Type-3 metabotropic glutamate receptors negatively modulate bone morphogenetic protein receptor signaling and support the tumourigenic potential of glioma-initiating cells

Exciting Times beyond the Brain: Metabotropic Glutamate Receptors in Peripheral and Non-Neural Tissues

“…Furthermore, systemic administration of the mGlu2/3 receptor antagonist, (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), inhibits the growth of glioma cells implanted either under the skin or inside the brain parenchima of nude mice. Treatment with LY341495 also significantly reduced the number of Ki-67-positive tumor cells (Arcella et al, 2005) and tumor cell aggregates (Ciceroni et al, 2008) in the brains of these mice. Chang et al (2005) studied the expression of mGlu4 receptor in several healthy and transformed human tissues.…”

Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas

“…We found that type-3 metabotropic glutamate receptors (mGlu3 receptors), which are coupled to G i /G o proteins, regulate GSCs and activate multiple signal-transduction pathways in GSCs and other cell types. 12,13 Pharmacological blockade of mGlu3 receptors promotes astroglial differentiation of GSCs by facilitating the activity of bone morphogenetic proteins. 12 In mice implanted with GSCs into the brain, a 3-month systemic treatment with a potent mGlu3 receptor antagonist started at the time of cell implantation substantially reduced tumor growth.…”

“…12,13 Pharmacological blockade of mGlu3 receptors promotes astroglial differentiation of GSCs by facilitating the activity of bone morphogenetic proteins. 12 In mice implanted with GSCs into the brain, a 3-month systemic treatment with a potent mGlu3 receptor antagonist started at the time of cell implantation substantially reduced tumor growth. 12 These data are interesting, but they have limited value in translational medicine because the treatment of malignant gliomas in humans usually starts when the tumor is already fully developed.…”

“…12 In mice implanted with GSCs into the brain, a 3-month systemic treatment with a potent mGlu3 receptor antagonist started at the time of cell implantation substantially reduced tumor growth. 12 These data are interesting, but they have limited value in translational medicine because the treatment of malignant gliomas in humans usually starts when the tumor is already fully developed. In pilot studies, we could not see any significant effect of the mGlu3 receptor antagonist when treatment started weeks after GSC implantation.…”

A hypothesis and theoretical model speculating the possible role of therapy mediated neoplastic cell loss in promoting the process of glioblastoma relapse

“…Among those factors which inhibit tumorogenicity (anti-TRIP property), activation of Smad1,5,8 mediated signaling [as result of exogenous BMP4 (Piccirillo et al, 2006) or m-Glutamate receptor blockade (Ciceroni et al, 2008)], inhibiting the Sonic Hedgehog (Shh) pathway (Clement et al, 2007) and blocking the cell adhesion molecule LICAM (Bao et al, 2008) leads to reduction of tumorogenicity of cultured GCSCs, while suppressing c-Myc expression or knocking down the polycomb group protein BMI1 (Abdouh et al, 2009) leads to loss of tumorogenicity in GCSCs. More recently blockade of Notch signaling by gamma secretase inhibitors (Fan et al, 2010) has also been shown to abrogate tumorogenicity.…”