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. glioblastoma, glioma initiating cells, neurotransmitters, tumor microenvironment Glioblastoma (GBM) is the most prevalent central nervous system (CNS) tumor in adults, with 10000 new diagnoses annually. It is also one of the most aggressive cancers; median survival is only 15 months.1 These outcomes occur despite the use of aggressive combination therapy, including surgery, radiation treatment, and chemotherapy drugs. While this treatment regimen is successful in the short term, recurrent tumors with resistance to available anti-glioma modalities are nearly universal and fatal. One of the key processes underlying this recurrence is the remarkable ability of GBM cells to adapt to the microenvironment. As such, a greater understanding of how GBM tumors interact with the microenvironment is needed to improve the treatment of GBM. In the case of brain tumors, microenvironmental interactions are especially complicated, as the CNS contains a variety of organ-specific molecules, growth factors, and cell types. Among these molecules, neurotransmitters—signaling molecules responsible for neuronal communication—have been shown to exert a great deal of influence over cell proliferation and differentiation, especially in neural stem cells and progenitor cells. It has been shown that a particularly aggressive and therapy-resistant subpopulation of GBM cells—glioma-initiating cells (GICs)—have similar protein expression profiles2 and self-renewal capacities to healthy neural stem cells and progenitor cells.3 Given this connection, it follows that GBM-initiating cells and tumor cells may maintain this responsiveness to neurotransmitters. Despite this organ-specific factor potentially at play in brain tumors, the role of neurotransmitters in the development of GBM remains poorly understood. Several lines of evidence from developmental neurobiology provide insight into the possible relationship between neurotransmitters and brain tumors. It has been shown that these molecules, especially the monoamine class of neurotransmitters, exhibit a high degree of control over proliferation and differentiation of progenitor cells. This review will focus on the 2 well-known monoamines—dopamine and serotonin. Dopamine (3,4-dihydroxyphenethylamine) participates in motor control,4 motivation, and reward.5 Critically, alterations in the production of dopamine and dysregulation of its receptors have been linked to neurological disorders6 and neurodegenerative diseases.7,8 Serotonin (5-hydroxytryptamine) regulates a variety of neural circuits, including those pathways responsible for mood, sexual desire, appetite, and circadian rhythms.9,10 Further, it has been shown that aberrations in serotonin signaling contribute to depression.11–13 These molecules, beyond their role in synaptic transmission, play a role in normal brain development and the generation of new neurons and glia in adult brains. This review will probe three critical questions regarding how monoamine neurotransmitters influence the progression of GBM. First, we examine reports regarding the role of dopamine and serotonin in governing the proliferation and differentiation of neural stem cells and brain progenitor cells. Particular emphasis will be placed on how these cells parallel GBM-initiating cells. Second, we analyze the source and availability of monoamines in the tumor microenvironment. Finally, we evaluate the current understanding of how neurotransmitters are influencing gliomagenesis by summarizing recent results, which have identified monoamine signaling as a key player in GBM growth. Overall, this review will highlight the importance of monoamine neurotransmitters as components of the GBM microenvironment and their potential as novel anti-glioma targets. Dopamine and Serotonin Influence Neurodevelopment and Cell Proliferation in the Adult Brain Overview of Dopamine and Serotonin Signaling Any discussion of dopamine and serotonin signaling must begin by acknowledging that these molecules act through interactions with a multitude of receptors. Dopamine is synthesized in the cytoplasm of the synaptic terminal.14 After the conversion of conditional amino acid tyrosine to L-DOPA by tyrosine hydroxylase (TH),15–17 L-DOPA is converted to dopamine by aromatic acid decarboxylase18 and loaded into synaptic vesicles by vesicular monoamine transporter 2 (VMAT2).19 Following its release, dopamine binds with its G-protein coupled receptors (GPCRs), which are organized into 2 families: D1-like and D2-like.20 The D1-like family includes dopamine receptor 1 (DRD1) and dopamine receptor 5 (DRD5).21 D1-like receptors interact with Gs alpha subunits, thereby activating adenylyl cyclase and stimulating intracellular 3ʹ,5ʹ-cyclic adenosine monophosphate (cAMP) production.22 In contrast, D2-like receptors stimulate Gi alpha subunits, thus inhibiting adenylate cyclase activity and reducing intracellular cAMP concentration.23 Thus, dopamine is not categorically an activating or inhibitory signal, but rather exercises a receptor-dependent influence. Finally, dopamine is either metabolized