Editors' ChoiceCancer

Abrogating Angiogenesis Just Got EZier

See allHide authors and affiliations

Science Translational Medicine  25 Aug 2010:
Vol. 2, Issue 46, pp. 46ec131
DOI: 10.1126/scitranslmed.3001600

It is clear that a tumor’s vasculature is a critical determinant of its growth properties. Indeed, therapies that block new blood vessel formation—angiogenesis—have shown clinical benefit in patients. However, the development of resistance to antiangiogenic therapeutics and eventual tumor progression are the rules rather than the exceptions in this therapeutic arena. Mechanisms that account for such resistance have not been fully clarified, but new work by Lu et al. defines a role for the EZH2 histone methyltransferase—which is known to be up-regulated in many cancers—in the formation and maintenance of the tumor vasculature.

Using published gene expression profiles, the authors showed that EZH2 was one of the most highly differentially expressed genes in ovarian tumor–associated endothelial cells versus nonmalignant tumor–associated endothelial cells. In addition, high expression of the EZH2 protein in ovarian tumor samples or tumor-associated endothelial cells was associated with poor clinical outcomes versus samples with low EZH2 expression. EZH2 gene expression in endothelial cells was up-regulated by the proangiogenic molecule VEGF, whereas a VEGF receptor–blocking antibody abrogated this effect. Lastly, EZH2 overexpression promoted blood vessel formation in in vitro assays, and this effect was dependent on repression of vash1, an antiangiogenic gene that is directly regulated by EZH2.

The authors next tested a novel antiangiogenic strategy in vivo in an orthopic mouse model of ovarian cancer. Human ovarian tumor cells were implanted into mice, and small interfering RNAs (siRNAs) that target human EZH2 (in the tumor) or mouse EZH2 (in nonmalignant cells, including the tumor-associated murine endothelial cells) were delivered to the tumor by nanoparticles. EZH2 siRNAs with sequence specificity to mouse EZH2 showed the greatest single-agent tumor-reducing effect, relative to the nontargeted control siRNA. Treatment of these mice with EZH2 siRNAs directed at both the human tumor and mouse nontumor cells (including endothelial cells) showed additive effects on reducing angiogenesis and increasing apoptosis.

Although these results are intriguing, determining whether the toxicity of such an approach outweighs the benefits will be critical, given the importance of EZH2 and other polycomb proteins in imprinting and control of cell fate. However, if further preclinical work with EZH2 siRNAs shows similar efficacy and an adequate safety profile, phase I human clinical trials would be warranted for a variety of tumors, given EZH2’s roles in tumor biology and angiogenesis.

C. Lu et al., Regulation of tumor angiogenesis by EZH2. Cancer Cell 18, 185–197 (2010). [Abstract]

Navigate This Article