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  • 1
    Online Resource
    Online Resource
    Jamming Transitions in Astrocytes and Glioblastoma Are Induced by Cell Density and Tension
    MDPI AG ; 2022
    In:  Cells Vol. 12, No. 1 ( 2022-12-21), p. 29-
    Details
    In: Cells, MDPI AG, Vol. 12, No. 1 ( 2022-12-21), p. 29-
    Abstract: Collective behavior of cells emerges from coordination of cell–cell-interactions and is important to wound healing, embryonic and tumor development. Depending on cell density and cell–cell interactions, a transition from a migratory, fluid-like unjammed state to a more static and solid-like jammed state or vice versa can occur. Here, we analyze collective migration dynamics of astrocytes and glioblastoma cells using live cell imaging. Furthermore, atomic force microscopy, traction force microscopy and spheroid generation assays were used to study cell adhesion, traction and mechanics. Perturbations of traction and adhesion were induced via ROCK or myosin II inhibition. Whereas astrocytes resided within a non-migratory, jammed state, glioblastoma were migratory and unjammed. Furthermore, we demonstrated that a switch from an unjammed to a jammed state was induced upon alteration of the equilibrium between cell–cell-adhesion and tension from adhesion to tension dominated, via inhibition of ROCK or myosin II. Such behavior has implications for understanding the infiltration of the brain by glioblastoma cells and may help to identify new strategies to develop anti-migratory drugs and strategies for glioblastoma-treatment.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells12010029
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2661518-6
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  • 2
    Online Resource
    Online Resource
    Opposite Effects of Neuroprotective Cannabinoids, Palmitoylethanolamide, and 2-Arachidonoylglycerol on Function and Morphology of Microglia
    Frontiers Media SA ; 2019
    In:  Frontiers in Neuroscience Vol. 13 ( 2019-11-7)
    Details
    In: Frontiers in Neuroscience, Frontiers Media SA, Vol. 13 ( 2019-11-7)
    Type of Medium: Online Resource
    ISSN: 1662-453X
    URL: Article
    DOI: 10.3389/fnins.2019.01180
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2019
    detail.hit.zdb_id: 2411902-7
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  • 3
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    Online Resource
    Nimodipine Exerts Time-Dependent Neuroprotective Effect after Excitotoxical Damage in Organotypic Slice Cultures
    MDPI AG ; 2022
    In:  International Journal of Molecular Sciences Vol. 23, No. 6 ( 2022-03-19), p. 3331-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 6 ( 2022-03-19), p. 3331-
    Abstract: During injuries in the central nervous system, intrinsic protective processes become activated. However, cellular reactions, especially those of glia cells, are frequently unsatisfactory, and further exogenous protective mechanisms are necessary. Nimodipine, a lipophilic L-type calcium channel blocking agent is clinically used in the treatment of aneurysmal subarachnoid haemorrhage with neuroprotective effects in different models. Direct effects of nimodipine on neurons amongst others were observed in the hippocampus as well as its influence on both microglia and astrocytes. Earlier studies proposed that nimodipine protective actions occur not only via calcium channel-mediated vasodilatation but also via further time-dependent mechanisms. In this study, the effect of nimodipine application was investigated in different time frames on neuronal damage in excitotoxically lesioned organotypic hippocampal slice cultures. Nimodipine, but not nifedipine if pre-incubated for 4 h or co-applied with NMDA, was protective, indicating time dependency. Since blood vessels play no significant role in our model, intrinsic brain cell-dependent mechanisms seems to strongly be involved. We also examined the effect of nimodipine and nifedipine on microglia survival. Nimodipine seem to be a promising agent to reduce secondary damage and reduce excitotoxic damage.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms23063331
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    THC Reduces Ki67-Immunoreactive Cells Derived from Human Primary Glioblastoma in a GPR55-Dependent Manner
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 5 ( 2021-03-03), p. 1064-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 5 ( 2021-03-03), p. 1064-