by monoamine oxidase or catecholamine methyl transferase, or reabsorbed by the dopamine transporter. In the case of serotonin, receptor diversity again plays a critical role. Serotonin is synthesized from the conversion of tryptophan to 5-hydroxy-tryptophan by tryptophan hydroxylase (TPH); this intermediate is then converted to active serotonin by aromatic acid decarboxylase.24,25 Serotonin is also loaded in vesicles by VMAT. Upon release, serotonin binds to and activates 5-hydroxytryptamine receptors (5-HTRs), of which there are 14 broken into 7 families. All of these receptors are metabotropic except for 5-HTR3, which are ligand gated ionotropic receptors. Critically, different serotonin receptors, like dopamine receptors, exert opposite effects based on which G-protein they complex with. 5-HTR1 and 5-HTR5 activate Gi/GO and decrease cAMP levels, while 5-HTR4, 5-HTR6, and 5-HTR7 induce cAMP elevation via GS. Finally, 5-HTR2 receptors activate Gq proteins to increase levels of inositol triphosphate and diacyl glycerol.26 Thus, activation of serotonin produces a variety of responses depending on the receptor expression profile of the responding cell. Beyond the variety of receptors, monoamine signaling is further complicated by interactions between receptors. For example, it has been shown that different dopamine receptors can heterodimerize with one another,27,28 as well as with other GPCRs, including endocannabanoid29 and somatostatin receptors.30 Likewise, serotonin receptors interact with different serotonin receptors and other GPCRs.31 Serotonin and dopamine receptors can also dimerize with one another.32 Therefore, dopamine and serotonin signaling represent a complex web of receptors and cascades. Untangling these intersected signaling mechanisms represents a key challenge in neuroscience and, by extension, in neuro-oncology. Dopamine and Serotonin Influence Neural Stem Cell and Progenitor Cell Behavior Before examining the role of monoamines in brain cancer, we must first understand how they participate in normal brain development. Given the unique functional requirements of the CNS, the processes governing the generation and differentiation of new cells must be tightly regulated. Neural circuits require a delicate balance between the maintenance of existing networks and the flexibility to respond to new information via potentiation of synaptic connections. A system where neurogenesis and synaptic plasticity are highly promiscuous would prevent the formation of stable neural circuitry and lead to disastrous behavioral consequences for the organism. Likewise, a system in which neurogenesis and plasticity are nonexistent would impede the incorporation of novel information, with equally problematic functional outcomes. As such, the creation of new neurons and the modulation of existing circuits must be fine-tuned. Further, glial cells must be able to rapidly respond to potential threats and replenish lost cells without inducing significant changes in existing neural circuitry. To address this problem, a variety of signaling mechanisms govern the induction of neurogenesis and gliogenesis from neural stem cells (NSCs) and other precursor cells. One of the key factors influencing the behavior of NSCs is the presence of monoamine neurotransmitters, including dopamine. Several studies have shown that progenitor cells in the developing brain express dopamine receptors33,34 and that activation of these receptors influences cell proliferation as well as differentiation. Specifically, it has been shown that ablation of dopaminergic neurons reduces the proliferation of progenitors in the subventricular zone (SVZ), a site of neurogenesis in the adult brain; this reduction can be counteracted by treatment with dopamine agonists.35–38 Further studies have shown that treatment with dopamine agonists is sufficient to increase progenitor proliferation in the SVZ.39 However, other studies have shown that blocking dopamine receptors can also increase proliferation. Two studies have demonstrated that treatment with haloperidol, a wide-acting dopamine antagonist, increases cell proliferation and neurogenesis in rodent brains.40,41 While these results may appear diametrically opposed, they may actually demonstrate one example of the effects of aforementioned receptor diversity. For example, the two studies that relied on haloperidol demonstrated that blocking dopamine receptors increases proliferation. However, haloperidol is selective for D2-like receptors, meaning that D1-like receptors can still be activated by dopamine. Thus, the outcome of these studies may depend on specific receptor activation; further study is required to delineate the roles of receptor subtypes in these processes. In addition to this ability to influence proliferation, dopamine has been shown to modulate cell-cycle status in neural progenitor cells. Work by Ohtani established that dopamine influences cell-cycle states in the lateral geniculate nucleus in a receptor-specific fashion—activation of D1-like receptors inhibited entry into the S phase, while activation of D2-like receptors promoted this