Tumour Angiogenesis, Invasion and Metastasis Flashcards
What are some characteristics of malignant tumours?
GROWTH: Unlimited growth (not self-limited as in benign tumours) - as long as an adequate blood supply is available to prevent hypoxia.
INVASIVENESS:
Migration of tumour cells into the surrounding stroma where they are free to disseminate via vascular or lymphatic channels to distant organs.
METASTASIS:
Spread of tumour cells from the primary site to form secondary tumours at other sites in the body.
What are the sequential steps of the process of metastasis?
- Transformation
- Angiogenesis
- Motility and invasion (through capillaries, venules, lymphatic vessels)
- Multicell aggregates (lymphocytes, platelets)
- Transport (embolism and circulation)
- Adherence (arrest in capillary beds)
- Extravasation into organ parenchyma
- Response to microenvironment
- Tumour cell proliferation and angiogenesis
- Metastases
- Metastasis of metastases
Summarise the key steps in cancer progression.
- extensive mutagenic and epigenetic changes followed by clonal selection
- angiogenesis (overcomes limitations imposed by hypoxia)
- epithelial to mesenchymal transition (invasive properties allowing intravasation and extravasation)
- colonisation of target organs (ability to expand from micrometastases)
- release of metastatic cells that have acquired the ability to colonise
What is angiogenesis and vasculogenesis?
Angiogenesis is the formation of new blood vessels from pre-existing vessels.
Vasculogenesis is the formation of new blood vessels from progenitors.
What are the different types of angiogenesis?
- developmental/ vasculogenesis: organ growth
- normal angiogenesis: wound repair, placenta during pregnancy, cycling ovary
- pathological angiogenesis: tumour angiogenesis, ocular and inflammatory disorders
What stimulates tumour angiogenesis?
Hypoxia is a strong stimulus for tumour angiogenesis.
Hypoxia – low oxygen tension <1% O2.
It increases with increasing distance from capillaries.
It activates transcription of genes involved in angiogenesis, tumour cell migration and metastasis.
What actually prompts the formation of the new blood vessels?
Some tumour cells produce factors that stimulate the directional growth of endothelial cells:
- Vascular Endothelial Growth Factor (VEGF)
- Fibroblast Growth Factor-2 (FGF-2)
- Transforming Growth Factor-β (TGF- β)
- Hepatocyte Growth Factor/Scatter Factor (HGF/SF)
These factors are mainly stored bound to components of the extracellular matrix and may be released by enzymes called matrix metalloproteinases.
What are some mechanisms of tumour cell invasion?
- increased mechanical pressure caused by rapid cellular proliferation
- increased motility of the malignant cells (epithelial to mesenchymal transition)
- increased production of degradative enzymes by both tumour cells and stromal cells
Describe the epithelial-mesenchymal transition.
The cell-to-cell adhesion molecules get downregulated, so you don’t get the tight junctions anymore.
That allows the cells to break off, and they then ‘switch on’ or upregulate different genes that are more involved in the smooth muscle cell like morphology, so there is actin reorganisation as well as an increase in matrix metalloproteinases (important enzymes that allow cells to degrade the local extracellular matrix and move in). This allows them to now invade blood vessels.
What is lost/acquired during the epithelial-mesenchymal transition?
LOSS OF:
- epithelial shape and cell polarity
- cytokeratin intermediate filament expression
- epithelial adherens junction protein (E-cadherin)
ACQUISITION OF:
- fibroblast-like shape and motility
- invasiveness
- vimentin intermediate filament expression
- mesenchymal gene expression (fibronectin, PDGF receptor, αvβ6 integrin)
- protease secretion (MMP-2, MMP-9)
Describe E-Cadherins.
- homotypic adhesion molecule (adhesion of cells with the same cadherin)
- calcium-dependent
- inhibits invasiveness
- binds β-catenin
E-cadherins allow cells to bind to each other (maintain cell to cell contact). This means, for the cells to break apart, we need to downregulate E-cadherin.
A mutated E-cadherin will cause cells to grow on top of each other instead of linearly.
Describe integrins.
- heterodimers (α and β subunits)
- heterotypic adhesion molecule
- adhesion to extracellular matrix (via collagen, fibronectin, laminin)
- cell migration
Describe stromal cell contribution to tumour progression.
Factors released by stromal cells (macrophages, mast cells, fibroblasts) include angiogenic factors, growth factors, cytokines, and proteases.
Example: Urokinase-type plasminogen activator (uPA); activated by tumour cells - resulting in plasmin production.
Plasmin activates matrix metalloproteinases (MMPs), which permit invasion by degrading extracellular matrix (ECM) thus releasing matrix-bound angiogenic factors.
What are the steps involved in cancer dissemination?
- primary tumour formation
- localised invasion
- intrainvasion (interaction with platelets, lymphocytes, and other blood components)
- transport through circulation
- arrest in microvessels of various organs
- extrainvasion
- formation of micrometastasis
- colonisation: formation of a macrometastasis
The overall process is highly inefficient: tumour cells can extravasate successfully (>80%), but the last two steps are very inefficient (<0.02% of cells actually form micrometastases).
From breast, colorectal, gastric, lung (NSCLC), pancreatic and prostatic cancer, what are the common sites of tumour metastases?
- BREAST: brain, lung, liver, bone
- COLORECTAL: liver, lung
- GASTRIC: liver, oesophagus, lung
- LUNG (NSCLC): brain, bone, liver, adrenal gland
- PANCREATIC: liver, lung
- PROSTATIC: bone
