L22 - Tumour Angiogenesis, Invasion & Metastasis Flashcards
What is Tumour Angiogenesis?
As the tunour grows, it requires additional vasculature. It secretes proteins that promote and stimulate blood vessel growth
Decsribe the characteristics of a malignant tumour?
GROWTH
- unlimited growth as long as there is n adequate blood supply
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 in other areas of the body
Describe the 4 key steps in cancer progression?
TRANSFORMATION:
- extensive mutagenic and epigenetic changes followed by clonal selection
ANGIOGENESIS:
- new blood vessel formation which overcomes the limitations of hypoxia
MOTILITY AND INVASION:
- epithelial to mesenchymal transition (circulation to tissues)
METASTASIS:
- colonisation of target organs
What is the difference between Angiogenesis and Vasculogenesis?
Angiogenesis is the formation of new blood vessels from pre-existing vessels, whereas vasculogenesis is the formation of new blood vessels from progenitor cells.
What is the Angiogenic switch?
when tumours switch on the expression of angiogenic genes/factors that initiate new blood vessel growth
Decsribe the process of Tumour Angiogenesis?
Small tumour eventually gets to a large enough size when delivery of oxygen and nutrients from nearby capillaries becomes limiting.
Tumour then switches on the xpression of angiogenic factors to initiate new blood vessel growth.
A new network of blood vessels grows in and around the tumour increasing the delivery of oxygen and helping with growth. Angiogenesis also provides a route for tumour cells to shed off and spread around the body
State some factors which are expressed to allow angiogenesis to occur?
VEGF - Vascular endothelial growth factor
GLUT1 - Glucose transporter 1
u-PAR - Urokinase plasminogen activator receptor
PAI-1 - Plasminogen activator Inhibitor 1
What enzymes can release Angiogenic factors?
Matrix Metalloproteinase 2 (MMP-2)
Describe the Vascular Endothelial Growth Factor signalling pathway?
VEGF binds to VEGF Receptors on endothelial cells and dimerises on the plasma membrane and recruits cofactors. This subsequently activates 3 major transduction pathways:
- cell survival
- cell proliferation and vasopermeability
- gene expression and cell proliferation
All of these pathways are essential for angiogenesis
Describe the Epithelial Mesenchymal Transition (EMT)?
It is a phenotypic switch of cells epithelial cells to Mesenchymal cells.
- There is a loss of epithelial shape and polarity (B-catenin and claudin-1)
- There is a loss of cytokeratin intermediae filament expression and epithelial adherens junction protein (E-cadherin)
There is an aqquisition of:
- fibrobalst shape and motility
- invasiveness
- vimetin intermediate filament expression
- mesenchymal gene expression (fibronectin, PDGF receptor, avB6 integrin)
- protease secretion (MMP-2 and MMP-9)
How do stromal cells contribute to tumour progression?
factors that are released by stromal cells (macrophages, mast cells and fibroblasts) include angiogenic factors, growth factors, cytokines and proteases
Urokinase type plasminogen activator is activatd by tumour cells resulting in plasmin production.
Plasmin then goes on to activate matrix Metalloproteinases, which permit invasion by degrading extracellular matrix. Plasmin also release matrix bound angiogenic factors such as transforming growth factor
Describe the process of cancer dissemination?
1) Primary tumour formation and angiogenesis
2) localised motility and invasion of tumour cells into bloodstream
3) Intravasation of of tumour cells into blood vessels and lymphatics
4) Tumour cells transported arouund the body through circulation
5) Arrests in microvessels of organs
6) Extravasation occurs and tumour cells leave the bloodstream
7) A micrometastasis forms and then colonisation to form a macrometastasis
What was the first specific anti-angiogenesis drug?
Avastin (bevacizumab)
approved for colorectal, lung, kidney and ovarian cancers.
What is the mechanism of action of Avastin?
It is an anti-VEGF antibody
It binds to VEGF and prevents the VEGF from binding to its receptors on the endothelial cells. As a result it prevents the downstream phosphorlylation of receptor and therefore inhibits angiogenesis, progression, metastasis and survival of tumour.
