A Glutamatergic Biomarker Panel Enables Differentiating Grade 4 Gliomas/astrocytomas from Brain Metastases

Overview

Journal Front Oncol

Specialty Oncology

Date 2024 Jun 5

PMID 38835368

Authors

Falko Lange

Richard Gade

Anne Einsle

Katrin Porath

Gesine Reichart

Claudia Maletzki

Bjorn Schneider

Christian Henker

Daniel Dubinski

Michael Linnebacher

Rudiger Kohling

Thomas M Freiman

Timo Kirschstein

Affiliations

Soon will be listed here.

Abstract

Background: The differentiation of high-grade glioma and brain tumors of an extracranial origin is eminent for the decision on subsequent treatment regimens. While in high-grade glioma, a surgical resection of the tumor mass is a fundamental part of current standard regimens, in brain metastasis, the burden of the primary tumor must be considered. However, without a cancer history, the differentiation remains challenging in the imaging. Hence, biopsies are common that may help to identify the tumor origin. An additional tool to support the differentiation may be of great help. For this purpose, we aimed to identify a biomarker panel based on the expression analysis of a small sample of tissue to support the pathological analysis of surgery resection specimens. Given that an aberrant glutamate signaling was identified to drive glioblastoma progression, we focused on glutamate receptors and key players of glutamate homeostasis.

Methods: Based on surgically resected samples from 55 brain tumors, the expression of ionotropic and metabotropic glutamate receptors and key players of glutamate homeostasis were analyzed by RT-PCR. Subsequently, a receiver operating characteristic (ROC) analysis was performed to identify genes whose expression levels may be associated with either glioblastoma or brain metastasis.

Results: Out of a total of 29 glutamatergic genes analyzed, nine genes presented a significantly different expression level between high-grade gliomas and brain metastases. Of those, seven were identified as potential biomarker candidates including genes encoding for AMPA receptors , , kainate receptors and , metabotropic receptor , transaminase and the glutamine synthetase (encoded by ). Overall, the biomarker panel achieved an accuracy of 88% (95% CI: 87.1, 90.8) in predicting the tumor entity. Gene expression data, however, could not discriminate between patients with seizures from those without.

Conclusion: We have identified a panel of seven genes whose expression may serve as a biomarker panel to discriminate glioblastomas and brain metastases at the molecular level. After further validation, our biomarker signatures could be of great use in the decision making on subsequent treatment regimens after diagnosis.

References

North W, Gao G, Jensen A, Memoli V, Du J . NMDA receptors are expressed by small-cell lung cancer and are potential targets for effective treatment. Clin Pharmacol. 2012; 2:31-40. PMC: 3262385. DOI: 10.2147/CPAA.S6262. View

Venkataramani V, Yang Y, Schubert M, Reyhan E, Tetzlaff S, Wissmann N . Glioblastoma hijacks neuronal mechanisms for brain invasion. Cell. 2022; 185(16):2899-2917.e31. DOI: 10.1016/j.cell.2022.06.054. View

Romano A, Moltoni G, Guarnera A, Pasquini L, Di Napoli A, Napolitano A . Single brain metastasis versus glioblastoma multiforme: a VOI-based multiparametric analysis for differential diagnosis. Radiol Med. 2022; 127(5):490-497. PMC: 9098536. DOI: 10.1007/s11547-022-01480-x. View

Robert S, Buckingham S, Campbell S, Robel S, Holt K, Ogunrinu-Babarinde T . SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma. Sci Transl Med. 2015; 7(289):289ra86. PMC: 4503260. DOI: 10.1126/scitranslmed.aaa8103. View

Noroxe D, Poulsen H, Lassen U . Hallmarks of glioblastoma: a systematic review. ESMO Open. 2017; 1(6):e000144. PMC: 5419216. DOI: 10.1136/esmoopen-2016-000144. View

Roslin M, Henriksson R, Bergstrom P, Ungerstedt U, Bergenheim A . Baseline levels of glucose metabolites, glutamate and glycerol in malignant glioma assessed by stereotactic microdialysis. J Neurooncol. 2003; 61(2):151-60. DOI: 10.1023/a:1022106910017. View

