15. The Tumour Microenvironment and Metastasis 2

Question 1

How can other cells contribute to cancer?

Answer 1

1. Proliferative signalling
2. inducing angiogenesis
3. activate metastasis

Question 2

what do epithelial cells provide?

Answer 2

a cell barrier between the outside and the inside of our bodies

Question 3

Why do some cell types rarely develop cancer?

Answer 3

Cells that don’t proliferate at all or very often rarely develop cancer.

Question 4

What are some examples of cells that don’t really develop cancer?

Answer 4

1. Neurones are only dividing in childhood so cause childhood cancers but rarely adult cancers
2. Muscle cells also rarely divide in adults so don’t really cause cancer

Question 5

Why are epithelial cells the source of 90% of human cancers?

Answer 5

1. They are the cells most exposed to toxic substances and mutagens.
2. They are constantly dividing to replace damaged cells. More replication leads to more mutations. Mutations in dividing and stem cells will be passed on to all progeny.
3. They can migrate during development to form limbs and during wound healing to cover and protect the wound.

Question 6

What cells make up a tumour?

Answer 6

1. Cancer cells
2. Cells in the connective tissue called stromal cells

Question 7

What is the stroma?

Answer 7

The connective tissue under the epithelium. It contains blood vessels, fibroblasts and immune cells.

Question 8

What is the role of stromal cells in a tumour?

Answer 8

It can contribute to the cancer once the cells enter the connective tissue

Question 9

What is the normal function of the stroma?

Answer 9

It provides elasticity and protection to the epithelium from the contraction of the smooth muscle underneath.

Question 10

What are fibroblasts?

Answer 10

1. They produce everything needed to make the ECM including collagens, glycosaminoglycans and glycoproteins.
2. They are essential for animal development.
3. They are vital in tissue repair in wound healing

Question 11

Why is the ECM important?

Answer 11

It provide elasticity to the tissue

Question 12

What is the role of fibroblasts in tissue repair?

Answer 12

1. They create new ECM to replace the damaged ECM
2. They support the repair of other cell types
3. They contract the wound to help repair the wound quicker so there is less area for the new epithelium to cover.

Question 13

What are Cancer-associated fibroblasts?

Answer 13

1. Tissue-resident fibroblasts or recruited fibroblasts that are modified by secreted factors from cancer cells
2. They produce growth factors and cytokines that promote cell growth including cancer cells, recruit immune cells, recruit endothelial cells.
3. Alter the ECM in the tumour to promote growth and spread.

Question 14

What is a tumour?

Answer 14

A wound that never heals

Question 15

Why do fibroblasts act in cancer?

Answer 15

1. Fibroblast don’t know the difference between cancer cells and a wound
2. They just recognise the tissue damage
3. they carry out their normal response to wound in cancer by producing ECM and contractile function
4. This helps the tumour form a solid mass

Question 16

why do fibroblasts produce growth factors?

Answer 16

Because they are needed in wound healing to cause proliferation and recruitment of cells.

Question 17

How do fibroblasts promote cancer cell proliferation?

Answer 17

1. Normally fibroblasts cause proliferation and recruit new cells to repair wounds.
2. They are carrying out their normal function but this promotes growth of the tumour

Question 18

Cancer-associated fibroblasts and tumour growth: EGF and HGF

Answer 18

The fibroblasts secrete Epidermal Growth Factor and Hepatocyte Growth Factor to stimulate epithelial growth.
HGF normally stimulate liver cell growth and wound healing but also cancer cell growth.

Question 19

Cancer-associated fibroblasts and tumour growth: VEGF

Answer 19

Stimulate angiogenesis which is needed in wound healing but it helps cancer cells grow.
In hypoxic response.

Question 20

Cancer-associated fibroblasts and tumour growth: TFG-ß

Answer 20

TGF-ß = tumour growth factor ß
It stimulates the movement of cancer cells and metastasis by causing the loss of cell-cell interactions and breakdown of ECM.
TFG-ß also suppresses T-cell function

Question 21

What is the function of macrophages in tumours?

Answer 21

1. They are abundant in tumours
2. They contribute to inflammation
3. Carries out its normal functions like phagocytosis and cytokine signalling
4. Does some good things like getting rid of debris in the tumour

Question 22

What are tumour-associated macrophages?

Answer 22

1. Tissue-resident macrophages and/or derived from blood monocytes.
2. Macrophages see a tumour as a wound that doesn’t heal so they promote inflammation.
3. Recruits other immune cells and is primed to fight infection should one occur in the tumour.
4. Produces growth factors and cytokines.

Question 23

What growth factors and cytokines do tumour-associated macrophages produce?