entry.33 More recent studies in salamanders have shown that dopamine antagonists perturb the usual quiescence of neuronal precursors.42 Beyond NSCs and neural progenitors, it has been shown that oligodendrocyte progenitor cells (OPCs), one of the cell types reported to initiate GBM,43 also express dopamine receptors. Interestingly expression of DRD3 has been shown in OPCs and developing, but not mature, oligodendrocytes; activation via dopamine agonist reduced the differentiation of precursors to a mature state and maintained the OPC population.44 This result shows that dopamine signaling maintains a dedifferentiated state in OPCs, suggesting that a similar effect may be at work during gliomagenesis. Clearly, dopamine molds the behavior of progenitor cells in the CNS, at the levels of both proliferation and differentiation. As with dopamine, multiple studies have probed the relationship between serotonin and cell proliferation in the CNS. Serotonin’s effects appear to be wide-ranging and critical in neurodevelopment. Serotoninergic neurons are some of the earliest neurons to develop, and serotonin release begins before the development of mature neuronal circuitry.24 However, the exact role of serotonin in the generation of the brain remains only partially understood; it is widely postulated that the diversity of serotonin receptors precludes a simple understanding of serotonin and development. Genetic studies in mice suggest that serotonin participates in the development of neuronal circuits and synaptic maturation (expertly reviewed45). In addition to the generation of the CNS, serotonin plays a key role in adult neurogenesis and gliogenesis. It has been shown that depletion of serotonergic neurons leads to decreased proliferation in the dentate gyrus (DG) and the SVZ; this loss of proliferation was rescued via grafting of serotonergic neurons.46 In addition, blocking serotonin receptors decreases proliferation in the SVZ.47 Further, mice that do not express serotonin transporters, elevating serotonin levels, showed increased proliferation in the DG.48 These knockdown and depletion studies suggest that serotonin influences the creation of new cells. Pharmacological studies corroborate these results. First, treatment with fluoxetine, a selective serotonin reuptake inhibitor, increased bromodeoxyuridine incorporation in the DG by early progenitor cells.49 Second, it has been shown that altering serotonin receptors affects proliferation of progenitor cells in both the SVZ and the subgranular zone.50 Beyond neural precursors, serotonin signaling has also been shown to affect the behavior of OPCs. For example, it has been shown that treatment with olanzapine, a drug that antagonizes several 5-HTRs as well as some dopamine receptors, maintained the OPC population and reduced the generation of mature oligodendrocytes.51 This study again suggests that monoamines regulated the behavior of OPCs. In summary, this group of studies indicate that activation of serotonin signaling promotes proliferation and differentiation. Clearly, both dopamine and serotonin help shape the proliferation of CNS cells, including NSCs. It has been postulated that GBM tumors are derived from a subpopulation of GICs. These cells express many canonical NSC markers (nestin,52 CD133,53 etc) and exhibit many NSC characteristics, including the ability to self-renew and undergo asymmetrical division. Given this kinship between GICs and NSCs, GICs likely hijack many molecular mechanisms utilized by NSCs to promote growth and differentiation, including monoamine signaling. GBM Cells Interact with Neurotransmitters Dopamine- and Serotonin-Related Genes Influence Survival in GBM Patients Bioinformatics provide the first line of evidence that monoamines alter the initiation and growth of GBM tumors in human patients. Table 1 provides a comprehensive list of genes found in The Cancer Genome Atlas (TCGA) related to monoamine signaling that significantly influence patient survival in GBM. Critically, several different dopamine and serotonin receptors, as well as enzymes responsible for the synthesis of these neurotransmitters, predict survival outcomes in GBM patients. These survival differences based on the expression of genes related to monoamine signaling suggest that these signaling mechanisms may influence GBM growth and progression. Figure 1 summarizes the published literature for how these transmitter receptors influence GBM growth. One factor complicating our understanding of the role of these receptors is the immense heterogeneity of GBM tumors, even down to the single cell level.59 Further, cell states are not static, but rather fluctuate and shift in response to the dynamics of the microenvironment. It is possible that these variability expression levels may represent differences in the differentiation status of individual tumors. Overall, these bioinformatic data suggest a potential role for monoamines in GBM. Table 1 GlioVis analysis reveals key genes related to dopamine and serotonin signaling influence patient survival in GBM. Neurotransmitter Gene Expression in All GBM vs Nontumor Subtype