue specialised to facilitate invasion and metastasis?

Answer 24

• Angiogenesis in cancerous tissue produces abnormal blood vessels that are abnormally porous.
• This facilitates migration of metastatic cells out of the circulation.

Question 25

Define anoikis.

Answer 25

Detachment-induced cell death.

Question 26

List 2 molecules secreted by tumours that contribute to the formation of pre-metastatic niches.

What is the name of the phase in which these molecules are secreted?

Answer 26

1 - Tumour-derived secreted factors.

2 - Extracellular vesicles.

• The priming phase.

Question 27

Which organ is involved in reinforcing pre-metastatic niches?

How does it do this?

What is the name of the phase in which these molecules are secreted?

Answer 27

• The bone marrow.
• By secreting cytokines.
• The licensing phase.

Question 28

What is the role of macrophages in tumour metastasis?

Answer 28

• Tumours recruit macrophages by CSF-1.
• Macrophages secrete epidermal growth factor, for which tumours have many receptors.
• This promotes growth.

Question 29

What is an invadopodia?

What is its function?

Answer 29

• A structure at the apical surface of a cell that is highly enriched with proteolytic enzymes and integrin adhesion receptors.
• Its function is to facilitate invasion.

Question 30

What is intussusceptive angiogenesis?

Answer 30

A rapid form of angiogenesis characteristic of tumours that increases the volume of the endothelial cells that already exists (rather than increasing the number of endothelial cells).

Question 31

What is vasculogenic mimicry?

Answer 31

A form of angiogenesis where the tumour cells align in a similar fashion to endothelial cells to extend a blood vessel.

Question 32

What is vessel co-option?

Answer 32

A non-angiogenic process through which tumour cells utilize pre-existing tissue blood vessels to support tumour growth.

Question 33

List 2 factors that are necessary to maintain a blood supply and avoid vessel destruction.

Answer 33

1 - VEGF.

2 - Angiopoietin 2.

*Both of these factors are needed simultaneously.

Question 34

List the stages involved in tumour angiogenesis.

Answer 34

1 - Angiopoietin 2 leads to tumour regression.

2 - The tumour becomes hypoxic.

3 - THe tumour upregulates VEGF and angiopoietin 2.

4 - Sprouting angiogenesis occurs.