The invasion promoting effect of microglia on glioblastoma cells is inhibited by cyclosporin A

Sliwa, Marcin; Marković, Darko; Gabrusiewicz, Konrad; Synowitz, Michael; Glaß, Rainer; Zawadzka, Małgorzata; Wesołowska, Aleksandra; Kettenmann, Helmut; Kamińska, Bożena

doi:10.1093/brain/awl263

Cited by 132 publications

(125 citation statements)

References 47 publications

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“…S1D). As previously described, microglial cells associated with the glioma had an ameboid morphology, indicating a certain degree of activation (10,11).…”

Section: Resultssupporting

confidence: 56%

“…We compared glioma invasion in brain slice cultures from MT1-MMP ϩ/ϩ MT1-MMP ϩ/Ϫ MT1-MMP Ϫ/Ϫ mice. EGFP-transfected glioma cells were injected and glioma size was quantified as established previously (8,10) by measuring the projected fluorescent area covered by the EGFP-transfected glioma cells within the slice 5 d after injection. These surface measurements give a good correlate for the invasiveness of a tumor (ref.…”

Section: Blocking the Mt1-mmp Expression By Shrna In Microglia Resultmentioning

confidence: 99%

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Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Marković

Vinnakota

Chirasani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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346

328

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for highly malignant gliomas (World Health Organization grade III and IV) there is no successful treatment; patients have an average survival time of approximately 1 y after diagnosis. Glioma cells are highly invasive and infiltrate normal brain tissue, and as a result, surgical resection is always incomplete. Degradation of ECM by membrane-bound and secreted metalloproteases facilitates glioma invasion. In particular, the membrane-bound metalloproteases are pivotal for tumor invasion as they very efficiently digest extracellular matrix proteins and also activate secreted metalloproteases (1) like matrix metalloproteinase-2 (MMP-2, also known as gelatinase A), which is one of the major proteases involved in glioma invasion in mouse models (2) and probably also in humans (3). Hence, membrane-inserted metalloproteases like membrane type 1 matrix metalloproteinase (MT1-MMP) can enable gliomas to invade the brain parenchyma as single cells (4).Microglia are the intrinsic immune cells of the brain; they control the innate and the adaptive immune response in the CNS and are activated by inflammatory or other pathological stimuli (5). Activation of microglial toll-like receptors (TLRs) triggers the innate immune response and can initiate host-defense and tissue repair mechanisms, but also CNS inflammation, neurodegeneration, and trauma (5, 6). As microglial cells are attracted toward glioma in large numbers-glioma tissue consists of as much as 30% microglial cells-and because microglia density in gliomas positively correlates with malignancy, invasiveness, and grading of the tumors (7-9), we investigated if microglia may actively contribute to glioma expansion. Here, we show that soluble factors released from glioma stimulate microglial TLRs, resulting in microglial MT1-MMP expression via the TLR downstream signaling molecules MyD88 and p38 MAPK. In turn, MT1-MMP expression and activity in these immune cells promotes glioma cell invasion and tumor expansion. ResultsGlioma Associated Microglia Over-Express MT1-MMP. We analyzed the expression pattern of the matrix protease MT1-MMP in mouse and human gliomas and found the enzyme to be expressed predominantly in microglial cells closely associated with the tumors. Whereas tumor-free human brain samples showed virtually no MT1-MMP expression, we detected intense MT1-MMP labeling, especially in higher-grade gliomas. Importantly, in human samples, immunolabeling for the microglial marker Iba1 and for MT1-MMP largely overlapped [supporting information (SI) Fig. S1 A-D and Table S1]. Likewise, after injection of a human glioma cell line (U373 cells) into immunodeficient mice, we detected that microglia represent the predominant cell type contributing intratumoral MT1-MMP expression (see Fig. S1E).In our in vivo mouse model, the glioma cells were identified by stable expression of EGFP and microglial cells by immunolabeling for Iba1. In sections obtained from mice 2 weeks after intracerebral injection with isogenic glioma cells (GL261 cells), we found an increased density of mic...

