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- Dijksterhuis, Jacomijn P., et al.
(author)
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High levels of WNT-5A in human glioma correlate with increased presence of tumor-associated microglia/monocytes
- 2015
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In: Experimental Cell Research. - : Elsevier. - 0014-4827 .- 1090-2422. ; 339:2, s. 280-288
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Journal article (peer-reviewed)abstract
- Malignant gliomas are among the most severe types of cancer, and the most common primary brain tumors. Treatment options are limited and the prognosis is poor. WNT-5A, a member of the WNT family of lipoglycoproteins, plays a role in oncogenesis and tumor progression in various cancers, whereas the role of WNT-5A in glioma remains obscure. Based on the role of WNT-5A as an oncogene, its potential to regulate microglia cells and the glioma-promoting capacities of microglia cells, we hypothesize that WNT-5A has a role in regulation of immune functions in glioma. We investigated WNT-5A expression by in silico analysis of the cancer genome atlas (TCGA) transcript profiling of human glioblastoma samples and immunohistochemistry experiments of human glioma tissue microarrays (TMA). Our results reveal higher WNT-5A protein levels and mRNA expression in a subgroup of gliomas (WNT-5A(high)) compared to non-malignant control brain tissue. Furthermore, we show a significant correlation between WNT-5A in the tumor and presence of major histocompatibility complex Class II-positive microglia/monocytes. Our data pinpoint a positive correlation between WNT-5A and a proinflammatory signature in glioma. We identify increased presence of microglia/monocytes as an important aspect in the inflammatory transformation suggesting a novel role for WNT-5A in human glioma.
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| 2. |
- Dijksterhuis, Jacomijn P
(author)
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WNT/FZD signaling : an odyssey from molecular pharmacology to brain (patho)physiology
- 2015
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Doctoral thesis (other academic/artistic)abstract
- The 19 members of the lipoglycoprotein family of WNTs interact with the highly conserved cysteine-rich domain (CRD) of ten members of the Frizzled (FZD1-10) family. The seven transmembrane-spanning surface receptors are listed as G protein-coupled receptors and are known to interact with heterotrimeric G proteins as well as the scaffolding protein disheveled. Upon ligand binding, activation of β-catenin-dependent and/or –independent pathways are induced. The WNT/Frizzled signaling pathway is highly conserved across species and plays an essential role in a plethora of physiological processes, such as embryonic stem cell differentiation, adult stem cell renewal, migration, proliferation and cell polarity. In humans, dysregulation of the pathway is related to developmental alterations, as well as numerous diseases, among which various types of cancers. The general aim of this thesis was to investigate the role of WNT/FZD signaling in physiological and pathophysiological processes of the central nervous system. Additionally, we attempted to dissect the molecular features of the WNT/FZD pathway regarding signaling specification, a contribution aimed at increasing the possibilities of future drug development. To date, WNT/FZD binding specificity, as well as the downstream signaling trigged by different ligand-receptor combinations, have not been systematically mapped. Furthermore, the involvement and role of heterotrimeric G proteins downstream of FZDs is unclear. In paper I, we demonstrated that WNT-5A is able to activate PTX-sensitive Gαi/o proteins in the microglia-like cell line N13. Additionally, in paper II we concluded that WNT-3A, -4, and -5A have a putative functional selectivity for individual downstream signaling pathways depending on the FZD present. WNT-5A is known to be expressed in the central nervous system, where it plays a role in various neurological processes. However, it had not been fully delineated which cell type expresses and secretes WNT-5A in the brain. In paper IV, we identified a subpopulation of astrocytes that express high levels of WNT-5A in the brain of adult mice. These astrocytes are localized in the subventricular zone, the rostral migratory stream, and in the hippocampus. By studying a WNT-5A+/- mouse model, we show that some astrocytes release WNT-5A and fulfill a crucial role in guiding the migration of neuronal precursor cells from the subventricular zone to the olfactory bulb. In paper V, we investigated the pathological implications of WNT-5A signaling to the prognostics of human glioblastomas, and described a strong association between WNT-5A expression in in the tumor microenvironment and increased infiltration of microglia. Besides the role in neuronal precursor migration, WNT-5A induced a proinflammatory response in mouse microglia cells, shown by the expression of several proinflammatory markers (paper III). Additionally, WNT-5A induced proliferation, invasion and calcium signaling in microglia. By employing the Gαi/o inhibitor PTX, as well as the MEK1/2 inhibitor, a part of these events could be blocked, suggesting G protein-dependent mechanisms downstream of WNT-5A.
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