Abstract
Glioblastoma is highly aggressive. Early dispersal of the primary tumor renders localized therapy ineffective. Recurrence always occurs and leads to patient death. Prior studies have shown that dispersal of Glioblastoma can be significantly reduced by Dexamethasone (Dex), a drug currently used to control brain tumor related edema. However, due to high doses and significant side effects, treatment is tapered and discontinued as soon as edema has resolved. Prior analyses of the dispersal inhibitory effects of Dex were performed on tissue culture plastic, or polystyrene filters seeded with normal human astrocytes, conditions which inherently differ from the parenchymal architecture of neuronal tissue. The aim of this study was to utilize an ex-vivo model to examine Dex-mediated inhibition of tumor cell migration from low-passage, human Glioblastoma neurospheres on multiple substrates including mouse retina, and slices of mouse, pig, and human brain. We also determined the lowest possible Dex dose that can inhibit dispersal. Analysis by Two-Factor ANOVA shows that for GBM-2 and GBM-3, Dex treatment significantly reduces dispersal on all tissue types. However, the magnitude of the effect appears to be tissue-type specific. Moreover, there does not appear to be a difference in Dex-mediated inhibition of dispersal between mouse retina, mouse brain and human brain. To estimate the lowest possible dose at which Dex can inhibit dispersal, LogEC50 values were compared by Extra Sum-of-Squares F-test. We show that it is possible to achieve 50% reduction in dispersal with Dex doses ranging from 3.8 x10-8M to 8.0x10-9M for GBM-2, and 4.3x10-8M to 1.8x10-9M for GBM-3, on mouse retina and brain slices, respectively. These doses are 3-30-fold lower than those used to control edema. This study extends our previous in vitro data and identifies the mouse retina as a potential substrate for in vivo studies of GBM dispersal.
Highlights
IntroductionRadiotherapy and adjuvant chemotherapy, glioblastoma remains an intractable disease with median survival of less than 30% at 1 year, 5% at 3 years and 3% at 5 years [1]
Despite advances in surgery, radiotherapy and adjuvant chemotherapy, glioblastoma remains an intractable disease with median survival of less than 30% at 1 year, 5% at 3 years and 3% at 5 years [1]
We tested whether spheroids composed of human primary GBM cells were able to disperse upon various tissue substrates, including mouse retina and brain slices of murine, porcine and human origin
Summary
Radiotherapy and adjuvant chemotherapy, glioblastoma remains an intractable disease with median survival of less than 30% at 1 year, 5% at 3 years and 3% at 5 years [1]. Most GBM patients relapse after undergoing the Stupp protocol [2], a widely used algorithm involving surgical resection of the primary tumor, followed by radiation therapy and Temozolomide (TMZ) chemotherapy. Aggressive and microscopic spread of tumor cells through the brain parenchyma renders GBM refractory to gross total surgical resection and targeted chemotherapy, leading to high rates of recurrence and overall poor prognosis and survival. Re-operation of recurrent disease yields weak added survival [3], due to the continued and ongoing spread of tumor cells, as well as increasing tumor cell resistance to TMZ chemotherapy. We believe that in order to help provide hope for possible increased survival and life expectancy, limiting the ability of GBM cells to disperse from the recurrence is paramount. A pharmacologic strategy using an agent that crosses the blood-brainbarrier with high bioavailability, but can reduce dispersal of GBM cells would be ideal
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