Limits...
Neurodegeneration in the Brain Tumor Microenvironment: Glutamate in the Limelight.

Savaskan NE, Fan Z, Broggini T, Buchfelder M, Eyüpoglu IY - Curr Neuropharmacol (2015)

Bottom Line: Neurodegenerative actions of malignant gliomas resemble mechanisms also found in many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis.Recent data demonstrate that gliomas seize neuronal glutamate signaling for their own growth advantage.Noteworthy is the finding, that reactive oxygen species (ROS) activate transient receptor potential (TRP) channels and thereby TRP channels can potentiate glutamate release.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Universitatsklinikum Erlangen, Friedrich Alexander University of Erlangen- Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany. nicolai.savaskan@uk-erlangen.de.

ABSTRACT
Malignant brain tumors are characterized by destructive growth and neuronal cell death making them one of the most devastating diseases. Neurodegenerative actions of malignant gliomas resemble mechanisms also found in many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis. Recent data demonstrate that gliomas seize neuronal glutamate signaling for their own growth advantage. Excessive glutamate release via the glutamate/cystine antiporter xCT (system xc-, SLC7a11) renders cancer cells resistant to chemotherapeutics and create the tumor microenvironment toxic for neurons. In particular the glutamate/cystine antiporter xCT takes center stage in neurodegenerative processes and sets this transporter a potential prime target for cancer therapy. Noteworthy is the finding, that reactive oxygen species (ROS) activate transient receptor potential (TRP) channels and thereby TRP channels can potentiate glutamate release. Yet another important biological feature of the xCT/glutamate system is its modulatory effect on the tumor microenvironment with impact on host cells and the cancer stem cell niche. The EMA and FDA-approved drug sulfasalazine (SAS) presents a lead compound for xCT inhibition, although so far clinical trials on glioblastomas with SAS were ambiguous. Here, we critically analyze the mechanisms of action of xCT antiporter on malignant gliomas and in the tumor microenvironment. Deciphering the impact of xCT and glutamate and its relation to TRP channels in brain tumors pave the way for developing important cancer microenvironmental modulators and drugable lead targets.

No MeSH data available.


Related in: MedlinePlus

The tumor microenvironment in brain tumors. Scheme of the brain tumor microenvironment and its various compartments. Tocover the heterogeneity of malignant gliomas the tumor zone model classifies gliomas into three distinct tumor zones [3]. Left, given is thetumor core or tumor zone I (TZI, black spot), peritumoral zone (yellow encircled), and the tumor zone III (margenda encircled). Right,higher magnification of the boxed area. The glioma microenvironment impacts on host cells such as neurons (orange), vessels (pink),astrocytes (blue) and microglia (purple). Glioma cells are given in green. The glutamate gradient is shown in red dots. Abbreviations: TZ,tumor zones (numbered I to III).
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Figure 2: The tumor microenvironment in brain tumors. Scheme of the brain tumor microenvironment and its various compartments. Tocover the heterogeneity of malignant gliomas the tumor zone model classifies gliomas into three distinct tumor zones [3]. Left, given is thetumor core or tumor zone I (TZI, black spot), peritumoral zone (yellow encircled), and the tumor zone III (margenda encircled). Right,higher magnification of the boxed area. The glioma microenvironment impacts on host cells such as neurons (orange), vessels (pink),astrocytes (blue) and microglia (purple). Glioma cells are given in green. The glutamate gradient is shown in red dots. Abbreviations: TZ,tumor zones (numbered I to III).

Mentions: Thus, the physical constrains in space and the hallmark of massive neuronal destruction made the hypothesis appealing that glioma-derived glutamate release is implicated in the mechanisms for creating space for tumor growth (Fig. 2). The level of tumor-derived extracellular glutamate has been determined in vitro and in vivo and glutamate levels above 250 µM have been monitored [44, 45, 68], a concentration known to be neurotoxic. Also, there are independent evidences that malignant gliomas destroy the peritumoral area which is also reflected by the development of cytotoxic edema. Moreover, these data are confirmed by studies utilizing the competitive NMDA receptor antagonist MK801 or uncompetitive NMDA receptor antagonist memantine in gliomas where neuronal cell death could be inhibited. However, pharmacological or genetic inhibition of xCT revealed that glioma cells grow unlimited albeit their neurodegenerative potential is restricted. Thus, the concept that the neurodegenerative potential of gliomas creates space for unrestricted tumor growth in the brain is thus not likely to be the main biological role of xCT in brain tumors. In favor for alternative explanation is the finding that tumor-derived glutamate induces a plethora of signaling events beside neuronal damage (Fig. 2).