Answer 23

1. EGF to promote cancer cell growth.
2. IL-10 and TGFß to suppress the T cell immune response to cancer cells.
3. VEGF to respond to hypoxia and recruit endothelial cells

Question 24

How could tumour-associated macrophages be a cancer drug target?

Answer 24

1. Macrophages require colony stimulating factor 1 (CSF-1) to proliferate.
2. Cancer cells can produce CSF-1 to stimulate tumour-associated macrophages to aid progression.
3. CSF-1 has a tyrosine kinase receptor on the macrophage surface.
4. A small molecule inhibitor can bind the tyrosine kinase domain and prevent its activity.
5. This prevents the receptor using ATP to trigger the signalling.
6. This means the macrophages cannot proliferate.

Question 25

What is the normal role of T cells?

Answer 25

1. Cytotoxic T cells kill virally infected and cancer cells. 2. Regulatory T cells control the T cell response

Question 26

What drives T cell proliferation?

Answer 26

IL-2

Question 27

Where can T cells be found?

Answer 27

1. In the stroma 2. In the blood 3. In tumours

Question 28

What inhibits T cell proliferation?

Answer 28

Inhibitors which turn off T cells once the infection is cleared. This includes receptors on the T cells called PD-1 and CTLA-4.

Question 29

What is PD-1?

Answer 29

1. Programmed cell death 1 2. Ligand = PD-L1 which is expressed on other cells including cancer cells 3. Suppressed on the surface of T cells 4. suppresses T-cell proliferation and causes them to die.

Question 30

What is CTLA-4?

Answer 30

1. Cytotoxic T-lymphocyte-associated protein 4 2. Ligand = B7 which is expressed on other cells including cancer cells 3. Expressed on T cell surface 4. Suppress T-cell proliferation

Question 31

What is another role of T-cell inhibitors?

Answer 31

They turn down the T cell response to suppress autoimmune responses.

Question 32

What is the normal function of cytotoxic T cells?

Answer 32

1. They kill intracellularly infected cells. 2. TCR recognises MHC1/2 presenting non-self antigens. 3. Kills the cells using cytotoxic granules.

Question 33

How do regulatory T-cells work?

Answer 33

1. They turn off the cytotoxic T cell response 2. Use IL-10 and TGFß to suppress cytotoxic T cell proliferation. 3. This can also be triggered by macrophages secreting IL-10 and TGFß 4. This prevents the killing of other cells and tissue damage

Question 34

What is the normal function of regulatory T cells?

Answer 34

1. Suppress cytotoxic T cells and other T cells with IL-10 and TGFß 2. Prevents response to harmless antigen in food or the air. 3. Suppresses autoimmunity (there are lots of cases where this goes wrong) 4. limits responses to pathogens to prevent expressive response

Question 35

What is the role of cytotoxic T cells in cancer?

Answer 35

1. T cells recognise the cancer cells as foreign due to the mutated proteins presented on the cancer cell MHC 2. The more advanced the cancer, the more mutations, the more different the protein so they are more likely to be recognised as foreign. 3. They kill cancer cells like they kill a virally infected cell.

Question 36

What is good about cytotoxic T cell function in cancer?

Answer 36

1. Most cancer cells are recognised as foreign by T cells and they are killed. 2. This keeps most cancers in check and prevents them from developing. 3. If the cancer isn't seen as foreign quick enough this response can be turned off.

Question 37

How can cytotoxic T cells become suppressed by cancer cells?

Answer 37

1. PD-1 and CTLA-4 start being expressed on T cells after a certain period of time. This is a normal function to prevent excessive response. 2. Cancer cells can start expressing PD-L1 and B7. 3. This can turn off T cell function before all the cancer cells are killed. 4. Regulatory T cells are also recruited. 5. Macrophages, fibroblasts and regulatory T cells secrete IL-10 which turns off cytotoxic T cells. 6. As the cancer progresses regulatory T cells increase to prevent a sustained immune response causing tissue damage. This is bad.

Question 38

How can we enhance cytotoxic T cell function for cancer treatment?

Answer 38

1. These treatments keep cytotoxic T cells active. 2. Antibodies to PD-1 and CTLA-4 prevent the ligand binding. 3. These compete with their ligands and bind really tightly. 4. This prevents the suppression of T cells and keeps them active and proliferating. 5. These work really well in melanoma as they have high levels of mutations so the cells look very different.

Question 39

When are Antibodies to PD-1 and CTLA-4 not suitable treatments?

Answer 39

When there are lots of other inhibition signals on the cytotoxic T cells. Only works when PD-1 and CTLA-4 are the main methods of inhibition.

Question 40

What is a downside of enhanced T cell treatments?

Answer 40

1. They would lead to autoimmune side effects. 2. This is because the treatment is not selective for the tumour and causes a systemic activation of cytotoxic T cells. 3. For some patients the side effects are so big they cannot continue with treatment.