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.
Highlights
Glioblastomas (World Health Organization (WHO) grade IV astrocytomas) are highly aggressive, angiogenic and infiltrating brain tumors representing more than 50% of all gliomas [1]
Expression of G-protein coupled receptors (GPCRs) was studied in five different human cell types comprising TG1 and OB1 glioblastoma cancer stem-like cells (GSCs) isolated from GBM biopsies of two patients, the GBM cancer cell line U-87 MG, fetal neural stem cells (f-NSCs) and human astrocytes (HA) in primary cultures
The complexity of GPCR signaling offered by the possible formation of homo- or hetero oligomers, interactions with a wealth of other proteins, including growth factor receptors [166,167,168,169] and downstream effectors, and its regulatory role in several pathways including the Hippo pathway which coordinates tissue homeostasis [170], unveils bewildering opportunities to target new diseases and fuel drug discovery [31]
Summary
Glioblastomas (World Health Organization (WHO) grade IV astrocytomas) are highly aggressive, angiogenic and infiltrating brain tumors representing more than 50% of all gliomas [1]. Their outcome is poor, most treatments currently in use remaining inefficient on long term survival [2,3,4] and less than 5% of patients survive 5 years post diagnosis [1]. Improvement of the standard Stupp protocol [3,6], association to topoisomerase inhibitors, alkylating agents, tyrosine kinase inhibitors, intercalating agents or antibodies targeting VEGF or the EGF receptor, development of new combinations of chemotherapeutic agents and testing new delivery drug devices have been used in different protocols (for exhaustive review see [5]). Seeking for new molecules acting on targets different from those explored so far and improvement of multi-targeted protocols are necessary to decrease recurrence and morbidity of this brain cancer that afflicts humans of all ages
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