    Abstract: Glioblastoma (GBM) is the most frequent malignant tumor of the central nervous system in humans with a median survival time of less than 15 months. ∆9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best-characterized components of Cannabis sativa plants with modulating effects on cannabinoid receptors 1 and 2 (CB1 and CB2) and on orphan receptors such as GPR18 or GPR55. Previous studies have demonstrated anti-tumorigenic effects of THC and CBD in several tumor entities including GBM, mostly mediated via CB1 or CB2. In this study, we investigated the non-CB1/CB2 effects of THC on the cell cycle of GBM cells isolated from human tumor samples. Cell cycle entry was measured after 24 h upon exposure by immunocytochemical analysis of Ki67 as proliferation marker. The Ki67-reducing effect of THC was abolished in the presence of CBD, whereas CBD alone did not cause any changes. To identify the responsible receptor for THC effects, we first characterized the cells regarding their expression of different cannabinoid receptors: CB1, CB2, GPR18, and GPR55. Secondly, the receptors were pharmacologically blocked by application of their selective antagonists AM281, AM630, O-1918, and CID16020046 (CID), respectively. All examined cells expressed the receptors, but only in presence of the GPR55 antagonist CID was the THC effect diminished. Stimulation with the GPR55 agonist lysophosphatidylinositol (LPI) revealed similar effects as obtained for THC. The LPI effects were also inhibited by CBD and CID, confirming a participation of GPR55 and suggesting its involvement in modifying the cell cycle of patient-derived GBM cells.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13051064
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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  • 5
    Online Resource
    Online Resource
    Radiosensitization and a Less Aggressive Phenotype of Human Malignant Glioma Cells Expressing Isocitrate Dehydrogenase 1 (IDH1) Mutant Protein: Dissecting the Mechanisms
    MDPI AG ; 2019
    In:  Cancers Vol. 11, No. 6 ( 2019-06-25), p. 889-
    Details
    In: Cancers, MDPI AG, Vol. 11, No. 6 ( 2019-06-25), p. 889-
    Abstract: The presence of an isocitrate dehydrogenase 1 (IDH1) mutation is associated with a less aggressive phenotype, increased sensitivity to radiation, and increased overall survival in patients with diffuse glioma. Based on in vitro experimentations in malignant glioma cell lines, the consequences on cellular processes of IDH1R132H expression were analyzed. The results revealed that IDH1R132H expression enhanced the radiation induced accumulation of residual γH2AX foci and decreased the amount of glutathione (GSH) independent of the oxygen status. In addition, expression of the mutant IDH1 caused a significant increase of cell stiffness and induced an altered organization of the cytoskeleton, which has been shown to reinforce cell stiffness. Furthermore, IDH1R132H expression decreased the expression of vimentin, an important component of the cytoskeleton and regulator of the cell stiffness. The results emphasize the important role of mutant IDH1 in treatment of patients with diffuse gliomas especially in response to radiation. Hence, detection of the genetic status of IDH1 before therapy massively expands the utility of immunohistochemistry to accurately distinguish patients with a less aggressive and radiosensitive IDH1-mutant diffuse glioma suitable for radiotherapy from those with a more aggressive IDH1-wildtype diffuse glioma who might benefit from an individually intensified therapy comprising radiotherapy and alternative medical treatments.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers11060889
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2527080-1
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  • 6
    Online Resource
    Online Resource
    MACC1 driven alterations in cellular biomechanics facilitate cell motility in glioblastoma
    Springer Science and Business Media LLC ; 2020
    In:  Cell Communication and Signaling Vol. 18, No. 1 ( 2020-12)
    Details
    In: Cell Communication and Signaling, Springer Science and Business Media LLC, Vol. 18, No. 1 ( 2020-12)
    Abstract: Metastasis-associated in colon cancer 1 ( MACC1 ) is an established marker for metastasis and tumor cell migration in a multitude of tumor entities, including glioblastoma (GBM). Nevertheless, the mechanism underlying the increased migratory capacity in GBM is not comprehensively explored. Methods We performed live cell and atomic force microscopy measurements to assess cell migration and mechanical properties of MACC1 overexpressing GBM cells. We quantified MACC1 dependent dynamics of 3D aggregate formation. For mechanistic studies we measured the expression of key adhesion molecules using qRT-PCR, and MACC1 dependent changes in short term adhesion to fibronectin and laminin. We then determined changes in sub-cellular distribution of integrins and actin in dependence of MACC1 , but also in microtubule and intermediate filament organization. Results MACC1 increased the migratory speed and elastic modulus of GBM cells, but decreased cell-cell adhesion and inhibited the formation of 3D aggregates. These effects were not associated with altered mRNA expression of several key adhesion molecules or altered short-term affinity to laminin and fibronectin. MACC1 did neither change the organization of the microtubule nor intermediate filament cytoskeleton, but resulted in increased amounts of protrusive actin on laminin. Conclusion MACC1 overexpression increases elastic modulus and migration and reduces adhesion of GBM cells thereby impeding 3D aggregate formation. The underlying molecular mechanism is independent on the organization of microtubules, intermediate filaments and several key adhesion molecules, but depends on adhesion to laminin. Thus, targeting re-organization of the cytoskeleton and cell motility via MACC1 may offer a treatment option to impede GBM spreading.
