TROY (TNFRSF19) Promotes Glioblastoma Survival Signaling and Therapeutic Resistance

Of the features that characterize glioblastoma, arguably none is more clinically significant 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 tumor necrosis factor 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. Moreover, knockdown of TROY expression in a primary glioblastoma xenograft significantly prolonged survival in vivo. We also report that TROY expression significantly increases resistance of glioblastoma cells to both IR- and TMZ- induced apoptosis in vitro 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.