Proapoptotic activation of death receptor 5 on tumor endothelial cells disrupts the vasculature and reduces tumor growth (Cancer Cell, 2012, 22:80-90)

報告日期: 2012/10/19
報告時間: 17:10/18:00
報告學生: 方偉宇
講評老師: 蔣輯武
附件下載: 下載[1234-1348725709-1.pdf] 

Proapoptotic Activation of Death Receptor 5 on Tumor Endothelial Cells Disrupts the Vasculature and Reduces Tumor Growth

Nicholas S. Wilson, Annie Yang, Becky Yang, Suzana Couto, Howard Stern, Alvin Gogineni, Robert Pitti, Scot Marsters, Robby M. Weimer, Mallika Singh, and Avi Ashkenazi

Cancer Cell 22, 80–90, July 10, 2012

Speaker: Wei-Yu Fang                         Date: 10/19/2012 17:10-18:00

Commentator: Chi-Wu Chiang, Ph.D.             Location: Room 602



Proapoptotic receptor agonists (PARAs) targeting death receptors (DRs) 4 and 5 hold promise for cancer therapy based on their selective ability to kill malignant versus healthy cells. However, in clinical trials they 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. In this study, the authors evaluated the effects of an oligomeric form of Apo2L/TRAIL, ligand of murine DR5 receptor, on murine tumors.After treatment, they found severe disruption of the tumor blood vessels 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 Apo2L/TRAIL had no effect in DR5-deficient mice.Apo2L/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. At last, 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 DR5 expression in the tumor endothelium. Furthermore, DR5 expression was not detected in the endothelium or in other cell types of normal tissues. These findings suggest that proapoptotic death receptor agonists may act as a unique class of tumor-selective vascular disruption agents.



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