Proapoptotic Death Receptor Agonists Act as Vascular Disrupting Agents Free

Agonistic antibodies and recombinant ligands targeting cancer cells that express proapoptotic death receptors 4 and 5 (DR4/5) have been evaluated in clinical trials but have had limited success. Preclinical studies with these agents, which frequently do not activate murine death receptors, have mainly been performed on cultured cells or human tumor xenografts and thus have not evaluated the effects of death receptor activation on the tumor microenvironment. Wilson and colleagues therefore evaluated the effects of an oligomeric form of TRAIL (also called Apo2L), capable of engaging murine DR5, on murine tumors. Within 24 hours of treatment, severe disruption of the tumor vasculature occurred, leading to extensive tumor hemorrhage and widespread tumor cell death. Surprisingly, these effects were dependent on DR5 expression in endothelial cells in the stroma of tumor-bearing mice, as oligomeric TRAIL had no effect in DR5-deficient mice. Oligomeric TRAIL rapidly and selectively induced apoptosis in tumor-associated endothelial cells, regardless of DR5 expression in the tumor cells. Endothelial DR5 activation led to decreases in tumor vascular density and increased vascular permeability, causing hemorrhagic tumor necrosis and reducing tumor growth. To determine whether these findings might be relevant in human cancers, the authors analyzed DR5 expression in a panel of 43 primary human non–small cell lung cancers and found that approximately 10% of the samples had regions of DR5 expression in the tumor endothelium. Because the authors did not observe DR5 expression in normal endothelium or in most other human tissues, these findings suggest that proapoptotic death receptor agonists may potentially be safely and effectively repurposed as vascular disrupting agents for anticancer therapy.

Wilson NS, Yang A, Yang B, Couto S, Stern H, Gogineni A, et al. Proapoptotic activation of death receptor 5 on tumor endothelial cells disrupts the vasculature and reduces tumor growth. Cancer Cell 2012;22:80–90.

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