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Understanding the role of Sphingosine 1-phosphate in regulating the microglia and glioma interactions

Sharma, Rakesh

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Abstract

Glioblastoma multiforme (GBM) are the most common highly malignant and most devastating brain tumors, with a 5-year survival rate below 10%. Based on molecular-genetic factors, GBM are sub-grouped into four distinct genetic subclasses, namely Proneural, Neural, Classical and Mesenchymal based on subtype metagene score and aberrations in genes including PDGFRA/IDH1, EGFR, and NF1. Within a GBM tumor, microglia/macrophages make up the largest population of tumor-infiltrating cells, contributing to at least one-third of the total tumor mass. Glioma cells recruit and exploit microglia for their proliferation and invasion ability, and transform microglia into an anti-inflammatory, i.e. tumor-supportive, phenotype.

Substantial evidence suggests that Sphingosine-1-phosphate (S1P), a pleotropic bioactive sphingolipid metabolite, is involved in glioma cell migration and invasion and functions as an important mitogen for glioma cells. S1P is formed inside the cell by two sphingosine kinases, SPHK1 and SPHK2. TCGA Analysis of the expression of Sphingosine Kinase 1 (SPHK1) in different subgroups of GBM revealed that SPHK1 expression correlated to poor survival outcome in GBM, among which the mesenchymal subtype showed the highest expression of SPHK1. Previous literature also suggested that the mesenchymal subtype showed a selective enrichment of microglia/macrophage- related genes. Thus, it was hypothesized that glioma-derived S1P, the secretory metabolite of SPHK1, could play an important role in regulating the microglia/macrophage – glioma crosstalk.

Using an iBidi Culture-Insert 3-well co-culture system, primary murine microglia co-cultured with glioma cells overexpressing human SPHK1, displayed an enhanced expression of pro-tumorigenic related microglial genes, as shown by an increased mRNA expression of Arginase 1 (Arg1) and Macrophage scavenger receptor 1 (Msr1). The selective inhibition of SPHK1 by the small-molecule inhibitor SKI-II, or knockdown of SPHK1 in glioma cells, inhibited the pro-tumorigenic phenotype of microglia, as shown by a decreased mRNA expression of Arg1 and Msr1, decreased production of IL-10 and significant increased production of pro-inflammatory cytokines such as TNFα and IL-6. Furthermore, inhibition of SPHK1 in gliomas also resulted in decreased activation of key signaling events that regulate anti-inflammatory phenotype, with subsequent activation of pro-inflammatory pathways in microglia/ macrophages. Inhibition of the sphingosine 1-phosphate receptors by FTY720 also shifted the activation state of microglia towards a pro-inflammatory phenotype.

In addition, S1P regulated the microglial phenotype by altering NF-κB signaling, a key pro-inflammatory pathway. S1P was able to reduce LPS induced pro-inflammatory polarization of microglia, by inhibiting the NF-κB pathway. S1P abrogated the LPS induced M1 phenotype via signaling through S1PR1 and activation of the non-canonical TLR4 pathway, possibly via activation of the TBK1/ IRF3 signaling. In summary, these results support the role of glioma-secreted S1P in maintaining the anti-inflammatory phenotype of microglia that promotes tumor progression and invasion.

Item Type: Dissertation
Supervisor: Angel, Prof. Dr. Peter
Place of Publication: Heidelberg
Date of thesis defense: 10 April 2019
Date Deposited: 29 Apr 2019 14:39
Date: 2019
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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