Tumour Progression, Invasion and Metastasis Flashcards
What are 3 characteristics of malignant tumours?
1) Progression - UNLIMITED GROWTH - as long as an adequate blood supply is available to prevent hypoxia
2) Invasiveness - MIGRATION of tumour cells into surrounding stroma = disseminate via vascular/lymphatics to distant organs
3) Metastasis - SPREAD of tumour cells from primary to secondary site
Describe 4 molecular bases for tumour progression? + causes of each (ACGE)
1) Acquisition of specific mutations - by tumour promoters
2) Clonal expansion - by tumour promoters
3) Genomic instability - by DNA repair defects, aneuploidy, loss of heterozygosity
4) Epigenetic changes - by gene promoter methylation
Describe what cellular heterogeneity is and how it is related to tumour composition
Selective pressures will determine the cellular composition of tumours, which vary in:
- Antigenicity
- Growth rate
- Response to hormones
- Response to cytotoxic drugs
- Capacity for invasion and metastasis
Outline the 4 mechanisms needed for tumour cell invasion
Increased mechanical pressure due to rapid cell proliferation
Inc. blood supply
Inc. malignant cell motility (change from epithelial to mesenchymal transition- EMC)
Inc. degradative enzymes by tumour & stromal cells
Why is the concept of hypoxia and angiogenesis important in tumour development?
A tumour cant grow beyond 2mm as its size is limited by hypoxia - however this hypoxia will promote Angiogenesis so tumour can continue to grow
Describe 4 step mechanism of hypoxia leading to angiogenesis and how this angiogenesis is regulated
Hypoxia induces HIF-1 which increases expression of angiogenic factors
Hypoxia also upregulates proteases, degrading the basement membrane
Specialised endothelial cells migrate to tumour, forming new vessels
VEGF stimulates DLL4, which binds to Notch-1 receptors =downregulating VEGF. This + PDGF-b suppresses vessel proliferation
4 key growth factors in angiogenesis?
What are they useful for?
1) Vascular Endothelial Growth Factor (VEGF)
2) Fibroblast Growth Factor-2 (FGF-2)
3) Transforming Growth Factor-β (TGF- β)
4)Hepatocyte growth factor/scatter factor (HGF/SF)
Useful for targeted therapies eg Sorafenib targets VEGFA
What is epithelial mesenchymal transition? Why is it related to tumor cell invasion?
EMT is the remodelling of cell-cell + cell-ECM interactions - leads to epith cells detaching from each other & the basement membrane
Causes increased metastatic potential, greater resistance + colonisation
How do epithelial cells change in EMT + 3 other things they gain?
Goes from:
Epithelial → fibroblast shape/ motility
Cytokeratin → Vimentin filament
E cadherin → N cadherin.
Also gains: invasiveness, mesynchymal genes, protease
How is proteolytic activity of tumours regulated?
Proteolysis depends on balance between proteinases & proteinase inhibitors
Most tissues have many TIMPs (Tissue Inhibitor of Metalloproteinases).
Some e.g. pancreatic tumours, have decreased levels of TIMPs
Describe the process of metastasis and its efficiency
- Primary tumour forms and gets vascularised - Tumour cells enter vasculature
- Transported to other organs via circulation
- Tumour cells leaves blood vessels and form a micrometastisis –> macrometastisis
Overall process is highly inefficient
Last step is very inefficient compared to the other steps
Describe the seed and soil hypothesis to explain how cancer cells metastasise
“Plant seeds are carried in all directions but can only live/grow if they fall on congenial soil”.
= therefore only specific adhesions between tumour & endothelial cells in the target organ can create good environments for colonization
What is a liquid biopsy?
3 advantages + 1 thing it can collect
Sampling non-solid tissue, primarily blood.
-Minimally invasive
-Detects molecular biomarkers
-Representative of tissue/s from which it has spread.
Can collect CTC’s (circulating tumour cells)
Describe circulating tumour cells + 2 limitations of them
- Single cells/cell clusters that detached from a tumour + travel through the bloodstream
- Marker for tumour growth, prognosis & treatment response
2 Limitations:
- BUT they’re v RARE (1-10 per 1ml blood)
- have SHORT HALF-LIFE (<2.5h)
So, sensitive/specific methods needed to study them
5 reasons why we use liquid biopsies?
1) Can detect mutations which are v specific to tumour cells
2) Primary tumour info may not= current cancer status
3) Molecular properties within tumour + between metastatic sites differ
4) No need to identify tumour site before biopsy, allows repeated sampling
5) Used in early detection, or checks for cancer resistance