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“…S1D). As previously described, microglial cells associated with the glioma had an ameboid morphology, indicating a certain degree of activation (10,11).…”

Section: Resultssupporting

confidence: 56%

Section: Blocking the Mt1-mmp Expression By Shrna In Microglia Resultmentioning

confidence: 99%

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Marković

Vinnakota

Chirasani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

346

328

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“…To determine whether macrophages were present in the tumors from our mice, we stained Ptprd +/+ p16 −/− , Ptprd +/− p16 −/− , and Ptprd −/− p16 −/− tumors with the Iba1 macrophage marker. Although the quantity of Iba1 + cells was similar for all tumors, we noted that tumors from Ptprd +/− p16 −/− tended to have amoeboid macrophage morphology, which is associated with a protumorigenic phenotype (25,31,32) (Fig. 5C); this was concentrated in the larger tumors.…”

Section: Heterozygous Loss Of Ptprd Results In P-stat3 Accumulation Andmentioning

confidence: 85%

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

Ortiz

Fabius²,

Wu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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PTPRD, which encodes the protein tyrosine phosphatase receptor-δ, is one of the most frequently inactivated genes across human cancers, including glioblastoma multiforme (GBM). PTPRD undergoes both deletion and mutation in cancers, with copy number loss comprising the primary mode of inactivation in GBM. However, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo, and the mechanistic basis of PTPRD function in tumors is unclear. Here, using genomic analysis and a glioma mouse model, we demonstrate that loss of Ptprd accelerates tumor formation and define the oncogenic context in which Ptprd loss acts. Specifically, we show that in human GBMs, heterozygous loss of PTPRD is the predominant type of lesion and that loss of PTPRD and the CDKN2A/p16 INK4A tumor suppressor frequently co-occur. Accordingly, heterozygous loss of Ptprd cooperates with p16 deletion to drive gliomagenesis in mice. Moreover, loss of the Ptprd phosphatase resulted in phospho-Stat3 accumulation and constitutive activation of Stat3-driven genetic programs. Surprisingly, the consequences of Ptprd loss are maximal in the heterozygous state, demonstrating a tight dependence on gene dosage. Ptprd loss did not increase cell proliferation but rather altered pathways governing the macrophage response. In total, we reveal that PTPRD is a bona fide tumor suppressor, pinpoint PTPRD loss as a cause of aberrant STAT3 activation in gliomas, and establish PTPRD loss, in the setting of CDKN2A/p16 INK4A deletion, as a driver of glioma progression.G lioblastoma multiforme (GBM) is a devastating disease. It is the most common and aggressive type of glioma and outcomes remain poor despite current treatments (1). To increase our understanding of the genetic basis of this malignancy, several mutational survey studies examining GBM have been completed and provide a detailed view of the molecular changes underlying this cancer (2-4). Because GBM is a highly heterogeneous tumor, a challenge remains to determine which molecular alterations drive tumorigenesis and to understand the underlying mechanisms of action. Recent work by our group and others have identified inactivation of protein tyrosine phosphatase receptor-δ (PTPRD) as a frequent alteration in GBM and other tumors, and showed that PTPRD copy number loss correlates with poor prognosis (5-10). Despite the high prevalence of PTPRD inactivation in human tumors, it is not known whether loss of PTPRD can promote tumorigenesis. Furthermore, the mechanisms of action and the oncogenic context in which PTPRD acts remain obscure.PTPRD belongs to a family of protein-tyrosine phosphatases that collectively have been implicated in functions, including the regulation of receptor tyrosine kinases, growth, cell migration, and angiogenesis (11). Previously, we demonstrated that phosphorylated STAT3 (p-STAT3) is a substrate of PTPRD and that cancer-specific mutations in PTPRD abrogate the ability of the phosphatase to dephosphorylate STAT3 (5). Interestingly, accumulation of phosphorylated STAT3 and STAT3 hyper...

