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Tumour cell-endothelial interactions: signal pathways<br />
and therapeutic targets<br />
Chryso Kanthou<br />
Tumour Microcirculation Group, Academic Unit of Surgical Oncology, Division of Clinical<br />
Sciences South, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield,<br />
United Kingdom.<br />
The interaction between a tumour and its vasculature is critical for both primary tumour<br />
growth and metastasis. Tumour blood vessels are both structurally and functionally<br />
different from those of normal tissues and these characteristics can be exploited as<br />
potential targets for cancer therapy.<br />
Vascular disruption, as an alternative approach to anti-angiogenesis, aims to selectively<br />
destroy the existing tumour blood vessel network, thereby causing blood flow shutdown<br />
and consequently secondary tumour cell necrosis. A number of tubulin-binding agents,<br />
including the combretastatins, are under development as tumour vascular disrupting<br />
agents (VDAs). We have identified important pathways for the mechanism of action<br />
of the lead tubulin-binding VDA, combretastatin A-4-phosphate (CA-4-P), currently<br />
in phase II cancer clinical trials. We found that rapid responses of endothelial cells<br />
to CA-4-P are mediated by signaling between interphase microtubules, the primary<br />
cellular target of CA-4-P, and the actin cytoskeleton, and involve the GTPase RhoA<br />
and mitogen-activated protein kinases (MAPKs). Activation of these pathways leads to<br />
altered endothelial morphology and cytoskeleton, disruption of VE-cadherin junctions<br />
and a rise in monolayer permeability. A rise in tumour vascular permeability also<br />
occurs in vivo at early times after CA-4-P, and is strongly implicated in the decrease of<br />
tumour blood flow observed within minutes of drug administration.<br />
The<br />
52l34<br />
specific characteristics of the tumour vasculature that determine susceptibility to<br />
VDAs are not well understood. Nevertheless, specificity is at least in part ascribed to the<br />
relative vascular immaturity of solid tumours. A prominent role in vascular maturation<br />
is played by vascular endothelial growth factor (VEGF) and the angiopoietins (Ang 1,<br />
2 and 4), which act on tyrosine kinase receptors specific for endothelial cells. We<br />
are currently investigating the role of VEGF and its various splice variants as well<br />
as the angiopoietins in modulating the sensitivity of the endothelial cytoskeleton<br />
toward damage by VDAs, and how this affects the extent of downstream activation<br />
of signaling pathways responsible for altering morphology and function. We have<br />
developed fibrosarcoma cell lines, expressing only single VEGF isoforms, as well as<br />
colorectal carcinoma lines genetically modified to overexpress Ang 1, Ang 2 or Ang 4<br />
for use in co-culture studies to mimic the tumour-endothelial interactions. Such studies<br />
have demonstrated that the sensitivity of the endothelial cytoskeleton is significantly<br />
altered by VEGF and the angiopoietins. Elucidation of the molecular mechanisms<br />
responsible for regulating endothelial responses to VDAs is necessary for improving<br />
the efficacy of these agents and identifying new leads for drug development in this area.<br />
This work was supported by Cancer Research UK