Faculty Collaboration Database

Endothelial expression of TNF receptor-1 generates a proapoptotic signal inhibited by integrin α6β1 in glioblastoma. Cancer Res 2012 Mar 15;72(6):1428-37

Date

03/08/2012

Pubmed ID

22396498

Pubmed Central ID

PMC3428239

DOI

10.1158/0008-5472.CAN-11-2621

Scopus ID

2-s2.0-84858235904 (requires institutional sign-in at Scopus site)   34 Citations

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 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 of ECs attached to laminin (which engages integrins α6β1 and α3β1). TNF-R1 expression was significantly higher in ECs in glioblastoma (GBM) tumors compared with ECs in normal brain specimens. TNFα was also expressed in GBM tumor-associated ECs, which was associated with longer patient survival. ECs plated on anti-integrin α2 or α3 antibody were susceptible to TNFα-induced apoptosis, whereas those plated on anti-integrin α6 antibody were not. Moreover, the ECs plated on laminin, but not collagen, expressed cellular FLICE inhibitory protein (cFLIP) and TNFα 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 α6β1 promotes the survival of brain ECs by inhibiting prodeath signaling by TNF-R1, in part by inducing cFLIP expression.

Author List

Huang P, Rani MR, Ahluwalia MS, Bae E, Prayson RA, Weil RJ, Nowacki AS, Hedayat H, Sloan AE, Lathia JD, Rich JN, Tipps R, Gladson CL

Author

Hirad S. Hedayat MD Associate Professor in the Neurosurgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Apoptosis
Brain
Brain Neoplasms
CASP8 and FADD-Like Apoptosis Regulating Protein
Collagen
Down-Regulation
Endothelium, Vascular
Fibronectins
Glioblastoma
Humans
Integrin alpha6beta1
Laminin
Receptors, Tumor Necrosis Factor, Type I
Signal Transduction
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha