Tumour biology

Question 1

What is a metastasis?

Answer 1

A tumour deposit discontinuous from the primary tumour. It is usually the cause of death as it is difficult to treat once it has spread. Metastasis is a multifactorial process.

Question 2

What are the 4 key properties of a metastatic cell?

Answer 2

1) Detachment from primary mass
2) Invasion of ECM and intravasation
3) Adhesion to endothelium and extravasation
4) Colonisation and survival in secondary site

Question 3

How does a tumour cell become detached from the primary mass?

Answer 3

Detachment occurs through loss of adhesion.

Adhesion molecules are DOWN regulated in cancer.

Question 4

How are epithelial cells normally adhered?

Answer 4

They are adhered to ECM and other cells through E-cadherin. E-cadherin is linked to beta-catenin. Beta-catenin has oncogenic properties when active.

Question 5

How does a cell normally prevent beta-catenin?

Answer 5

Free beta-catenin will be degreaded by APC, a TSG. APC binds to its proteosome for breakdown.

Question 6

How does the loss of adhesion lead to metastasis?

Answer 6

Down regulation of E-cadherin allows free b-catenin to enter the cytoplasm. In cancer cells, APC is suppressed and so catenin is stabilised and active in its free form. This then promotes oncogenic transcription by binding to lef TF to activate genes of the cell cycle e.g. cMYC to drive proliferation.

Question 7

What must be lost in order for metastasis to occur in detachment?

Answer 7

Loss of APC and E-cadherin

Question 8

What is the normal function of MMPs?

Answer 8

Matrix metalloproteinases (MMPs) can degrade the ECM. Normally used for tissue remodelling and wound healing.

Question 9

How do MMPs play a role in invasion?

Answer 9

MMPs can be secreted in the microenvironment by non-tumour cells such as fibroblasts.

Question 10

What is the microenvironment?

Answer 10

The environment surrounding the cancer cells, composed or malignant and non-malignant cells and ECM.

Question 11

How does the stroma become active for invasion?

Answer 11

As the cancer cells develop, the secrete soluble factors across the BM to activate the stroma to release the enzymes for degrading the BM and ECM.

Question 12

Why is epithelial-mesenchyme transition important for cancer cells?

Answer 12

Cancer cells hijack EMT to change their morphology to mesenchymal cells (mulitpotent stromal cell) to allow proliferation and therefore invasion and metastasis.

Question 13

How is EMT normally regulated?

Answer 13

TF slug and snail

Question 14

What happens to allow cancer cells to adhere to the endothelium and extravasate?

Answer 14

As the cells enter the small capillaries, they slow to an arrest due to the size restriction. This allows receptor ligand interaction between INTEGRINS of the tumour cell and SELECTINS on endothelium. Hijacks immune response.

Question 15

What determines the pattern of metastasis?

Answer 15

Premetastatic niche and the availability of GF.
Metastatic signature of the particular cancer which determines the secondary location.
Mechanical circulation to reach the site
Gradient of chemokines to the distant microenvironment.

Question 16

What is CTC-mediated metastasis?

Answer 16

The continuous circulation of tumour cells within the blood and lymph. Detectable.

Question 17

What is the premetastatic niche?

Answer 17

Preparation of the microenvironment for survival. Tumour cells secrete factors that act systemically to modify the local environment and recruit host immune cells to prepare sites for colonisation.

Question 18

What will a tumour cell release before it become metastatic?

Answer 18

Tumour derived secreted factors and extracellular vesicles.

Question 19

What is an epigenetic mutation?

Answer 19

An alteration in phenotype, without mutating genotype/DNA. Results in changes in expression levels of proteins.

Question 20

What environmental changes occur in the stroma?

Answer 20

Recruitment of cells to secrete factors.
Macrophages secerte EGF for growth
Fibroblasts secrete MMPs for matrix degradation.

Question 21

What do these genetic changes and EMT results in?

Answer 21

Loss of cell-cell contact
Mesenchymal change
Loss of cell-ECM interaction
Loss of polarity 
Caused by a change in the adhesion complexes = ability to migrate and invade

Question 22

What are invadopodia?

Answer 22

Actin-rich protrusions of the plasma membrane that help with invasion through BM and stroma for intravasation. They are rich in integrins and MMPs.

Question 23

How is the vasculature of a tumour different to a normal cell?

Answer 23

It is developed rapidly using different mechanisms so the endothelium contains holes allowing easy access of the tumour cells into the circulation.

Question 24

What is the role of hypoxia in tumour growth?

Answer 24

Hypoxia drives angiogenesis. As tumours grow their diffusion distance increases and they become hypoxic as they’re dependent on existing vessels. This causes HEF (hypoxic inducable factors) to be translocated into the nucleus to initiate transcription of proteins for glycolysis to allow ANAEROBIC respiration as a short term solution.

Question 25

What is the long term solution for the hypoxic environment?

Answer 25

The tumour releases GF to induce growth of vessels e.g. VEGF
Sprouting of existing vessels via Ang 2
Angiogenesis
Recruit progenitor endothelial cells
Induce lymphogenesis
Intrapoceptive angiogenesis remodells existing vessles, thinning vessels to make new ones.
Mimicry - tumour cells mimic endothelial cells due to the mesenchymal nature.

Question 26

What is vessel co-option?

Answer 26

As a tumour grows around resistance vessels, the vessels begin to regress as they cannot survive in the stroma due to Ang 2, so tumours release VEGF as it becomes more hypoxic. Ang 2 and VEGF together cause sprouting

Question 27

What is the glycolytic switch?

Answer 27

Allows anaerobic metabolism to produce ATP and lactic acid during anaerobic conditions.

Question 28

How do tumours become more efficient at using glucose?

Answer 28

They upregulate glucose uptake and metabolism by increasing glucose transporters on the surface and increasing the activity of the enzymes in metabolism.

Question 29

How does a PET scan work?

Answer 29

Use glucose analogue uptake of flurodeoxyglucose to detect the areas that are consuming the highest levels of glucose, showing the malignant cells.

Question 30

How does the upregulation of glycolysis in a tumour cell lead to facilitation of local invasion?

Answer 30

As a tumour cell upregulates glycolysis, it can outcompete normal cells for supply. The normal cells will die if they lack glucose, nutrients and O2. As the tumour produces lactic acid during glycolysis, it creates an acidic environment which the cells cannot survive in. This leaves more room for the cancer cells to migrate into.