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Endothelial expression of TNF receptor-1 generates a proapoptotic signal inhibited by integrin ?6?1 in glioblastoma.

ABSTRACT: Activation of TNF receptor 1 (TNF-R1) 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 extracellular matrix in the tumor microenvironment. Specifically, through studies of glioblastoma, we showed that TNF? stimulation induced apoptosis of primary brain endothelial cells (EC) attached to collagen or fibronectin (which engage integrins ?2?1/?3?1 and ?5?1, respectively), but did not induce apoptosis of ECs attached to laminin (which engages integrins ?6?1 and ?3?1). TNF-R1 expression was significantly higher in ECs in glioblastoma (GBM) tumors compared with ECs in normal brain specimens. TNF? was also expressed in GBM tumor-associated ECs, which was associated with longer patient survival. ECs plated on anti-integrin ?2 or ?3 antibody were susceptible to TNF?-induced apoptosis, whereas those plated on anti-integrin ?6 antibody were not. Moreover, the ECs plated on laminin, but not collagen, expressed cellular FLICE inhibitory protein (cFLIP) and TNF? stimulation of laminin-attached cells in which cFLIP had been downregulated resulted in the induction of apoptosis. In contrast, attachment to laminin did not induce cFLIP expression in GBM tumor stem cells. Together, our findings indicate that the laminin receptor integrin ?6?1 promotes the survival of brain ECs by inhibiting prodeath signaling by TNF-R1, in part by inducing cFLIP expression.

SUBMITTER: Huang P 

PROVIDER: S-EPMC3428239 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Endothelial expression of TNF receptor-1 generates a proapoptotic signal inhibited by integrin α6β1 in glioblastoma.

Huang Ping P   Rani M R Sandhya MR   Ahluwalia Manmeet S MS   Bae Eunnyung E   Prayson Richard A RA   Weil Robert J RJ   Nowacki Amy S AS   Hedayat Hirad H   Sloan Andrew E AE   Lathia Justin D JD   Rich Jeremy N JN   Tipps Russell R   Gladson Candece L CL  

Cancer research 20120306 6

Activation of TNF receptor 1 (TNF-R1) 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 extracellular matrix in the tumor microenvironment. Specifically, through studies of glioblastoma, we showed that TNFα stimulation induced apoptosis of primary brain endothelial cells (EC) attached to collagen or fibronectin (which engage integrins α2β1/α3β1 and α5β1, respectively), but did not induce apoptosis o  ...[more]