L03 - Tumour Biology Flashcards
Define metastasis.
A tumour deposit that is discontinuous with the primary tumour.
What are the key properties of a metastatic cell?
1 - Detachment from primary tumour
2 - Invasion of ECM
3 - Intravasation
4 - Migration
5 - Adhesion to endothelium
6 - Extravasation
7 - Colonisation of, & survival in, secondary organ
What are the 3 different outcomes following extravasation?
1 - Dormancy
2 - Cell death (most likely)
3 - Proliferation (leading to metastases)
What is the rate limiting step in metastasis?
Why might this be?
- Colonisation
- This is because most metastatic cells die after extravasating because they are unlikely to be adapted to the new environment
What facilitates detachment of metastatic cells from the primary tumour?
Downregulation of adhesion molecules, commonly E-cadherin
How does E-cadherin work?
- E-cadherin dimer of one cell interacts with the E-cadherin dimer of another
- E-cadherin linked to actin cytoskeleton by intracellular β-catenin
What happens to β-catenin if E-cadherin is downregulated?
Why is this important?
- It becomes free in the cytoplasm, triggering a failsafe response which clears β-catenin from the cell by way of the ubiquitin-proteasome system
- This is important because free β-catenin promotes oncogenic transcription of cell cycle genes
What is APC?
A tumour suppressor gene which acts as a negative regulator of beta catenin
How does free beta catenin increase risk of developing cancer?
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
What are matrix metalloproteinases (MMPs)?
- 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
How are matrix metalloproteinases involved in metastasis?
- 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
How do benign tumours feel different from malignant tumours on palpation?
Why might this be?
- Benign tumours feel soft
- Malignant tumours feel hard
- This is because malignant tumour tissue contains many collagen-producing fibroblasts which secrete matrix metalloproteinases
Briefly describe the process of epithelial-mesenchyme transition.
What is the clinical importance of this process?
- 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)
Which gene regulates epithelial-mesenchyme transition?
- SLUG gene
- Downregulation of epithelial markers (e.g. E-cadherin, occludin & claudins)
- Upregulation of mesenchymal markers (e.g. N-cadherin, vimentin & fibronectin)
Briefly describe the process of tumour extravasation.
- As tumour cells enter small capillaries they slow by size restriction
- Selectins on endothelial cells interact with integrins on tumour cells
What is the seed & soil hypothesis?
Certain tumor cells (the seeds) can only successfully colonise selective organs (the soil) that have suitable growth environments
Define metastatic niche.
Tumour cells secrete factors that act systemically to modify secondary sites & recruit host immune cells, which facilitates appropriation of these sites for later colonisation
What are the advantages of glycolytic switch in cancers that are normoxic?
- Upregulation of glycolysis by tumour cells enables them to outcompete normal cells for scarce glucose supply (‘Warburg effect’)
- Production of lactic acid causes surrounding healthy cells to die
- These both facilitate tissue invasion
How is angiogenesis in cancerous tissue specialised to facilitate invasion and metastasis?
Angiogenesis promotes tumour cell survival & spread due to delivery of O2 & holes in blood vessels allowing cells to metastasise
How are PET scans used to produce images of cancer?
- PET scans used to visualise tumours through metabolic activity
- Most cancers show increased glucose uptake of glucose analogue fluorodeoxyglucose (FdG)
