Monoamines in glioblastoma: complex biology with therapeutic potential

Abstract

Glioblastoma (GBM) is characterized by extremely poor prognoses, despite the use of gross surgical resection, alkylating chemotherapeutic agents, and radiotherapy. Evidence increasingly highlights the role of the tumor microenvironment in enabling this aggressive phenotype. Despite this interest, the role of neurotransmitters, brain-specific messengers underlying synaptic transmission, remains murky. These signaling molecules influence a complex network of molecular pathways and cellular behaviors in many CNS-resident cells, including neural stem cells and progenitor cells, neurons, and glia cells. Critically, available data convincingly demonstrate that neurotransmitters can influence proliferation, quiescence, and differentiation status of these cells. This ability to affect progenitors and glia-GBM-initiating cells-and their availability in the CNS strongly support the notion that neurotransmitters participate in the onset and progression of GBM. This review will focus on dopamine and serotonin, as studies indicate they contribute to gliomagenesis. Particular attention will be paid to how these neurotransmitters and their receptors can be utilized as novel therapeutic targets. Overall, this review will analyze the complex biology governing the interaction of GBM with neurotransmitter signaling and highlight how this interplay shapes the aggressive nature of GBM.

Fig. 1

Synaptic monoamines in the microenvironment can influence tumor growth and angiogenesis. GBM cells exist in a highly specific microenvironment and are exposed to many secreted factors. Spillover of both dopamine and serotonin from the synaptic cleft is likely to interact with both GBM cells and surrounding endothelial cells. Given that these cells express receptors for monoamines, activation of these receptors can influence GBM onset and progression, as well as endothelial cell behavior. A wide range of receptors exist for each transmitter, meaning the specific composition of each tumor and its surrounding stromal cells will play a critical role in the effect of these transmitters. For example, it has been shown that certain serotonin receptors can influence MAPK signaling and gene expression. Likewise, activation of dopamine receptors can alter the cell cycle status of tumor cells. Thus, monoamines present in the microenvironment may represent a key player in GBM progression and a potential novel therapeutic target.