Molecular analysis of the role of VEGF splice variants on tumour blood vessel
‘maturation’ and responsiveness to vascular disrupting agents
Supervisors: Dr Chryso Kanthou and Professor Gillian Tozer
Background
The general aim of the research programme of the Tumour Microcirculation Group is to
develop new and existing methods for therapeutic targeting of the tumour vasculature. In
particular, we are focusing on novel drug targeting approaches with vascular disrupting
agents (VDAs) aimed at causing rapid and catastrophic collapse of tumour blood vessels
and therefore indirectly killing tumour cells by starving them of oxygen and nutrients.
Tumours blood vessels have distinct morphological and functional features, which
generally characterise them as ‘immature’. These include complex and ‘chaotic’
networks with variable blood flow, poorly developed vascular walls, weak cell-to-cell
junctions and poor contact between endothelial cells and peri-vascular pericytes,
resulting in fragile highly permeable vessels. Despite these generalities, tumours display
wide variations in vascular ‘maturity’. In particular, pericyte stabilisation of tumour blood
vessels is variable, with stabilised vessels being relatively resistant to vascular
disruption. Our group has recently shown that alternatively spliced variants of vascular
endothelial growth factor (VEGF), the most important growth factor for stimulating
vascularisation of tumours, have differential effects on pericyte recruitment to tumour
blood vessels. In particular, matrix-bound VEGF188 is associated with higher levels of
pericyte coverage than VEGF120 or VEGF164 isoforms. VEGF188 tumour vessels are
also less permeable to macromolecules, suggestive of stronger endothelial cell-to-cell
interactions, and are relatively resistant to disruption by the lead tubulin-binding VDA
combretastatin A-4-phosphate (CA-4-P). Cross talk between tumour cells, endothelial
cells and pericytes has been implicated in the process of pericyte recruitment and vessel
stabilisation, and endothelial and tumour cells produce growth factors that act as
guidance signals for pericytes. Our work therefore provides a link between tumour VEGF
isoform expression and vascular maturity.
Aims
The aim of this study is to investigate cellular and molecular mechanisms through which
individual VEGF isoforms expressed by tumour cells interact to control vessel maturation
and consequently responsiveness to treatment with VDAs. This information will enable
us to identify molecular parameters for predicting tumour susceptibility to VDA cancer
therapy and to develop novel strategies for targeting tumour blood vessels for therapy.
The student will join a well-funded group and the project will provide extensive training in
a diverse range of cell and molecular biology techniques. He/she will also benefit from
interacting with other PhD students, staff and clinical fellows in the group, working on
related projects associated with VDA treatment strategies. The group also has close
contact with clinical groups and there will be opportunities to attend national/international
conferences.
References
1. Tozer GM, Kanthou C, Baguley B. (2005). Disrupting tumour blood vessels. Nat
Rev Cancer 5:423-435
2. Kanthou C, Tozer GM. (2009). Microtubule depolymerizing vascular disrupting
agents: novel therapeutic agents for oncology and other pathologies: Int J Exp
Pathol. 90:284-94.
PhD studentship proposal; C. Kanthou and G. Tozer; December 2009.
3. Tozer GM, Akerman S, Cross NA, Bjorndahl MA, Greco O, Harris, S, Hill SA,
Honess DJ, Ireson CR, Peettjohn KL, Prise VE, Reyes-Aldasoro CC, Ruhrberg C.
Shima DT, Kanthou C. (2008). Blood vessel maturation and response to vasculardisrupting therapy in single vascular endothelial growth factor-A isoform-producing
tumors.Cancer Res 68:2301-2311.
Contact Details
Dr Chryso Kanthou
Telephone: 0114 271 1725
Email: C.Kanthou@sheffield.ac.uk
Professor Gillian Tozer
Tel: 0114 271 2423
Email: G.Tozer@sheffield.ac.uk
http://www.tumour-microcirculation.group.shef.ac.uk/
PhD studentship proposal; C. Kanthou and G. Tozer; December 2009.