02 BOOK OF ABSTRACTS .indd

Tumour cell-endothelial interactions: signal pathways
and therapeutic targets
Chryso Kanthou
Tumour Microcirculation Group, Academic Unit of Surgical Oncology, Division of Clinical
Sciences South, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield,
United Kingdom.
The interaction between a tumour and its vasculature is critical for both primary tumour
growth and metastasis. Tumour blood vessels are both structurally and functionally
different from those of normal tissues and these characteristics can be exploited as
potential targets for cancer therapy.
Vascular disruption, as an alternative approach to anti-angiogenesis, aims to selectively
destroy the existing tumour blood vessel network, thereby causing blood flow shutdown
and consequently secondary tumour cell necrosis. A number of tubulin-binding agents,
including the combretastatins, are under development as tumour vascular disrupting
agents (VDAs). We have identified important pathways for the mechanism of action
of the lead tubulin-binding VDA, combretastatin A-4-phosphate (CA-4-P), currently
in phase II cancer clinical trials. We found that rapid responses of endothelial cells
to CA-4-P are mediated by signaling between interphase microtubules, the primary
cellular target of CA-4-P, and the actin cytoskeleton, and involve the GTPase RhoA
and mitogen-activated protein kinases (MAPKs). Activation of these pathways leads to
altered endothelial morphology and cytoskeleton, disruption of VE-cadherin junctions
and a rise in monolayer permeability. A rise in tumour vascular permeability also
occurs in vivo at early times after CA-4-P, and is strongly implicated in the decrease of
tumour blood flow observed within minutes of drug administration.
The
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specific characteristics of the tumour vasculature that determine susceptibility to
VDAs are not well understood. Nevertheless, specificity is at least in part ascribed to the
relative vascular immaturity of solid tumours. A prominent role in vascular maturation
is played by vascular endothelial growth factor (VEGF) and the angiopoietins (Ang 1,
2 and 4), which act on tyrosine kinase receptors specific for endothelial cells. We
are currently investigating the role of VEGF and its various splice variants as well
as the angiopoietins in modulating the sensitivity of the endothelial cytoskeleton
toward damage by VDAs, and how this affects the extent of downstream activation
of signaling pathways responsible for altering morphology and function. We have
developed fibrosarcoma cell lines, expressing only single VEGF isoforms, as well as
colorectal carcinoma lines genetically modified to overexpress Ang 1, Ang 2 or Ang 4
for use in co-culture studies to mimic the tumour-endothelial interactions. Such studies
have demonstrated that the sensitivity of the endothelial cytoskeleton is significantly
altered by VEGF and the angiopoietins. Elucidation of the molecular mechanisms
responsible for regulating endothelial responses to VDAs is necessary for improving
the efficacy of these agents and identifying new leads for drug development in this area.
This work was supported by Cancer Research UK