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 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 key steps in cancer progression?
- Transformation: extensive mutagenic and epigenetic changes to a normal cell followed by clonal selection
- Starts to become limited in oxygen so tumour switches on a process called angiogenesis: new blood vessel formation (overcomes limitations imposed by hypoxia)
- Motility and invasion: the epithelial to mesenchymal transition (invasive properties allowing intravasation into circulation and extravasation from circulation to tissues)
How they do that is they acquire adhesion molecules on their cell surface that allow them to adhere to distant capillary beds - Metastasis: colonisation of target organs (ability to expand from micrometastases)
What is the difference between 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 types of angiogenesis?
Developmental/vasculogenesis: - Organ growth like in the developing embryo Normal angiogenesis: - Wound repair - Placenta during pregnancy - Cycling ovary Pathological angiogenesis: - Tumour angiogenesis - Ocular and inflammatory disorders
Why does neovascularisation start?
Tumours will generally not grow beyond a size of about 1-2 mm3 without their own blood supply
So the tumour initiates a process that allows it to acquire a new network of blood vessels from pre-existing capillaries in that tissue
What are the steps of tumour angiogenesis?
A. Small tumour eventually gets to a large enough size when delivery of oxygen and nutrients from nearby capillaries becomes limiting
B. Tumour switches (angiogenic switch) 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 causes tumour angiogenesis?
Tumour hypoxia
The switch that causes the release of growth factors from the tumour
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 such as VEGF, GLUT-1, u-PAR, PAI-1
What are angiogenic factors? (+e)
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)
How do angiogenic factors work?
VEGF and Ang2 will get released by the tumour and bind to receptors expressed on endothelial cells
The MMPs allow the endothelial cells to migrate through the extracellular matrix
What does VEGF do?
Vascular endothelial growth factor (VEGF)
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 of these pathways are essential for angiogenesis ❹
What are the mechanisms behind tumour cell motility and 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
What is the Epithelial-Mesenchymal Transition (EMT) and its characteristics?
It’s a phenotypic switch of the cells from epithelial cell type to mesenchymal phenotype
Epithelium cells have a distinct shape and polarity
Loss of:
- Epithelial shape and cell polarity (β-catenin, claudin-1)
- 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)
What are E-cadherins?
E-Cadherins
- Homotypic adhesion molecule (adhesion of cells with the same cadherin) expressed in epithelial cells - Calcium-dependent - Inhibits invasiveness - Binds β-catenin intracellularly
What role do E-cadherins play in tumour growth?
In a normal cell, once the epithelial cells are in high density and you have the cell-cell adhesion there’s a process called contact inhibition
- Once a cell binds to another cell through these adhesion molecules that is a signal for them not to migrate or invade
When there is loss of E cadherin or it becomes mutated, then the contact inhibition is deregulated.
They become more motile and become more invasive.
Instead of a monolayer cells will start to grow on top of each other in a tumour mass.
How do stromal cells contribute to tumour progression?
Cancer cells will secrete enzymes like the MMPs, that allow for cell invasion but also:
- 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)