Dataset Beneficial Expression Level Survival Benefit (mo) Wilcoxon P-value Dopamine DRD1 Reduced*** All REMBRANDT High 12.2 *** DRD2 Reduced*** Proneural REMBRANDT High 10.4 ** Classical REMBRANDT High 1 * DRD3 No difference Proneural REMBRANDT High 7.9 * DRD5 Reduced*** All REMBRANDT High 16 *** TH No difference All REMBRANDT Low 6 * DDC No difference Mesenchymal TCGA-GBM High 4 * EN1 Increased*** Proneural TCGA-GBM Low 7.1 ** Serotonin 5-HTR1A Reduced* All TCGA-GBM Low 3.5 * 5-HTR1B Reduced*** All TCGA-GBM Low 1 + 5-HTR1F No difference Classical TCGA-GBM Low .4 * 5-HTR2B No difference Mesenchymal TCGA-GBM High 3.8 + 5-HTR3E Reduced*** Mesenchymal TCGA-GBM High 2.3 + 5-HTR5A Reduced*** Proneural TCGA-GBM Low 8.3 ** 5-HTR7 Reduced* Proneural TCGA-GBM Low 8.1 * TPH-1 No difference All REMBRANDT High 4.6 * TPH-2 Reduced*** Mesenchymal REMBRANDT High 3.8 * Neurotransmitter Gene Expression in All GBM vs Nontumor Subtype Dataset Beneficial Expression Level Survival Benefit (mo) Wilcoxon P-value Dopamine DRD1 Reduced*** All REMBRANDT High 12.2 *** DRD2 Reduced*** Proneural REMBRANDT High 10.4 ** Classical REMBRANDT High 1 * DRD3 No difference Proneural REMBRANDT High 7.9 * DRD5 Reduced*** All REMBRANDT High 16 *** TH No difference All REMBRANDT Low 6 * DDC No difference Mesenchymal TCGA-GBM High 4 * EN1 Increased*** Proneural TCGA-GBM Low 7.1 ** Serotonin 5-HTR1A Reduced* All TCGA-GBM Low 3.5 * 5-HTR1B Reduced*** All TCGA-GBM Low 1 + 5-HTR1F No difference Classical TCGA-GBM Low .4 * 5-HTR2B No difference Mesenchymal TCGA-GBM High 3.8 + 5-HTR3E Reduced*** Mesenchymal TCGA-GBM High 2.3 + 5-HTR5A Reduced*** Proneural TCGA-GBM Low 8.3 ** 5-HTR7 Reduced* Proneural TCGA-GBM Low 8.1 * TPH-1 No difference All REMBRANDT High 4.6 * TPH-2 Reduced*** Mesenchymal REMBRANDT High 3.8 * *All datasets were accessed using the GlioVis portal. Median gene expression was used as the cutoff point for high vs low gene expression. Tumor subclassifications were made based on TCGA criteria.139,140 +P < 0.10; *P < 0.05; **P < 0.01, ***P < 0.001. REMBRANDT = Repository of Molecular Brain Neoplasia Data. View Large Table 1 GlioVis analysis reveals key genes related to dopamine and serotonin signaling influence patient survival in GBM. Neurotransmitter Gene Expression in All GBM vs Nontumor Subtype Dataset Beneficial Expression Level Survival Benefit (mo) Wilcoxon P-value Dopamine DRD1 Reduced*** All REMBRANDT High 12.2 *** DRD2 Reduced*** Proneural REMBRANDT High 10.4 ** Classical REMBRANDT High 1 * DRD3 No difference Proneural REMBRANDT High 7.9 * DRD5 Reduced*** All REMBRANDT High 16 *** TH No difference All REMBRANDT Low 6 * DDC No difference Mesenchymal TCGA-GBM High 4 * EN1 Increased*** Proneural TCGA-GBM Low 7.1 ** Serotonin 5-HTR1A Reduced* All TCGA-GBM Low 3.5 * 5-HTR1B Reduced*** All TCGA-GBM Low 1 + 5-HTR1F No difference Classical TCGA-GBM Low .4 * 5-HTR2B No difference Mesenchymal TCGA-GBM High 3.8 + 5-HTR3E Reduced*** Mesenchymal TCGA-GBM High 2.3 + 5-HTR5A Reduced*** Proneural TCGA-GBM Low 8.3 ** 5-HTR7 Reduced* Proneural TCGA-GBM Low 8.1 * TPH-1 No difference All REMBRANDT High 4.6 * TPH-2 Reduced*** Mesenchymal REMBRANDT High 3.8 * Neurotransmitter Gene Expression in All GBM vs Nontumor Subtype Dataset Beneficial Expression Level Survival Benefit (mo) Wilcoxon P-value Dopamine DRD1 Reduced*** All REMBRANDT High 12.2 *** DRD2 Reduced*** Proneural REMBRANDT High 10.4 ** Classical REMBRANDT High 1 * DRD3 No difference Proneural REMBRANDT High 7.9 * DRD5 Reduced*** All REMBRANDT High 16 *** TH No difference All REMBRANDT Low 6 * DDC No difference Mesenchymal TCGA-GBM High 4 * EN1 Increased*** Proneural TCGA-GBM Low 7.1 ** Serotonin 5-HTR1A Reduced* All TCGA-GBM Low 3.5 * 5-HTR1B Reduced*** All TCGA-GBM Low 1 + 5-HTR1F No difference Classical TCGA-GBM Low .4 * 5-HTR2B No difference Mesenchymal TCGA-GBM High 3.8 + 5-HTR3E Reduced*** Mesenchymal TCGA-GBM High 2.3 + 5-HTR5A Reduced*** Proneural TCGA-GBM Low 8.3 ** 5-HTR7 Reduced* Proneural TCGA-GBM Low 8.1 * TPH-1 No difference All REMBRANDT High 4.6 * TPH-2 Reduced*** Mesenchymal REMBRANDT High 3.8 * *All datasets were accessed using the GlioVis portal. Median gene expression was used as the cutoff point for high vs low gene expression. Tumor subclassifications were made based on TCGA criteria.139,140 +P < 0.10; *P < 0.05; **P < 0.01, ***P < 0.001. REMBRANDT = Repository of Molecular Brain Neoplasia Data. View Large Fig. 1 View largeDownload slide 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. Fig. 1 View largeDownload slide 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. Neurotransmitters Are Part of the Tumor Microenvironment In order to analyze the effect of neurotransmitters on tumor development, we must first probe the extent to which these molecules are present in the tumor microenvironment. As discussed above, monoamine neurotransmitters are synthesized by the neurons and released upon activation into the synaptic cleft. While neurons do cluster vesicle release machinery in the active zone of the bouton,60 not all neurotransmitters remain in the cleft. Many molecules will diffuse out from the cleft and activate