Abstract
Abnormal secretion of epidermal growth factor (EGF) by non-neuronal cells (e.g., glioma-associated microglia) establishes a feedback loop between glioblastoma multiforme (GBM) invasion and a functional disruption of brain tissue. Considering the postulated significance of this vicious circle for GBM progression, we scrutinized mechanisms of EGF-dependent pro-invasive signaling in terms of its interrelations with energy metabolism and reactive oxygen species (ROS) production. The effects of EGF on the invasiveness of human glioblastoma T98G cells were estimated using time-lapse video microscopy, immunocytochemistry, cell cycle assay, immunoblot analyses, and Transwell® assay. These techniques were followed by quantification of the effect of EGFR (Epidermal Growth Factor Receptor) and ROS inhibitors on the EGF-induced T98G invasiveness and intracellular ROS, ATP, and lactate levels and mitochondrial metabolism. The EGF remarkably augmented the proliferation and motility of the T98G cells. Responses of these cells were accompanied by cellular rear–front polarization, translocation of vinculin to the leading lamellae, and increased promptness of penetration of micropore barriers. Erlotinib (the EGFR inhibitor) significantly attenuated the EGF-induced T98G invasiveness and metabolic reprogramming of the T98G cells, otherwise illustrated by the increased mitochondrial activity, glycolysis, and ROS production in the EGF-treated cells. In turn, ROS inhibition by N-acetyl-L-cysteine (NAC) had no effect on T98G morphology, but considerably attenuated EGF-induced cell motility. Our data confirmed the EGFR/ROS-dependent pro-neoplastic and pro-invasive activity of EGF in human GBM. These EGF effects may depend on metabolic reprogramming of GBM cells and are executed by alternative ROS-dependent/-independent pathways. The EGF may thus preserve bioenergetic homeostasis of GBM cells in hypoxic regions of brain tissue.
Highlights
Despite the development of new oncological regimens, glioblastoma multiforme (GBM) treatment represents an indisputable challenge for contemporary neuro-oncology [1]
Expression of functional ligand-binding epidermal growth factor (EGF) receptors in GBM cells seems to play a pivotal role in GBM-related pathogenesis, but the details of the EGF-related signaling involved in GBM cell invasion still remain elusive [13,14,15,16]
The effects of EGF on the cell morphology, proliferation, and metabolism were inhibited by erlotinib administration (Erl, a chemical inhibitor of the EGF receptor (EGFR); Figure 1A–D)
Summary
Despite the development of new oncological regimens, glioblastoma multiforme (GBM) treatment represents an indisputable challenge for contemporary neuro-oncology [1]. The clinical picture of GBM is often characterized by rapid development of invasiveness accompanied by swift recurrences after therapeutic cycles [2,3,4,5]. The epidermal growth factor (EGF) is secreted by glioma-associated microglia and macrophages (GAMs), which infiltrate the GBM-violated brain tissue continuum and participate in paracrine loops within glioblastoma niches [10,12]. EGFR signaling seems to be crucial for GBM invasion and progression [13]. Almost 50% of diagnosed gliomas show amplification of the constitutively active EGF receptor (EGFR type III or EGFRvIII [13]). Expression of functional ligand-binding EGF receptors in GBM cells seems to play a pivotal role in GBM-related pathogenesis, but the details of the EGF-related signaling involved in GBM cell invasion still remain elusive [13,14,15,16]
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