Graeme Finlay 9 Flashcards
(10 cards)
Why must angiogenesis occur in cancer?
The diffusion limit for mammalian cells is 100-200 micrometers from a blood vessel, therefore a tumour nodule can not grow beyond 0.4mm unless it becomes vascularized
Why does tumour vasculature represent a promising target for cancer therapies?
Normal endothelial cells are quite quiescent, and new vasculature is only made during wound repair or ovulation. This makes the tumour vasculature abnormal and therefore a potential target
How does basic fibroblast growth factor mediate angiogenesis in cancer?
It is widely expressed and stored in the extra cellular matrix. It can be mobilized by an FGF-Binding protein. Basic fibroblast growth factor then stimulates VEGF expression allowing the two growth factors to act synergistically inducing angiogenesis
How does the fibroblast growth factor binding protein mediated the angiogenic switch in tumour cells?
This binding protein is typically only expressed perinatally but it is upregulated in cancer. Cells which express ribozymes targeting FGF-BP mRNA result in tumours with lower blood vessel density and growth rate.
How does vascular endothelial growth factor mediate angiogenesis in cancer?
A vascular, endothelial cell specific growth factor which is regulated by hypoxia allowing HGF, oncogenic Ras and mutant p53 to induce survival migration and proliferation of endothelial cells, elongation and network formation of non-proliferating endothelial cells and increased vascular permeability
What is the receptor for VEGF and what is the effect of therapies targeting these receptors ?
VEGF binds to VEGFR-1 which is found on haematopoietic precursor cells and VEGFR2 which is found exclusively on endothelial cells
Anti VEGFR1 has no effect on tumour growth but does eliminate perivascular myeloid cells from tumours
Anti VEGFR2 disrupts tumour blood vessels preventing tumour growth
Both antibodies together can cause total tumour necrosis
How can a novel enzyme inducer contribute to angiogenesis in tumours?
Platelet derived growth factor is often angiogenic with over expression correlating to vessel density and poor prognosis. It is a thymidine phosphorylase enzyme
In hypoxic regions of tumours necrotic cells release thymidine this is then enzymatically altered to form 2-deoxyribose-1-phosphatase this can form an amadori product which generate reactive oxygen species inducing oxidative stress which induces VEGF and IL-8 which induce angiogenesis and MMP-1 which degrades interstitial collagen promoting angiogenesis
How can VEGF signalling be suppressed experimentally?
Antisense oligonucleotides suppressing VEGF mRNA
Humanized monoclonal antibodies to VEGFR1 of VEGF
Soluble VEGFR to sequester the growth factor
Low molecular weight synthetic inhibitors such as sunitinib and sorafenib which act as antagonists of the adenine-binding pocket of VEGFR2 tyrosine kinase domain
Where do the endothelial cells come from in classical tumour angiogenesis?
They are recruited from neighbouting, pre-existing capillaries and from ne capillary networks known as sprouting
Where do the endothelial cells come from in non classical tumour angiogenesis?
Circulating bone marrow derived endothelial progenitor cells. This is dependent on a functional VEGFR2
