title: TROY (TNFRSF19) promotes glioblastoma survival signaling and therapeutic resistance.
abstract: Of the features that characterize glioblastoma, arguably none is more clinically relevant than the propensity of malignant glioma cells to aggressively invade into the surrounding normal brain tissue. These invasive cells render complete resection impossible, confer significant resistance to chemo- and radiation-therapy, and virtually assure tumor recurrence. Expression of TROY (TNFRSF19), a member of the TNF receptor superfamily, inversely correlates with patient survival and stimulates glioblastoma cell migration and invasion in vitro. In this study, we report that TROY is overexpressed in glioblastoma tumor specimens and TROY mRNA expression is increased in the invasive cell population in vivo. In addition, inappropriate expression of TROY in mouse astrocytes in vivo using glial-specific gene transfer in transgenic mice induces astrocyte migration within the brain, validating the importance of the TROY signaling cascade in glioblastoma cell migration and invasion. Knockdown of TROY expression in primary glioblastoma xenografts significantly prolonged survival in vivo. Moreover, TROY expression significantly increased resistance of glioblastoma cells to both IR- and TMZ-induced apoptosis via activation of Akt and NF-κB. Inhibition of either Akt or NF-κB activity suppressed the survival benefits of TROY signaling in response to TMZ treatment. These findings position aberrant expression and/or signaling by TROY as a contributor to the dispersion of glioblastoma cells and therapeutic resistance.
  
  
  CONCLUSIONS
  Targeting of TROY may increase tumor vulnerability and improve therapeutic response in glioblastoma. Mol Cancer Res; 11(8); 865-74. ©2013 AACR.
authors.affiliation: The Translational Genomics Research Institute, 445 North Fifth Street, Suite 400, Phoenix, AZ 85004, USA. ntran@tgen.org
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Loftus
authors.forename: Harshil
authors.initials: H
authors.lastname: Dhruv
authors.forename: Serdar
authors.initials: S
authors.lastname: Tuncali
authors.forename: Jean
authors.initials: J
authors.lastname: Kloss
authors.forename: Zhongbo
authors.initials: Z
authors.lastname: Yang
authors.forename: Cassie A
authors.initials: CA
authors.lastname: Schumacher
authors.forename: Brian
authors.initials: B
authors.lastname: Cao
authors.forename: Bart O
authors.initials: BO
authors.lastname: Williams
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Eschbacher
authors.forename: Julianna T D
authors.initials: JT
authors.lastname: Ross
authors.forename: Nhan L
authors.initials: NL
authors.lastname: Tran
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002645:Chickens; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004827:Epilepsy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; C411850:TNFRSF19 protein, human; D003606:Dacarbazine; D051057:Proto-Oncogene Proteins c-akt; D000077204:Temozolomide