Employing a Combination of Chemoattractants to Trap Glioblastoma Cells in a Macroporous Hydrogel

Background: A new paradigm for treating glioblastoma multiforme (GBM) cells was proposed. Instead of trying to eliminate cancer cells infiltrated in the brain, this new treatment is based on attracting them into a macroporous gel-based trap, where they are retained and then irradiated with a localized, higher radiation dose. The objective of this study is to identify a cytokine combination that would attract GBM cells while considering heterogeneity among GBM cell lines. Methods: The ability of different combinations of cytokines CXCL12, IL-1β, IL-6, and EGF to stimulate the migration of the GBM cell lines U87, U87 CXCR4+, F98, and U118 was assessed with a two-layer Matrigel device that simulates the extracellular environment in brain. The accumulation of GBM cells within a cancer cell trap made from a macroporous hydrogel consisting of 1% alginate, 0.75% chitosan, and 0.05% genipin was determined. This hydrogel was grafted with RGD and features fully interconnected pores with an average diameter of 300 µm. CXCL12 is the most frequently used for attracting GBM cells. The other cytokines were chosen to enhance CXCR4 expression, the receptor for CXCL12, increase matrix metalloproteinase-2 and -9 (MMP-2 and -9) production, and promote the epithelial-mesenchymal transition (EMT), a phenotype shift that facilitates cell migration. Results: IL-1β significantly enhanced CXCR4 expression in the F98 and U118 cells. The production of MMP-2 was significantly stimulated with IL-1β and IL-6 in F98 cells. The combination of the cytokines IL-1β + IL-6 + CXCL12 + EGF, on the other hand, induced a decrease in MMP-2 levels. The EMT was induced by EGF in all GBM cells tested. The results obtained using the two-layer Matrigel device showed that the combination of the cytokines IL-1β + CXCL12 + EGF was the most effective in promoting the migration of the four GBM cell lines. Regarding accumulation in the macroporous hydrogel, U118 cells showed the best response to this cytokine combination. Conclusions: A significant challenge in developing a cancer cell trap is to identify a cytokine combination to attract the heterogeneous population of GBM cells. In this study, the cytokine combination IL-1β + CXCL12 + EGF was found to be the most effective in promoting the migration of GBM cells.