Endothelial Expression of TNF Receptor-1 Generates a Proapoptotic Signal Inhibited by Integrin α6β1 in Glioblastoma

Activation of TNF receptor 1 (TNF-) can generate signals that promote either apoptosis or survival. In this study, we show that these signals can be determined by the character of the extra.cellular matrix in the tumor microenvironrnent. Specifically, through studies of glioblastoma, we showed that TNEu stimulation induced apoptosis of primary brain endothelial cells (EC) attached to collagen or fibronectin (which engage integrins u2131/a3131 and a5131, respectively), but did not induce apoptosis of ECs attached to larninin (which engages integ,rins u(ifil and a301). TIVF-R1 expression was significantly higher in ECs in glioblastoma (GBM) tumors compared with ECs in normal brain specimens. TNE0( was also expressed in GBM tumor-associated ECs, which was associated with longer patient survival. ECs plated on anti-integ,rin u2 or u3 antibody were susceptible to TNEa-induced apoptosis, whereas those plated on anti-integrin a6 antibody were not. Moreover, the ECs plated on laminin, but not collagen, expressed cellular FLICE inhibitory protein (cFLIP) and TNEa stimulation of larninin-atta.ched cells in which cFLIP had been downregulated resulted in the induction of apoptosis. Iii contrast, attachment to la.minin did not induce cELIP expression in GBM tumor stem cells. Together, our findings indicate that the laminin receptor integrin u6131 promotes the survival of brain ECs by inhibiting prodeath signaling by TNE-R1, in part by inducing cFLIP expression. Cancer Res; 72(6); 1428-37. 2012 AACR