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“…Treatment with CS, a specific T lymphocyte inhibitor, was safely tolerated and did not affect survival in this model despite its induction of an accelerated cachexia. Cyclosporine is an immunosuppressant that has been shown to possess intrinsic antitumor activity 11 and to inhibit p-glycoprotein, a multidrug resistance protein that is a candidate target for brain tumor chemosensitivity modulation 12 . We may conclude that further pre-clinical and clinical testing with CS in brain tumors is warranted.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporin safety in a simplified rat brain tumor implantation model

Félix

Fontenele

Teles

et al. 2012

Arq. Neuro-Psiquiatr.

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There is a continuing need for experimental neuro-oncology for animal models that can be used to assess the efficacy of innovative approaches for the treatment of brain tumors. The rat has been one of the most widely used of all experimental animals, and rat brain tumor models have been used extensively ABStrActBrain cancer is the second neurological cause of death. A simplified animal brain tumor model using W256 (carcinoma 256, Walker) cell line was developed to permit the testing of novel treatment modalities. Wistar rats had a cell tumor solution inoculated stereotactically in the basal ganglia (right subfrontal caudate). This model yielded tumor growth in 95% of the animals, and showed absence of extracranial metastasis and systemic infection. Survival median was 10 days. Estimated tumor volume was 17.08±6.7 mm 3 on the 7 th day and 67.25±19.8 mm 3 on 9 th day post-inoculation. Doubling time was 24.25 h. Tumor growth induced cachexia, but no hematological or biochemical alterations. This model behaved as an undifferentiated tumor and can be promising for studying tumor cell migration in the central nervous system. Dexamethasone 3.0 mg/kg/day diminished significantly survival in this model. Cyclosporine 10 mg/kg/day administration was safely tolerated.Key words: brain neoplasms, neoplasms, experimental, carcinoma 256, Walker, cachexia, cell movement, immunosuppressive agents.reSUMO Neoplasias encefálicas constituem a segunda causa neurológica de morte. Foi desenvolvido um modelo animal simplificado de tumor cerebral em ratos utilizando a linhagem celular W256 (carcinoma 256 de Walker) para permitir teste de novos tratamentos. Ratos Wistar foram inoculados nos gânglios da base (caudato subfrontal direito) com uma solução celular tumoral, por via estereotáxica. Este modelo demonstrou crescimento tumoral em 95% dos animais inoculados com sucesso, além de mostrar ausência de metástases extracranianas e infecção sistêmica. A mediana de sobrevida dos animais foi de 10 dias. O volume tumoral estimado foi de 17,08±6,7 mm 3 no sétimo dia e de 67,25±19,8 mm 3 no nono dia após a inoculação. O tempo de duplicação foi estimado em 24,25 h. O crescimento tumoral induziu a caquexia, mas não houve alterações bioquímicas ou hematológicas. Esse modelo permite fácil reprodução e comporta-se como um tumor indiferenciado, mostrando potencial para estudar migração celular tumoral no sistema nervoso central. Dexametasona 3,0 mg/kg/dia reduziu significantemente a sobrevida dos animais inoculados com tumor nesse modelo. Ciclosporina 10 mg/kg/dia não teve efeito na sobrevida, sendo sua administração bem tolerada.Palavras-Chave: neoplasias encefálicas, neoplasias experimentais, carcinoma 256 de Walker, caquexia, movimento celular, imunossupressores.since the mid 1970s. Rat tumor models have a series of advantages when compared to mouse models despite the recent and frequent use of knockout genetic mice models.It was first reported in the early 1970s that central nervous system (CNS) tumors could be reproducibly and

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The invasion promoting effect of microglia on glioblastoma cells is inhibited by cyclosporin A

Cited by 132 publications

References 47 publications

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

Cyclosporin safety in a simplified rat brain tumor implantation model

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