Endostatin (right) prevents secondary axis induction by β-catenin (left).

The ability of endostatin to inhibit angiogenesis has produced sensational headlines, but efforts to understand how this collagen fragment actually works have drawn considerably less fanfare. On page 529, Hanai et al. now demonstrate that endostatin acts through a novel pathway to inhibit Wnt signaling, suggesting that the effects of endostatin on tumors may be more complex than previously thought.

Using Xenopus embryonic development as a model system, the authors found that high concentrations of endostatin produced developmental abnormalities characteristic of Wnt signaling defects, a notion that was confirmed in cultured mammalian cells. Endostatin seems to act through a novel pathway to target β-catenin, a mediator of Wnt signaling, for proteasomal degradation. A downstream transcriptional activator that acts independently of β-catenin rescues cells from two of the effects of endostatin: cell cycle arrest and inhibition of endothelial cell migration.

The new work raises the possibility that endostatin may have direct antitumor effects, mediated by the inhibition of Wnt signaling, in addition to its antiangiogenic activity. The results also implicate Wnt and β-catenin in the regulation of endothelial cell migration and cell cycle progression, suggesting that downstream effectors of this pathway might be promising targets for future cancer therapies. ▪