Several microtubule-disrupting agents that are used in cancer therapy, such as colchicine and combretastatin A4 phosphate (CA4P), also have interesting additional anti-tumour effects, such as causing rapid and catastrophic shutdown of the tumour vasculature. The mechanism of these effects has been unclear, but Shahin Rafii and colleagues report that CA4P induces the regression of unstable tumour neovessels by disrupting the endothelial cell junction molecule vascular endothelial cadherin (VE-cadherin).

CA4P is a stilbene compound that was isolated from a South African bush willow, Combretum caffrum. CA4P binds tubulin with a higher efficacy than colchicines, and was therefore initially investigated as an anti-mitotic agent. However, it was later observed to also induce vascular shutdown and necrosis in tumours. Clinical trials have revealed its positive effects, either as a single agent or in combination with chemotherapy, in patients with ovarian, lung or anaplastic thyroid cancer.

Rafii's group evaluated the effects of this compound on the neo-angiogenic endothelial cells that form blood vessels during tumour angiogenesis. They found that at low, non-toxic doses, CA4P not only inhibited the proliferation of endothelial cells, but also disrupted cell–cell junctions, cell migration and anchorage, resulting in cell death.

VE-cadherin is an important mediator of cell–cell contacts and cytoskeletal organization, so the authors investigated its role in the endothelial cell's response to this drug. After only 3–6 hours of exposure to CA4P, VE-cadherin and its signalling partner β-catenin, which normally localize to cell–cell contacts, were redistributed, and by 18 hours, cell contacts were lost. Stabilization of the VE-cadherin complex through expression of the adenovirus E4 gene protected cells against the effects of CA4P, indicating that disruption of this complex is an important mechanism of this drug. Biochemical analyses revealed that CA4P rapidly diminished the tyrosine phosphorylation of VE-cadherin and β-catenin, thereby blocking the endothelial signalling pathway that is necessary for maintaining a functional endothelial cell structure and survival.

So, what effects does this drug have on established vessels? Three-dimensional tube formation assays revealed that CA4P blocks not only the formation of a capillary tube network, but could destabilize a pre-established endothelial network. This only occurred, however, in the absence, of the smooth muscle cells that normally stabilize vessels. Furthermore, in vivo studies showed that CA4P caused tumour necrosis and the loss of tumour vasculature in mouse models.

Rafii's group proposes a model in which normal blood vessels, which are lined with smooth muscle cells, are stable and protected against CA4P. Because nascent unstable tumour neovessels are not ensheathed by the smooth muscle cells, they are selectively destabilized by CA4P by disrupting VE-cadherin-mediated cell–cell contacts. This drug could therefore be used as a tumour-specific agent with low levels of toxicity to the normal vasculature — clinical trials that are underway have shown this to be the case.

Further studies are required to determine whether CA4P functions by directly disrupting the VE-cadherin–β-catenin complex, or how it might indirectly alter the phosphorylation and signalling of this complex, perhaps by interfering with cytoskeletal reorganization in endothelial cells.