Valente V, Teixeira S, Neder L, Okamoto O, Oba-Shinjo S, Marie S . Selection of suitable housekeeping genes for expression analysis in glioblastoma using quantitative RT-PCR. BMC Mol Biol. 2009; 10:17. PMC: 2661085. DOI: 10.1186/1471-2199-10-17. View

Ishiuchi S, Tsuzuki K, Yoshida Y, Yamada N, Hagimura N, Okado H . Blockage of Ca(2+)-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nat Med. 2002; 8(9):971-8. DOI: 10.1038/nm746. View

Muller-Langle A, Lutz H, Hehlgans S, Rodel F, Rau K, Laube B . NMDA Receptor-Mediated Signaling Pathways Enhance Radiation Resistance, Survival and Migration in Glioblastoma Cells-A Potential Target for Adjuvant Radiotherapy. Cancers (Basel). 2019; 11(4). PMC: 6520759. DOI: 10.3390/cancers11040503. View

10.

Lange F, Hornschemeyer J, Hornschemeyer M, Kirschstein T . Glutamatergic Mechanisms in Glioblastoma and Tumor-Associated Epilepsy. Cells. 2021; 10(5). PMC: 8156732. DOI: 10.3390/cells10051226. View

11.

North W, Liu F, Lin L, Tian R, Akerman B . NMDA receptors are important regulators of pancreatic cancer and are potential targets for treatment. Clin Pharmacol. 2017; 9:79-86. PMC: 5522667. DOI: 10.2147/CPAA.S140057. View

12.

Marcus H, Carpenter K, Price S, Hutchinson P . In vivo assessment of high-grade glioma biochemistry using microdialysis: a study of energy-related molecules, growth factors and cytokines. J Neurooncol. 2009; 97(1):11-23. DOI: 10.1007/s11060-009-9990-5. View

13.

Huberfeld G, Vecht C . Seizures and gliomas--towards a single therapeutic approach. Nat Rev Neurol. 2016; 12(4):204-16. DOI: 10.1038/nrneurol.2016.26. View

14.

Corsi L, Mescola A, Alessandrini A . Glutamate Receptors and Glioblastoma Multiforme: An Old "Route" for New Perspectives. Int J Mol Sci. 2019; 20(7). PMC: 6479730. DOI: 10.3390/ijms20071796. View

15.

Stepulak A, Luksch H, Gebhardt C, Uckermann O, Marzahn J, Sifringer M . Expression of glutamate receptor subunits in human cancers. Histochem Cell Biol. 2009; 132(4):435-45. DOI: 10.1007/s00418-009-0613-1. View

16.

Aronica E, Ciusani E, Coppola A, Costa C, Russo E, Salmaggi A . Epilepsy and brain tumors: Two sides of the same coin. J Neurol Sci. 2023; 446:120584. DOI: 10.1016/j.jns.2023.120584. View

17.

Ciceroni C, Arcella A, Mosillo P, Battaglia G, Mastrantoni E, Oliva M . Type-3 metabotropic glutamate receptors negatively modulate bone morphogenetic protein receptor signaling and support the tumourigenic potential of glioma-initiating cells. Neuropharmacology. 2008; 55(4):568-76. DOI: 10.1016/j.neuropharm.2008.06.064. View

18.

Hills K, Kostarelos K, Wykes R . Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma. Front Mol Neurosci. 2022; 15:903115. PMC: 9271928. DOI: 10.3389/fnmol.2022.903115. View

19.

Castegna A, Menga A . Glutamine Synthetase: Localization Dictates Outcome. Genes (Basel). 2018; 9(2). PMC: 5852604. DOI: 10.3390/genes9020108. View

20.

Buckingham S, Campbell S, Haas B, Montana V, Robel S, Ogunrinu T . Glutamate release by primary brain tumors induces epileptic activity. Nat Med. 2011; 17(10):1269-74. PMC: 3192231. DOI: 10.1038/nm.2453. View