Angiogenesis inhibitors have great potential as anticancer therapies, but have so far given disappointing results in clinical trials. Reporting in Cancer Cell, Shoukat Dedhar and colleagues reveal that integrin-linked kinase (ILK) has two key roles in tumour angiogenesis, and is therefore a promising new target for anti-angiogenic therapies.

Vascular endothelial growth factor (VEGF) is crucial for tumour angiogenesis, as it is produced by tumour cells and promotes the proliferation and migration of endothelial cells. VEGF expression can be stimulated by the phosphatidylinositol-3-kinase (PI3K) pathway. PI3K stimulates the phosphorylation and activity of AKT, which, in turn, increases the synthesis of transcription factors such as hypoxia-induced factor-1α (HIF-1α), to upregulate VEGF expression.

As ILK is directly upstream of AKT in the PI3K pathway, Dedhar and colleagues investigated whether it is also required for tumour angiogenesis. Overexpression of ILk in rat intestinal epithelial cells led to increased VEGF expression compared with control cells, and to increases in the levels of phosphorylated AKT and Hif-1α-mediated transcription. Conversely, a small-interfering RNA (siRNA) directed against ILk suppressed VEGF expression. The authors also showed ILK is required for high levels of VEGF expression in the PC3 human prostate cancer cell line, and went on to show that this involves the activation of mTOR, a target of AKT. So, ILK has a key role in the ability of tumour cells to stimulate VEGF expression through its effects on AKT activation (see figure).

To test the potential of ILK inhibition as an anti-angiogenic therapy, the authors exposed PC3 cells and DU145 cells — another prostate cancer cell line — to an ILK inhibitor. This suppressed both VEGF and HIF-1α expression in a dose-dependent manner.

As ILK is known to promote cell motility in response to growth factors, Dedhar and colleagues tested whether ILK might also function in endothelial cells in VEGF-mediated migration and vasculogenesis. Human umbilical-vein endothelial cells (HUVECs) that were exposed to VEGF showed increased ILK activity. This was dependent on PI3K, as this effect was blocked by the addition of a PI3K inhibitor. Furthermore, inhibition of ILK function suppressed the migration and proliferation of HUVECs in response to VEGF. The authors also showed that ILK inhibitors block VEGF-stimulated angiogenesis in two standard assays.

A mouse xenograft model was used to test the effects of ILK inhibitors in vivo. Nude mice were injected with PC3 cells, and animals bearing well-established tumours were treated with an ILK inhibitor. Treated mice showed a reduced density of tumour-associated blood vessels and a decrease in tumour mass, as compared with untreated mice, and did not show any obvious side-effects. These results indicate that ILK, with its dual role in tumour angiogenesis, might prove to be a useful target for anticancer therapies.