Comparative Expression Study of the Endo–G Protein Coupled Receptor (GPCR) Repertoire in Human Glioblastoma Cancer Stem-like Cells, U87-MG Cells and Non Malignant Cells of Neural Origin Unveils New Potential Therapeutic Targets

Abstract

Glioblastomas (GBMs) are highly aggressive, invasive brain tumors with bad prognosis and unmet medical need. These tumors are heterogeneous being constituted by a variety of cells in different states of differentiation. Among these, cells endowed with stem properties, tumor initiating/propagating properties and particularly resistant to chemo- and radiotherapies are designed as the real culprits for tumor maintenance and relapse after treatment. These cells, termed cancer stem-like cells, have been designed as prominent targets for new and more efficient cancer therapies. G-protein coupled receptors (GPCRs), a family of membrane receptors, play a prominent role in cell signaling, cell communication and crosstalk with the microenvironment. Their role in cancer has been highlighted but remains largely unexplored. Here, we report a descriptive study of the differential expression of the endo-GPCR repertoire in human glioblastoma cancer stem-like cells (GSCs), U-87 MG cells, human astrocytes and fetal neural stem cells (f-NSCs). The endo-GPCR transcriptome has been studied using Taqman Low Density Arrays. Of the 356 GPCRs investigated, 138 were retained for comparative studies between the different cell types. At the transcriptomic level, eight GPCRs were specifically expressed/overexpressed in GSCs. Seventeen GPCRs appeared specifically expressed in cells with stem properties (GSCs and f-NSCs). Results of GPCR expression at the protein level using mass spectrometry and proteomic analysis are also presented. The comparative GPCR expression study presented here gives clues for new pathways specifically used by GSCs and unveils novel potential therapeutic targets.

PAR1 inhibition suppresses the self-renewal and growth of A2B5-defined glioma progenitor cells and their derived gliomas in vivo

“…That said, the attractiveness of PAR1 as a therapeutic target is tempered by its expression by normal astrocytic and neuronal populations alike, 52 as well as by resident neural stem cells. 53,54 Although tumor cells, and especially the tumor-initiating fraction thereof, selectively overexpress the receptor, its lower level basal expression by other normal cells of the central nervous system introduces the possibility of dose-dependent off-target effects that will mandate cautious titration in any therapeutic efforts targeting PAR1 itself. In that regard, those PAR1-targeted small molecules now available for clinical use, such as the novel direct PAR1 antagonist vorapaxar, have limited brain–barrier penetrance, further limiting current options for targeting PAR1-overexpressing TPCs.…”

G Protein–Coupled Receptor Multimers: A Question Still Open Despite the Use of Novel Approaches

“…Most cells express multiple GPCR subtypes and are consequently able to respond to at least a corresponding number of different agonists (Vassilatis et al, 2003;Regard et al, 2008;Insel et al, 2012;Fève et al, 2014). Distinct GPCRs can affect each other's functions to come to an integrative cellular response through direct physical interactions in heteromeric complexes.…”

G protein-coupled receptors as oncogenic signals in glioma: Emerging therapeutic avenues

“…Because the search for new targets to treat these malignant tumors is ongoing, an exhaustive study published by Feve, Saliou, and Zeniou et al examined the GPCR expression profile between primary GSCs, U87MG cells, neural precursor cells, and healthy astrocytes to identify new GPCR candidates that are differentially expressed and could be used for targeted therapies (Feve et al, 2014)…”

“…A recent study aimed at profiling GPCR expression in GSCs, healthy astrocytes, neural stem cells, and GBM cell lines identified eight GPCRs that are exclusively expressed by GSCs (including LPHN2, GPR37, CALCRL, HRH2, GPR73, S1PR 5 , GPR128, and GPR103), revealing several new therapeutic targets to explore within the GPCR family (Feve et al, 2014). Accordingly, GPCRs represent valuable molecular modulators to control the stem cell phenotype.…”