Expression of metabotropic glutamate receptor 4 in osteosarcoma

Xing, Wei; Chen, Bingyao; Zhao, Min; Song, Guangze; Zhang, Zengliang; Li, Nan

doi:10.3892/mco.2015.661

Cited by 8 publications

(5 citation statements)

References 18 publications

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“…In osteoblast-like osteosarcoma cells, MG63 cells dexamthasone induced expression of mGluR5 [ 51 ]. Interestingly, a recent study has shown that only 20% of osteosarcoma screened showed higher mGluR4 expression [ 52 ]. Exaggerated glutamate signaling plays an important role in tumorigenicity and malignancy of osteosarcoma.…”

Section: Discussionmentioning

confidence: 99%

Osteosarcoma cell proliferation and survival requires mGluR5 receptor activity and is blocked by Riluzole

et al. 2017

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Osteosarcomas are malignant tumors of bone, most commonly seen in children and adolescents. Despite advances in modern medicine, the poor survival rate of metastatic osteosarcoma has not improved in two decades. In the present study we have investigated the effect of Riluzole on a human and mouse metastatic osteosarcoma cells. We show that LM7 cells secrete glutamate in the media and that mGluR5 receptors are required for the proliferation of LM7 cells. Riluzole, which is known to inhibit glutamate release, inhibits proliferation, induces apoptosis and prevents migration of LM7 cells. This is also seen with Fenobam, a specific blocker of mGluR5. We also show that Riluzole alters the phosphorylation status of AKT/P70 S6 kinase, ERK1/2 and JNK1/2. Thus Riluzole is an effective drug to inhibit proliferation and survival of osteosarcoma cells and has therapeutic potential for the treatment of osteosarcoma exhibiting autocrine glutamate signaling.

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Section: Discussionmentioning

confidence: 99%

Osteosarcoma cell proliferation and survival requires mGluR5 receptor activity and is blocked by Riluzole

et al. 2017

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“…The gene encoding mGluR4 was identified in a genome-wide association (GWAS) study of osteosarcoma [155]. mGluR4 was found to be expressed in a significant percentage of both osteosarcoma (~20%) and benign giant cell tumors of bone (~40%), and expression correlated positively with overall survival in osteosarcoma [156]. The function of NMDA-mediated or AMPA-mediated glutamatergic signaling in bone cancers remians to be determined.…”

Section: The Role Of Neurons In Mesodermal Tissuesmentioning

confidence: 99%

Neuronal Activity in Ontogeny and Oncology

Venkatesh

Monje

2017

Trends in Cancer

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The nervous system plays a central role in regulating the stem cell niche in many organs and thereby critically modulates development, homeostasis and plasticity. A similarly powerful role for neural regulation of the cancer microenvironment is emerging. Neurons promote the growth of cancers of the brain, skin, prostate, pancreas and stomach. Parallel mechanisms shared in development and cancer suggest that neural modulation of the tumor microenvironment may prove a universal theme, although the mechanistic details of such modulation remain to be discovered for many malignancies. Here, we review what is known about the influences of active neurons on stem cell and cancer microenvironments across a broad range of tissues and discuss emerging principles of neural regulation of development and cancer.

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“…Its expression has been associated with poor prognosis in several cancers, including malignant gliomas, colorectal cancer, and rhabdomyosarcoma (10), whereas GRM4 agonists have shown in vitro or xenograft activity in medulloblastoma (11) and glioblastoma cell lines (12), and recently in bladder cancer (13). In osteosarcoma, a small study has shown GRM4 expression correlates with better survival (14). Here, we sought to investigate the biological and therapeutic roles of GRM4 in vivo using genetic models of osteosarcoma.…”

Section: Introductionmentioning

confidence: 99%

Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23

et al. 2019

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The glutamate metabotropic receptor 4 ( GRM4 ) locus is linked to susceptibility to human osteosarcoma, through unknown mechanisms. We show that Grm4 − / − genetargeted mice demonstrate accelerated radiation-induced tumor development to an extent comparable with Rb1 +/ − mice. GRM4 is expressed in myeloid cells, selectively regulating expression of IL23 and the related cytokine IL12. Osteosarcoma-conditioned media induce myeloid cell Il23 expression in a GRM4-dependent fashion, while suppressing the related cytokine Il12 . Both human and mouse osteosarcomas express an increased IL23:IL12 ratio, whereas higher IL23 expression is associated with worse survival in humans. Consistent with an oncogenic role, Il23 −/− mice are strikingly resistant to osteosarcoma development. Agonists of GRM4 or a neutralizing antibody to IL23 suppressed osteosarcoma growth in mice. These fi ndings identify a novel, druggable myeloid suppressor pathway linking GRM4 to the proinfl ammatory IL23/IL12 axis. SIGNIFICANCE:Few novel systemic therapies targeting osteosarcoma have emerged in the last four decades. Using insights gained from a genome-wide association study and mouse modeling, we show that GRM4 plays a role in driving osteosarcoma via a non-cell-autonomous mechanism regulating IL23, opening new avenues for therapeutic intervention.Osteosarcoma is an aggressive primary malignant tumor of the bone and a signifi cant cause of cancer-related death in the young. Patients are commonly treated with multimodal approaches, including surgery and adjuvant chemotherapy. Few effective systemic therapies have emerged in the last four decades for relapsed or metastatic osteosarcoma ( 1, 2 ). Osteosarcomas represent a promising indication for strategies that target the immune system ( 2 ); however, a recent clinical trialResearch.on July 16, 2020. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): M. Kansara, K. Thomson, P. Pang, D.M. Thomas Study supervision: M. Kansara, D.M. ThomasResearch.on July 16, 2020.

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Expression of metabotropic glutamate receptor 4 in osteosarcoma

Cited by 8 publications

References 18 publications

Osteosarcoma cell proliferation and survival requires mGluR5 receptor activity and is blocked by Riluzole

Osteosarcoma cell proliferation and survival requires mGluR5 receptor activity and is blocked by Riluzole

Neuronal Activity in Ontogeny and Oncology

Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23

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