autoreceptors on the releasing neuron,61–63 as well as receptors on surrounding astrocytes64 and oligodendrocytes.65,66 Remarkably, it has been shown that astrocytes alter intracellular calcium levels in response to gamma-aminobutyric acid,67 glutamate,68 and acetylcholine.69 In addition, some neurotransmitter will be degraded70 or absorbed71 by enzymes and transporters on neurons and glia. Finally, vascular pericytes and brian endothelial cells express functional enzymes for absorbing and metabolizing monoamines. Clearly, the CNS has developed specific mechanisms contingent on the availability of ambient neurotransmitters. Thus, CNS cells that have been transformed into tumor-initiating cells are likely exposed to neurotransmitters, including monoamines, which are expected to regulate a multitude of functions during gliomagenesis. Indeed, the ability of neuronal activity to influence glioma growth has recently been established. Using optogenetics, a technique by which specific neuronal populations can be selectively activated, Venkatesh and associates demonstrated that neuron-secreted neuroligin-3, released in response to neural activity, increases proliferation of GBM.72 Interestingly, this study involved activation of a specific subpopulation of cortical neurons that do not secrete monoamines. Given this role for one population of neurons, it seems within the realm of possibility that the activity of other types of neurons, including dopaminergic and serotonergic neurons, may influence the progression of GBM via paracrine secretion. Could Tumors Synthesize and Secrete Their Own Neurotransmitters? Ambient neurotransmitters are the most likely source of these molecules. This theory is supported by epidemiological studies (excellent analysis by Diamandis et al73). One study analyzing nearly 150000 patients with Parkinson’s disease (PD), a condition characterized by the loss of dopamine neurons, found a 5-fold reduction in GBM relative to controls.74 Another study found, in a smaller cohort, that PD patients are at higher risk of glioma in the first year following diagnosis but are protected against glioma 5 or more years from diagnosis.75 These epidemiological studies suggest that reduced dopamine signaling reduces the likelihood of gliomagenesis. However, a second line of evidence may argue in favor of the notion that some GBM cells themselves also synthesize and secrete dopamine in an autocrine fashion. While it may seem highly unlikely that GBM cells gain the ability to produce and secrete monoamines, several studies from the literature provide clues for such a possibility. First, GBM cells can co-opt the expression of proteins considered exclusive to neurons. Osswald et al showed that GBM cells utilize growth associated protein 43, a neuronal growth cone protein, in order to interconnect.76 Second, it has been shown that GBM tumors secrete glutamate, which in turn is able to alter cortical brain activity.77 Finally, as summarized in Table 1, the expression of enzymes responsible for the synthesis of both dopamine and serotonin in GBM cells themselves, not surrounding brain cells, influence patient outcomes. This influence on survival has been confirmed in a recent report.78 These lines of evidence, combined, raise the tantalizing possibility that GBM cells can gain the ability to synthesize and secrete neurotransmitters. PET scanning protocols offer a non-invasive mechanism to test this theory. MRI/PET analysis of dopamine binding and activity relies on a radioactively tagged analog of dopamine, 18F-DA, which binds to dopamine receptors and is absorbed into cells by the dopamine transporter.79 If scanning reveals increased signal in tumors, it can be concluded that tumors are in fact binding and trafficking dopamine. Further, PET with 18F-DOPA can identify cells that synthesize and secrete dopamine. Uptake of this tagged DOPA indicates a dopaminergic cell. These methods are well established in PD patients.80,81 Additionally, some studies have utilized other amino acid analogs, similar in structure to DOPA, in imaging brain tumors.82,83 In the case of serotonin, similar methods have been established in studying depression and sleep.84 PET scanning can identify serotonin binding to various receptors and serotonin uptake.85 These techniques have previously been applied to glioblastoma; Kamson et al demonstrated that the amount of alpha-[11C]methyl-L-tryptophan absorbed by GBM tumors is a strong independent prognosticator—increased tryptophan uptake correlated with decreased survival.86 Tryptophan utilization can be the result of a variety of processes, including supporting transformed cells’ metabolic needs and elevated proliferation state. Further, tryptophan metabolism by GBM has been implicated in immunosuppression.87 In addition to these factors, tryptophan uptake may potentially reflect elevated serotonin synthesis. Further research is required to determine the exact role of tryptophan uptake in GBM. Given the wide use of PET imaging in neuro-oncology practice today, these techniques can be quickly applied to understanding the role of monoamines in