Tumour angiogenesis, invasion and metastasis Flashcards
What are the characteristics of malignant tumours?
Growth
Unlimited growth (not self-limited as in benign tumours) – as long as an adequate blood supply is available
Invasiveness
Migration of tumour cell into the surrounding stoma 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 4 steps of cancer progression?
- Transformation: extensive mutagenic and epigenetic changes followed by clonal selection
- Angiogenesis: new blood vessel formation (overcomes limitations imposed by hypoxia). Nearby capillary starts to send new vessels to the tumour so it can soon expand.
- Motility and invasion: epithelial to mesenchymal transition (invasive properties allowing intravasation into circulation and extravasation from circulation to tissues). This allows them to invade the circulation.
- Metastasis: colonisation of target organs (ability to expand from micrometastases)
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 3 types of angiogenesis?
On image
What size to tumours grow to?
Tumours will generally not grow beyond a size of about 1-2mm3 without their own blood supply
How does the tumour obtain a new blood supply?
(A) Small tumour eventually gets to a large enough size when delivery of oxygen and nutrients from nearby capillaries becomes limiting
(B) Tumour switches on expression of angiogenic genes/factors that initiate new blood vessel growth
(C) New network of blood vessels grows in and around the tumour (tumour angiogenesis) increasing the delivery of oxygen and nutrients that allows it to increase growth and provides a route for cells to shed off and spread
What is tumour hypoxia?
- Hypoxia is a strong stimulus for tumour angiogenesis
- Hypoxia – low oxygen tension <1% O2
- Increases with increasing distance from capillaries
- Activates transcription of genes involved in angiogenesis, tumour cell migration and metastasis
Some tumours cells produce factors that stimulate the directional growth of endothelial cells:
Some tumour cells produce factors that stimulate the directional growth of endothelial cells:
• Vascular Endothelial Growth Factor (VEGF)
• Fibroblast Growth Factor 2 (FGF 2)
• Placental growth factor (PlGF)
• Angiopoietin 2 (Ang 2)
These factors are secreted by tumour cells or are stored bound to components of the extracellular matrix and may be released by enzymes called matrix metalloproteinases:
• Matrix metalloproteinase 2 (MMP-2)
Describe the Vascular endothelial growth factor (VEGF) signalling
- VEGF binds to VEGF-R2 on endothelial cells ❶
- VEGF/VEGF-R2 dimerizes at the plasma membrane and recruits’ cofactors ❷ that subsequently activate 3 major signal transduction pathways ❸
- Ultimately, VEGF activates cell survival, vascular permeability, gene expression and cell proliferation
- All these pathways are essential for angiogenesis ❹
How does cancer move around the body?
- 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
What is EMT transition?
Loss of:
• Epithelial shape and cell polarity ( down regulation of proteins such as β-catenin, claudin-1)
• Cytokeratin intermediate filament expression are down regulated
• 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)
This goes from a normal epithelial cell to mesenchymal cells which can move
What are E-Cadherins?
- Homotypic adhesion molecule (adhesion of cells with the same cadherin)
- Calcium-dependent
- Inhibits invasiveness
- Binds β-catenin
How do stromal cells contribute to tumour progression?
- Factors released by stromal cells (macrophages, mast cells, fibroblasts) include angiogenic factors, growth factors, cytokines, 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) and releasing matrix-bound angiogenic factors such as transforming growth factor-β1 (TGF-β1)
What steps are involved in cancer dissemination?
On image
What determines the pattern of tumour spread?
Mechanical Hypothesis
Anatomical considerations: Blood and lymphatic systems, entrapment in capillary beds (20-30µm carcinoma cell, ~8µm capillary)
Seed and Soil Hypothesis
Specific adhesions between tumour cells and endothelial cells in the target organ, creating a favourable environment in the target organ for colonisation
Genetic alterations acquired during progression allow tumour cells to metastasize
