An Update on Glioblastoma Biology, Genetics, and Current Therapies: Novel Inhibitors of the G Protein-Coupled Receptor CCR5
Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia
Faculty of Chemistry and Chemical Technology, University of Ljubljana, 1000 Ljubljana, Slovenia
Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, USA
School of Medicine, Xavier University, Santa Helenastraat #23, Oranjestad, Aruba
Division of Perinatal Research, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW 2065, Australia
Sydney Medical School Northern, University of Sydney, Sydney, NSW 2006, Australia
Lankenau Institute for Medical Research Philadelphia, 100 East Lancaster Ave., Wynnewood, PA 19069, USA
Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia
The Wistar Cancer Center, Philadelphia, PA 19107, USA
Authors to whom correspondence should be addressed.
Academic Editor: Guillermo Gomez
Int. J. Mol. Sci. 2021, 22(9), 4464; https://doi.org/10.3390/ijms22094464
Received: 4 April 2021 / Revised: 20 April 2021 / Accepted: 21 April 2021 / Published: 24 April 2021
(This article belongs to the Special Issue Novel Therapeutic Treatments to Target Glioblastoma Intratumoral Heterogeneity and Plasticity)
The mechanisms governing therapeutic resistance of the most aggressive and lethal primary brain tumor in adults, glioblastoma, have increasingly focused on tumor stem cells. These cells, protected by the periarteriolar hypoxic GSC niche, contribute to the poor efficacy of standard of care treatment of glioblastoma. Integrated proteogenomic and metabolomic analyses of glioblastoma tissues and single cells have revealed insights into the complex heterogeneity of glioblastoma and stromal cells, comprising its tumor microenvironment (TME). An additional factor, which isdriving poor therapy response is the distinct genetic drivers in each patient’s tumor, providing the rationale for a more individualized or personalized approach to treatment. We recently reported that the G protein-coupled receptor CCR5, which contributes to stem cell expansion in other cancers, is overexpressed in glioblastoma cells. Overexpression of the CCR5 ligand CCL5 (RANTES) in glioblastoma completes a potential autocrine activation loop to promote tumor proliferation and invasion. CCL5 was not expressed in glioblastoma stem cells, suggesting a need for paracrine activation of CCR5 signaling by the stromal cells. TME-associated immune cells, such as resident microglia, infiltrating macrophages, T cells, and mesenchymal stem cells, possibly release CCR5 ligands, providing heterologous signaling between stromal and glioblastoma stem cells. Herein, we review current therapies for glioblastoma, the role of CCR5 in other cancers, and the potential role for CCR5 inhibitors in the treatment of glioblastoma.