GBM. Evidence Linking Monoamines to Gliomagenesis Dopamine Interacts with Proliferation Pathways Implicated in GBM Dopamine, either from surrounding neurons or self-generated, is likely available in the tumor microenvironment and may participate in tumor growth. Evidence is beginning to accrue to support this role for dopamine in GBM onset and progression. Critically, DRD2 mRNA and protein expression are significantly increased in GBM samples from human patient biopsies.88 Comparison of tumor biopsies to matched normal brain tissues convincingly illustrated that DRD2 expression is significantly elevated in neoplastic tissue.89 Murine models of GBM exhibit a 14-fold increase in dopamine receptor expression compared with isogenic controls.90 Furthermore, DRD2 silencing reduces U87 GBM growth by about 70%–90%.89 Thus, it appears that dopamine receptors are unregulated in GBM and influence cell proliferation. It has been demonstrated that administration of a dopamine precursor prolongs survival in the C6 glioma model in rats.91 Several pathways have been suggested as underpinning DRD signaling in GBM. One of the most intriguing interactions is between DRD2 and epidermal growth factor receptor (EGFR). Amplifying mutations in the EGFR gene have been reported in 30% of epithelial cancers,92 and supraphysiological EGFR levels are essential for the growth of different brain tumor subsets.93,94 EGFR activating mutations have been shown to inflate proliferation rates and reduce apoptotic signaling in GBM.95 EGFR induces growth by activating Ras and its downstream pathway—Raf kinase, which phosphorylates mitogen-activated protein kinase kinase (MEK).96 MEK then activates mitogen-activated protein kinase (MAPK), which translocates to the nucleus and phosphorylates nuclear targets, inducing proliferation.97 DRD2 signaling also alters the MAPK pathway—treating brain slices with DRD2 agonists induces MAPK phosphorylation.98 This induction is G-protein–dependent, suggesting that DRD2 interacts with an upstream component of the cascade.99 Another study found that DRD2 activates a disintegrin and metalloprotease (ADAM) to induce EGFR transactivation, a phenomenon shown to increase the number of dopaminergic neurons in wild-type mice.100 Finally, a recent short hairpin (sh)RNA screen identified DRD2 signaling as a key pro-proliferative force in murine models of GBM, mediated by the guanine nucleotide-binding protein alpha-2/Rap1/Ras/extracellular signal-regulated kinase (ERK); combined inhibition of both DRD2 and EGFR caused a synergistic tumor-killing effect.89 These reports suggested the possibility of DRD2 and EGFR being closely linked to GBM tumors. Interestingly, dopamine ablation studies have demonstrated that selective targeting of dopamine neurons led to a decrease in cell proliferation in the SVZ; this effect was most pronounced in EGFR+ progenitor cells.36,101 These data suggest that dopamine interacts with EGFR in healthy brain tissue, further highlighting a potential connection between these signaling pathways that may be maintained in GBM tumors. Dopamine Influences Angiogenic Pathways While the pro-proliferative properties dopamine displays may contribute to GBM progression, another line of evidence has emerged suggesting that dopamine may regulate tumor progression by modulating blood vessel formation. This evidence connects dopamine signaling to another critical problem in the treatment of brain cancer—tumor-induced vascularization. The induction of new blood vessels by tumor cells recruits new supplies of nutrients to the tumor. As such, agents that ablate neovascularization in tumors have tremendous potential as novel adjuvant therapies; several such agents have shown clinical promise for treating brain tumors.102–105 GBMs are among the most vascularized solid tumors,106,107 because of their ability to initiate angiogenesis via the release of regulatory factors that promote endothelial cell migration.108 One of the factors required for this process is vascular endothelial growth factor (VEGF). This molecule stimulates angiogenesis109 by binding to VEGF receptor 2 (VEGFR2), which triggers downstream phosphorylation of a variety of factors, including MAPK, v-Akt murine thymoma viral oncogene homolog (AKT), and protein tyrosine kinase 2 (PTK2).110 Remarkably, dopamine has been shown to interact with the VEGF pathway and induce multiple anti-angiogenic mechanisms. When dopaminergic neurons were ablated in a murine model of glioma, tumor vascularization increased.111 In another study, exogenous administration of dopamine reduced angiogenesis and tumor growth in both breast-cancer- and colon-cancer-bearing mice.112 Likewise, rats altered to have a hyperactive dopaminergic system exhibited lessened angiogenesis.113 Other studies provide evidence that the mechanism governing reduced angiogenesis after dopamine treatment is, in fact, the VEGF pathway. First, VEGFR2 phosphorylation robustly increased in DRD2 knockout mice, suggesting that blocking DRD2 signaling activates the VEGF pathway.111 In addition to its connection to VEGFR, dopamine signaling also influences the