Neurodegeneration in the Brain Tumor Microenvironment: Glutamate in the Limelight.

Savaskan NE, Fan Z, Broggini T, Buchfelder M, Eyüpoglu IY - Curr Neuropharmacol (2015)

The tumor microenvironment in brain tumors. Scheme of the brain tumor microenvironment and its various compartments. Tocover the heterogeneity of malignant gliomas the tumor zone model classifies gliomas into three distinct tumor zones [3]. Left, given is thetumor core or tumor zone I (TZI, black spot), peritumoral zone (yellow encircled), and the tumor zone III (margenda encircled). Right,higher magnification of the boxed area. The glioma microenvironment impacts on host cells such as neurons (orange), vessels (pink),astrocytes (blue) and microglia (purple). Glioma cells are given in green. The glutamate gradient is shown in red dots. Abbreviations: TZ,tumor zones (numbered I to III).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4598438&req=5

Figure 2: The tumor microenvironment in brain tumors. Scheme of the brain tumor microenvironment and its various compartments. Tocover the heterogeneity of malignant gliomas the tumor zone model classifies gliomas into three distinct tumor zones [3]. Left, given is thetumor core or tumor zone I (TZI, black spot), peritumoral zone (yellow encircled), and the tumor zone III (margenda encircled). Right,higher magnification of the boxed area. The glioma microenvironment impacts on host cells such as neurons (orange), vessels (pink),astrocytes (blue) and microglia (purple). Glioma cells are given in green. The glutamate gradient is shown in red dots. Abbreviations: TZ,tumor zones (numbered I to III).
Mentions: Thus, the physical constrains in space and the hallmark of massive neuronal destruction made the hypothesis appealing that glioma-derived glutamate release is implicated in the mechanisms for creating space for tumor growth (Fig. 2). The level of tumor-derived extracellular glutamate has been determined in vitro and in vivo and glutamate levels above 250 µM have been monitored [44, 45, 68], a concentration known to be neurotoxic. Also, there are independent evidences that malignant gliomas destroy the peritumoral area which is also reflected by the development of cytotoxic edema. Moreover, these data are confirmed by studies utilizing the competitive NMDA receptor antagonist MK801 or uncompetitive NMDA receptor antagonist memantine in gliomas where neuronal cell death could be inhibited. However, pharmacological or genetic inhibition of xCT revealed that glioma cells grow unlimited albeit their neurodegenerative potential is restricted. Thus, the concept that the neurodegenerative potential of gliomas creates space for unrestricted tumor growth in the brain is thus not likely to be the main biological role of xCT in brain tumors. In favor for alternative explanation is the finding that tumor-derived glutamate induces a plethora of signaling events beside neuronal damage (Fig. 2).

Bottom Line: Neurodegenerative actions of malignant gliomas resemble mechanisms also found in many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis.Recent data demonstrate that gliomas seize neuronal glutamate signaling for their own growth advantage.Noteworthy is the finding, that reactive oxygen species (ROS) activate transient receptor potential (TRP) channels and thereby TRP channels can potentiate glutamate release.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Universitatsklinikum Erlangen, Friedrich Alexander University of Erlangen- Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany. nicolai.savaskan@uk-erlangen.de.

ABSTRACT
Malignant brain tumors are characterized by destructive growth and neuronal cell death making them one of the most devastating diseases. Neurodegenerative actions of malignant gliomas resemble mechanisms also found in many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis. Recent data demonstrate that gliomas seize neuronal glutamate signaling for their own growth advantage. Excessive glutamate release via the glutamate/cystine antiporter xCT (system xc-, SLC7a11) renders cancer cells resistant to chemotherapeutics and create the tumor microenvironment toxic for neurons. In particular the glutamate/cystine antiporter xCT takes center stage in neurodegenerative processes and sets this transporter a potential prime target for cancer therapy. Noteworthy is the finding, that reactive oxygen species (ROS) activate transient receptor potential (TRP) channels and thereby TRP channels can potentiate glutamate release. Yet another important biological feature of the xCT/glutamate system is its modulatory effect on the tumor microenvironment with impact on host cells and the cancer stem cell niche. The EMA and FDA-approved drug sulfasalazine (SAS) presents a lead compound for xCT inhibition, although so far clinical trials on glioblastomas with SAS were ambiguous. Here, we critically analyze the mechanisms of action of xCT antiporter on malignant gliomas and in the tumor microenvironment. Deciphering the impact of xCT and glutamate and its relation to TRP channels in brain tumors pave the way for developing important cancer microenvironmental modulators and drugable lead targets.

No MeSH data available.


Related in: MedlinePlus