gms | German Medical Science

Objective: Tumor microtubes (TMs) are ultralong membrane protrusions of tumor cells in astrocytic gliomas, including glioblastomas. TMs play a role in brain invasion and functional network of glioma cells. This network mediates resistance against the cytotoxicity of radiation and chemotherapy. Our hypothesis is that interference with the integrity of the glioblastoma cell network is key to a more successful glioma therapy. Many cellular structures are potential subjects to electrical forces [3, 4, 5]. Based on the theoretical electric field distribution TMs could be susceptible to the alternating electric fields of TTFields. We were therefore interested in the effect of TTFields on glioma network maintenance.

Methods: To examine the effect of TTFields on glioma TMs we have established a 2D and 3D in vitro model. We analyzed the disruption of tumor network complexity and disruption of functionality by measuring intra- and intercellular calcium waves [2]. Tumor cell death and proliferation was investigated in the 2D in vitro glioma model treated with TTFields using the inovitroTM-System.

Results: A peculiar “cricked-TM” phenotype that rarely occurred under control conditions was observed in TTField-treated cells (16.22% ±5.12). Cell number was reduced by 75% in two lines of GBSCs (S24, P3) after 5 days of TTField exposure; predominantly TM-rich GBSCs (> 4 TMs) were affected. This reduction in tumor cell number corresponded with an increase in cell death (0.3% ±0.09 in untreated cells; 1.4% ±0.45 at day 5 of TTField exposure). Of note, we did not observe a significant change in proliferation rate in our GBSCs while exposed to TTFields. The frequency of intercellular calcium transients, a measurement for calcium wave frequency in the glioma networks, was instantly reduced after TTField exposure to 58% ±20.42 of control levels in the primary GBSC 2D culture, and to 57.78% ±12.34 in tumor organoids derived from 3 glioblastoma patients.

Conclusion: This data suggests a potential effect of TTFields application on tumor cell networks, at least in vitro. Interestingly, particularly those glioblastoma cells that have so far been proven to be resistant to radio- and chemotherapy appeared to be affected. We will confirm the observed effects of TTFields on tumor cell calcium signaling in our in vivo chronic cranial window mouse model. We anticipate that the results of our project will provide important insights into the underlying mechanism of TTField therapy.