recruitment of endothelial progenitor cells (EPCs) and subsequently regulates tumor neo-vascularization.114 VEGF-dependent mobilization of EPCs is essential to support tumor growth; dopamine has been shown to antagonize this critical process by reducing the ERK-dependent expression of bone marrow matrix metalloproteinase 9. In DRD2-knockout transgenic mice, tumor burden was significantly increased and microvessel density elevated; it could not be rescued by dopamine treatment.111,114 Thus, there appear to be 2 mechanisms by which dopamine signaling can influence tumor vessel formation: VEGF-mediated angiogenesis and recruitment of EPCs. These two lines of evidence—that dopamine promotes tumor growth but inhibits tumor-induced angiogenesis—complicate the potential use of dopamine-targeting drugs for the treatment of GBM. While studies that focus on angiogenesis advocate for the use of DRD2 agonists for combating cancer progression, other studies suggest that DRD2 antagonists are beneficial antitumor agents because of their observed antiproliferative properties. Despite this complication, we do not think that these two lines of evidence preclude the use of dopamine-targeting drugs as adjuvant therapies in GBM. Rather, it is critical that more research unravels the precise mechanisms by which dopamine signaling influences both proliferation and angiogenesis. The wide range of available drugs acting on the dopamine system may provide the neuro-oncologist with a new toolbox for sculpting an ideal microenvironmental landscape and inhibiting GBM progression. Serotonin Influences Canonical Growth Pathways In addition to this emerging evidence connecting dopamine with oncogenesis, studies have begun to analyze how serotonin alters cell proliferation. This research has highlighted the ability of serotonin to alter canonical growth factor pathways.115 Specifically, it has been shown that serotonin receptors interact with the mitogen-activated protein phosphorylation signaling pathways such as the MAPK and AKT cascades.116,117 Recent studies have shown that serotonin may use these pathways to participate in cancer progression and oncogenesis in several types of tumors.118 Several studies have utilized pharmacological intervention to probe serotonin’s role in GBM growth; they have revealed a complex relationship. C6 rat glioma cells treated with HTR2A agonists increased propagation and migration.119,120 This highlights the potential for serotonin receptor activation to promote GBM growth. However, other studies found that activation of different families of receptors produces the opposite effect. In this study, azapirones, a class of agonists of HTR1A, were shown to robustly inhibit neurosphere formation. Likewise 5-HTR1B and 5-HTR2C agonists proved fatally toxic for neural stem cells, suggesting that they may also inhibit the growth and limit the viability of glioma cells.121 Thus, it appears that in vitro data support the notion that GBM cells are responsive to serotonin with receptor-specific effects. More investigation is needed to delineate the specific role of each receptor and design targeted therapies. Serotonin Alters Blood Flow and Vessel Formation In addition to its ability to influence proliferation, serotonin has a potent ability to influence blood flow and angiogenesis. As discussed above, tumor vascularization is a critical problem in the treatment of GBM. Low dose treatment with serotonin has been shown to inhibit tumor growth by reducing blood supply.118 Thus, it seems possible that GBM cells specifically regulate HTR expression patterns to avoid reduced blood supply. In addition, other studies have shown that serotonin enhances endothelial cell growth and allows it to act as a potent pro-angiogenic factor.25,122 This increase in endothelial cells is mediated by a variety of kinases, including mechanistic target of rapamycin, phophoinositide 3-kinase, and sarcoma proto-oncogene non-receptor tyrosine kinase, all of which have been implicated in tumorigenesis.25,122 Once again, it appears that the precise effect of serotonin on vessel formation and blood flow is dependent on receptor subtype. Future Directions and Conclusions Monoamines in GBM—a Multitude of Receptors Responding to Dynamic Concentrations Clearly, monoamines represent a key feature of the GBM microenvironment. Their specific roles and mechanisms remain to be fully elucidated. Developmental neurobiology indicates that monoamines influence the behavior of NSCs and progenitors. Neural stem cells are the progenitor to neurons, astrocytes, and oligodendrocytes, all of which respond to neurotransmitters. GBM cells, derived from these same progenitors, seem to hijack these signaling pathways in order to successfully thrive in the CNS. This sensitivity to monoamines showcases GBM’s pronounced ability to sense and respond to the CNS microenvironment. The effect of monoamines on GBM are complex, as the referenced studies demonstrate. There are two explanations for this range of experimental outcomes. First, transmitter effects are highly dependent on the receptor subtypes expressed on tumors cells. A