TROY (TNFRSF19) promotes glioblastoma survival signaling and therapeutic resistance

Mol Cancer Res. 2013 Aug;11(8):865-74. doi: 10.1158/1541-7786.MCR-13-0008. Epub 2013 May 22.


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.

Implications: Targeting of TROY may increase tumor vulnerability and improve therapeutic response in glioblastoma. Mol Cancer Res; 11(8); 865-74. ©2013 AACR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Astrocytes / physiology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / drug effects
  • Cell Survival
  • Chickens
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / pharmacology
  • Drug Resistance, Neoplasm / genetics
  • Epilepsy
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Glioblastoma / drug therapy
  • Glioblastoma / genetics*
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology
  • Humans
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • NF-kappa B / antagonists & inhibitors
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / pathology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor / genetics*
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Signal Transduction / drug effects
  • Temozolomide
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • NF-kappa B
  • Receptors, Tumor Necrosis Factor
  • TNFRSF19 protein, human
  • Dacarbazine
  • Proto-Oncogene Proteins c-akt
  • Temozolomide