Abstracts Category : Other

The Influence of Metformin and TGF-2 on Proliferation and Migration of Glioblastoma Cells

by Anne-Louise Meyer

To this day, glioblastoma (GBM) remains a brain tumor impossible to cure. Among its tumor properties are rapid proliferation and aggressive migration, two hallmarks investigated in this study. GBM's rapid recurrence after treatment is attributed to tumor cells exhibiting stem cell properties, the so called brain tumor initiating cells (BTICs). These are targeted by the anti-diabetic drug metformin which has demonstrated its anti-glioma potential in previous studies. However, metformin's mechanisms and especially its links to transforming growth factor beta 2 (TGF-2) are not yet fully understood. Therefore, this study explored the effects of different doses of metformin and a single dose of TGF-2 on proliferation and migration of proneural and mesenchymal BTICs and their differentiated counterparts (TCs) as well as possible functional interactions. Proliferation and migration of 5 BTIC and 5 TC lines were assessed in cell counts, CyQuant assays, spheroid migration assays and scratch migration assays. The functional investigation showed that 10 mM metformin reliably reduced proliferation and migration of primary GBM cell lines and also demonstrated that low doses of metformin may inhibit proliferation of proneural BTICs. Proneural cells were more susceptible to metformin than mesenchymal cells and BTICs were more susceptible than TCs providing possible predictors for successful metformin treatment. The low-dose effects of metformin also seem attainable in brain tissue of human cancer patients. Hence, this study sets the rationale to explore higher doses of metformin in patients who may profit from metformin treatment, especially since proneural cells respond less to standard temozolomide (TMZ) treatment. The effects of TGF-2, a cytokine held responsible for GBM's proliferation, invasion, angiogenesis and immunosuppression, were also assessed. Unexpectedly, TGF-2 had either no effects or it decreased proliferation and migration. Generally, mesenchymal cells showed an increased sensitivity. As TGF-2 has been described to increase proliferation and migration while metformin may lower both, this study investigated whether their functional effects were opposite. This was not the case. The effects of the combination of TGF-2 and metformin were anti-proliferative and anti-migratory. They were either as strong as those of the single agents or stronger indicating that there is no functional opposition of the two but rather uniform effects possibly potentiating each other. Thus, this study suggests that metformin and TGF-2 exert their functional effects independently of each other. Das Glioblastom (GBM) ist ein bis heute nicht heilbarer Hirntumor. Diese Studie untersuchte zwei der wichtigsten Tumoreigenschaften des Glioblastoms, seine rasche Proliferation und seine Migration. Die hohe Rezidivrate bei Glioblastompatienten wird einer Zellpopulation mit Stammzelleigenschaften zugeschrieben, den sogenannten Hirntumor-initiierenden Zellen (BTICs). Bisherige Studien zeigten, dass die Vermehrung und die Wanderung vonAdvisors/Committee Members: Hau, Peter (advisor).