multitude of receptors exist for both transmitters, and these receptors often have competing effects. Given the immense heterogeneity and dynamic nature of GBM tumors, it is easy to imagine that variable expression of receptors underlies the observed range of effects on proliferation and vascularization. Second, it is well established that neurotransmitter signaling and expression are highly dynamic in the functioning brain. It is, therefore, unlikely that monoamines activate pathways in a simple on/off mechanism. Rather, we posit that monoamine transmitters have a concentration-dependent effect on GBM cells. A concentration effect has been shown for dopamine and serotonin in many studies of the normal brain; we suspect this may carry over to tumor cells.26,125,126 In addition, OPCs exhibit differential response to dopamine agonists based on dose, with high doses actually demonstrating some toxicity.127 Further, it is highly likely that varied transmitter concentrations exist in different tumor compartments, as dopamine and serotonin neurons differentially innervate anatomical compartments of the brain.128,129 This means that tumor location relative to monoamine-synthesizing nuclei will influence progression. Another key factor in determining the availability of monoamines is the prevalence of seizures in GBM patients. Seizure activity has been shown to elevate levels of dopamine and serotonin.130,131 Such increased seizure activity may lead to increased levels of monoamines in the tumor microenvironment, thereby shaping the tumor’s response. Overall, the range of receptor subtypes and variable concentrations of neurotransmitters in the tumor environment complicate the mechanism by which these molecules influence GBM. Despite the complex interaction of monoamines and GBM, we remain optimistic that, with further investigation, drugs targeting these signaling pathways may be repurposed to target brain cancer. A growing body of evidence highlights drugs targeting dopamine and serotonin receptors as new therapeutics for glioblastoma. Several studies have shown that antipsychotic drugs are capable of reducing proliferation in glioblastoma. These drugs, which antagonize dopamine and serotonin receptors, represent a large class of potential therapeutics. Recently, Dolma and colleagues showed that antagonizing D4 receptors blocks GBM growth and, critically, that combining antagonists of this receptor with temozolomide administration reduces median survival in xenograft mice models; evaluation of the mechanism underlying this increased survival highlighted the ability of this drug to prevent normal autophagy.78 Several studies identified other antipsychotic drugs, including clozapine,132 thiordiazine,133 olanzapine,134 haloperidol,89 aripiprazole,135 and trifluoperazine,136–138 as being capable of inhibiting GBM growth. In light of these promising results in murine models, antipsychotics appear to have potential to treat GBM. One key question when considering this repurposing is how these drugs will influence the behavior of nontumor cells. Given that dopamine and serotonin signaling is not specific for tumors, targeting these pathways as anticancer agents will require a strong understanding of the effect of dopamine and serotonin on surrounding cells. While we have discussed their effect on endothelial cells and CNS progenitor cells at length, it cannot be ignored that monoamines influence the normal behavior of neurons and astrocytes54–56 (expertly reviewed57). As such, any pharmacological intervention targeting monoamines in GBM will likely have side effects, including disturbances in mood and movement. In the short term, we believe that these side effects would be tolerable for patients if they were to significantly prolong life. In the long term, we are hopeful that increased research will unravel the complex and tumor-specific monoamine signaling mechanisms that can then be targeted with great precision. These specific mechanisms may involve unique dimerization and receptor patterning. Thus, the multitude of receptors targeted by these antipsychotics, as well as their roles in normal brain function, prevent a simple repurposing process. This complexity, however, is a double-edged sword. The broad spectrum of binding affinities and target receptor combinations provide clinicians with a massive toolbox of FDA-approved drugs. Combined with rising use of genomic and proteomic analysis of tumors, these drugs represent a potential wellspring for personalized medicine. Tumors with high expression of dopamine receptors could be selectively targeted with precisely matched antipsychotics. Further understanding of the tools in the antipsychotic toolbox will enable innovative adjuvant therapy for glioblastoma. Taken together, the evidence summarized in this review suggests that dopamine and serotonin signaling are key players in the microenvironmental milieu in which GBM cells originate and proliferate. 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Neuro-Oncology – Oxford University Press
Published: Nov 4, 2017
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