Research Progress of EMR2 Receptor Function in Glioma and its Potential Application as Therapeutic Target

The most frequent primary brain malignancy is glioma. Alterations in several adhesion G-protein-coupled receptors (aGPCRs) are present in cancer as they regulate adhesion, migration, and guidance. Epidermal growth factor (EGF) module-containing mucin-like receptor 2 (EMR2) is included in group II GPCRs and functionally in a family of brain angiogenesis inhibitor molecules (BAIs). Recent studies have shown that BAIs regulate phagocytosis and synaptogenesis, and their extracellular domain inhibits angiogenesis and tumor growth. In neoplastic processes, EMR2 appears to play a role in disease aggressiveness, patient survival rates, and tumor grade. This review summarizes the EMR2 involvement in cellular mechanisms and pathologies, particularly in cancer. We searched the Pubmed Central, Google Scholar and Scopus databases for terms "EMR2" and "glioma". The initial search yielded a total of 92 results. After excluding studies not written in English, based on design, and excluding duplicates and non-relevant studies, we included 38 studies in the review. EMR2 was shown to be expressed in various histologic grades of gliomas and to be linked to the PI3K pathway, as both are upregulated in glioblastoma after bevacizumab therapy. The PI3K-Akt pathway is involved in tumorigenesis, and upregulation of EMR2 may in turn upregulate PI3K, leading to increased tumor invasiveness. Indeed, overexpression of EMR2 was associated with the mesenchymal glioblastoma subtype, tumor invasiveness, and poor survival. EMR2 also regulates neutrophil function by producing reactive oxygen species (ROS) and degranulation. Possible therapeutic approaches have been studied, such as the stimulation of microglia and monocytes to inhibit tumor-initiating cells by down-regulating the EMR2 gene or through an antibody against EMR2. The current review summarizes the knowledge about the EMR2 receptor that can serve as motivation for future studies on its role in the clinical evolution and tumor biology of gliomas in order to find new modulator therapeutic approaches.