CCR5-mediated signaling is involved in invasion of glioblastoma cells in its microenvironment

Novak, Metka (author), Koprivnikar Krajnc, Miha (author), Hrastar, Barbara (author), Breznik, Barbara (author), Majc, Bernarda (author), Mlinar, Mateja (author), Rotter, Ana (author), Porčnik, Andrej (author), Mlakar, Jernej (author), Stare, Katja (author), Pestell, Richard G. (author), Lah Turnšek, Tamara (author)

The chemokine CCL5/RANTES is a versatile inflammatory mediator, which interacts with the receptor CCR5, promoting cancer cell interactions within the tumor microenvironment. Glioblastoma is a highly invasive tumor, in which CCL5 expression correlates with shorter patient survival. Using immunohistochemistry, we identified CCL5 and CCR5 in a series of glioblastoma samples and cells, including glioblastoma stem cells. CCL5 and CCR5 gene expression were significantly higher in a cohort of 38 glioblastoma samples, compared to low-grade glioma and non-cancerous tissues. The in vitro invasion of patients-derived primary glioblastoma cells and glioblastoma stem cells was dependent on CCL5-induced CCR5 signaling and is strongly inhibited by the small molecule CCR5 antagonist maraviroc. Invasion of these cells, which was enhanced when co-cultured with mesenchymal stem cells (MSCs), was inhibited by maraviroc, suggesting that MSCs release CCR5 ligands. In support of this model, we detected CCL5 and CCR5 in MSC monocultures and glioblastoma-associated MSC in tissue sections. We also found CCR5 expressing macrophages were in close proximity to glioblastoma cells. In conclusion, autocrine and paracrine cross-talk in glioblastoma and, in particular, glioblastoma stem cells with its stromal microenvironment, involves CCR5 and CCL5, contributing to glioblastoma invasion, suggesting the CCL5/CCR5 axis as a potential therapeutic target that can be targeted with repositioned drug maraviroc.

• Language: English
• Keywords: CCL5, CCR5, chemokines, glioblastoma, invasion, maraviroc, mesenchymal stem cells
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine; FKKT - Faculty of Chemistry and Chemical Technology
• Publication status: Published
• Publication version: Version of Record
• Year: 2020
• Number of pages: 20 str.
• Numbering: Vol. 21, iss. 12, art. 4199
• PID: 20.500.12556/RUL-133933
• UDC: 577
• ISSN on article: 1422-0067
• DOI: 10.3390/ijms21124199
• COBISS.SI-ID: 19416067
• Publication date in RUL: 20.12.2021

Record is a part of a journal

• Title: International journal of molecular sciences
• Shortened title: Int. j. mol. sci.
• Publisher: MDPI
• ISSN: 1422-0067
• COBISS.SI-ID: 2779162

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 12.06.2020

Secondary language

• Language: Slovenian
• Keywords: glioblastom, kemokini, tumorsko mikrookolje, invazija