Teaching an Old Drug New Tricks: Dexamethasone as an In Vivo Inhibitor of Glioblastoma Dispersal.

Arthur Carminucci,Yong Huang,Shabbar Danish,Roland H Friedel,Ramsey Foty,Rut Tejero

doi:10.7759/cureus.7749

Abstract

Identifying drugs that can mitigate dispersal of glioblastoma cells, particularly after patients undergo radiotherapy and concomitant chemotherapy, may increase the length of time to recurrence and improve overall survival. Previous studies have shown that dexamethasone (Dex), a drug currently used to treat brain tumor-related edema, which is tapered immediately after the edema has resolved, induces fibronectin matrix assembly (FNMA) and reduces dispersal of primary human glioblastoma multiforme (GBM) cells in vitro and ex vivo. Here, we utilized an in vivo mouse retina dispersal assay to demonstrate that Dex also inhibits dispersal in vivo. We show that 1) Dex significantly reduces z-axis penetration of glioblastoma cells into mouse retina; 2) treatment alters the morphology of dispersal; 3) without Dex, the presence of fibronectin increases dispersal; 4) treatment activates in vivo FNMA by glioblastoma cells, leading to the containment of the tumor mass; and 5) Dex-mediated activation of FNMA is fibronectin dose-dependent. Dispersal inhibition could be achieved at human equivalent doses as low as 1 mg/day, a dose significantly lower than currently used to reduce edema. This is the first step towards future studies in which patients can be potentially maintained on low-dose dexamethasone therapy with the aim of increasing the time between initial resection and recurrence.

Highlights

Glioblastoma multiforme (GBM) is a highly aggressive disease with a poor overall prognosis
We show that 1) Dex significantly reduces z-axis penetration of glioblastoma cells into mouse retina; 2) treatment alters the morphology of dispersal; 3) without Dex, the presence of fibronectin increases dispersal; 4) treatment activates in vivo fibronectin matrix assembly (FNMA) by glioblastoma cells, leading to the containment of the tumor mass; and 5) Dex-mediated activation of FNMA is fibronectin dose-dependent
The anti-dispersal effects of Dex are exerted through the formation of fibronectin matrix assembly (FNMA), which acts as a “glue” between GBM cells

Summary

Introduction

Glioblastoma multiforme (GBM) is a highly aggressive disease with a poor overall prognosis. A clinical hallmark of GBM is its capacity for early and continued dispersal throughout the brain parenchyma [1]. It is this dispersal that, in part, renders this disease resistant to localized therapy [2]. The anti-dispersal effects of Dex are exerted through the formation of fibronectin matrix assembly (FNMA), which acts as a “glue” between GBM cells. Dex-induced formation of FNMA in conventional two-dimensional (2D) cultures and three-dimensional (3D) spheroids of human primary GBM cells results in increased strength of the cell-extracellular matrix (ECM) adhesion, increased cell-cell cohesion, and decreased cell motility [8]. Dex-mediated inhibition of tumor cell migration was demonstrated ex vivo with GBM neurospheres on human brain slices [9]

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