BOD L17 Tumour angiogenesis Flashcards
To discuss the steps and determinants of angiogenesis and how it relates to tumour progression & metastasis
Angiogenesis occurs twice in the development of cancers. Where are these?
First at the start of the growth of primary tumour, and secondly once the cancer has metastasised at distant sites.
What is angiogenesis?
The growth and proliferation of new blood vessels.
This occurs in tumours, where blood vessels grow and penetrate into tumours.
How is angiogenesis initiated in tumour growth?
Releasing molecules (eg VEGF) that promote blood vessel growth down gradient.
What cells ‘lead’ the blood vessel extensions?
Endothelial cells.
How does tumour vasculature compare to normal tissue?
Tumour vasculature is very disorganised.
What is the experimental evidence of the effect of angiogenesis on tumour growth?
In vivo and vitro
In vivo, two colonies introduced into eye, one in suspension, one in iris (near vasculature).
Suspension only grew to 2mm.
Tumour grew way beyond 2mm where angiogenesis was possible.
In vitro, chamber placed beneath animals skin, with cancer cells inside. Observed that host vasculature was able to penentrate porous chamber.
Also in vivo evidence that tumours have less metastsis when treated with angiostatin (inhibitor of angiogenesis). compared to control.
What does angiostatin do?
Inhibits metastsis, via inhibtion of angiogenesis in new tumours.
What are the three main growth factors stimulators of angiogenesis?
EGF, FGF, VEGF.
What is a GF inhibitor of angiogenesis?
TNF-alpha
What is the paradox surrounding IL-4 and angiogenesis?
It is both a stimulator and inhibitor in different conditions.
What oncogenes stimulate angiogenesis?
c-myc, ras.
Which genes (tumour suppressors) inhibit angiogenesis
p53, Rb
What is thrombospondin?
Angiogenesis inhibitor that was used as a therapy to inhibit cancer angiogenesis. Not great results though
What on the endothelial cell leads the new capillary branch?
Pseudopidal processes. Guide development of capillary sprout along gradient.
What are pericytes?
Cells that provide support to capillary endothelial cells.
Provide support for endothelial in blood vessels.
Thought to play oncogenic role in promoting cancer angiogenesis. Target for therapy.
What is the basic mechanism of how angiogenesis is induced?
HIF inversely proportional to oxygen concentration.
High O2, low HIF. low O2, high HIF.
HIF is produced by cells undergoing hypoxia.
HIF regulates VEGF secretion, therefore capillary sprouting into hypoxic tissue.
What are the different steps in blood vessel formation?
- VEGF/FGF bind receptors on endothelial cells, activate signal transduction pathways.
- MMPs activated and degrade ECM, allowing endo cells to migrate out of wall and proliferate.
- EC’s express integrin avB3 to facilitate their adhesion to ECM and migration.
- Angiopoetin-1 binds Tie-2 receptors, stimulates pericyte recruitment, vessil sprouting and stabilisation.
- PDGF is released by ECs and acts as chemoattractant for pericyte precurcors. They join together.
What are the main stimulators of angiogenesis?
Growth factors - VEGF, EGF, FGF, PFDG
Cytokines - IL-8, TNFalpha, TGFalpha
Small molecules (hormones) - adenosine, nicotinamide, prostoglandins
What three things happen to endothelial cells upon VEGF binding?
Growth proliferation, secretion of MMPs, increased motility of cell.
How can angiogenesis be a target with chemotherapy?
Using mAbs to target different parts of the VEGF signalling cascade.