    Type of Medium: Online Resource
    ISSN: 1478-811X
    URL: Article
    URL: Article
    DOI: 10.1186/s12964-020-00566-1
    DOI: 10.21203/rs.3.rs-100903/v1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2126315-2
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    MACC1-induced migration in tumors: Current state and perspective
    Frontiers Media SA ; 2023
    In:  Frontiers in Oncology Vol. 13 ( 2023-3-27)
    Details
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 13 ( 2023-3-27)
    Abstract: Malignant tumors are still a global, heavy health burden. Many tumor types cannot be treated curatively, underlining the need for new treatment targets. In recent years, metastasis associated in colon cancer 1 (MACC1) was identified as a promising biomarker and drug target, as it is promoting tumor migration, initiation, proliferation, and others in a multitude of solid cancers. Here, we will summarize the current knowledge about MACC1-induced tumor cell migration with a special focus on the cytoskeletal and adhesive systems. In addition, a brief overview of several in vitro models used for the analysis of cell migration is given. In this context, we will point to issues with the currently most prevalent models used to study MACC1-dependent migration. Lastly, open questions about MACC1-dependent effects on tumor cell migration will be addressed.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    URL: Article
    DOI: 10.3389/fonc.2023.1165676
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2649216-7
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  • 8
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    Online Resource
    MACC1-Induced Collective Migration Is Promoted by Proliferation Rather Than Single Cell Biomechanics
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 12 ( 2022-06-09), p. 2857-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 12 ( 2022-06-09), p. 2857-
    Abstract: Metastasis-associated in colon cancer 1 (MACC1) is a marker for metastasis, tumor cell migration, and increased proliferation in colorectal cancer (CRC). Tumors with high MACC1 expression show a worse prognosis and higher invasion into neighboring structures. Yet, many facets of the pro-migratory effects are not fully understood. Atomic force microscopy and single cell live imaging were used to quantify biomechanical and migratory properties in low- and high-MACC1-expressing CRC cells. Furthermore, collective migration and expansion of small, cohesive cell colonies were analyzed using live cell imaging and particle image velocimetry. Lastly, the impact of proliferation on collective migration was determined by inhibition of proliferation using mitomycin. MACC1 did not affect elasticity, cortex tension, and single cell migration of CRC cells but promoted collective migration and colony expansion in vitro. Measurements of the local velocities in the dense cell layers revealed proliferation events as regions of high local speeds. Inhibition of proliferation via mitomycin abrogated the MACC1-associated effects on the collective migration speeds. A simple simulation revealed that the expansion of cell clusters without proliferation appeared to be determined mostly by single cell properties. MACC1 overexpression does not influence single cell biomechanics and migration but only collective migration in a proliferation-dependent manner. Thus, targeting proliferation in high-MACC1-expressing tumors may offer additional effects on cell migration.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14122857
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 9
    Online Resource
    Online Resource
    Interaction of Glia Cells with Glioblastoma and Melanoma Cells under the Influence of Phytocannabinoids
    MDPI AG ; 2022
    In:  Cells Vol. 11, No. 1 ( 2022-01-03), p. 147-
    Details
    In: Cells, MDPI AG, Vol. 11, No. 1 ( 2022-01-03), p. 147-
    Abstract: Brain tumor heterogeneity and progression are subject to complex interactions between tumor cells and their microenvironment. Glioblastoma and brain metastasis can contain 30–40% of tumor-associated macrophages, microglia, and astrocytes, affecting migration, proliferation, and apoptosis. Here, we analyzed interactions between glial cells and LN229 glioblastoma or A375 melanoma cells in the context of motility and cell–cell interactions in a 3D model. Furthermore, the effects of phytocannabinoids, cannabidiol (CBD), tetrahydrocannabidiol (THC), or their co-application were analyzed. Co-culture of tumor cells with glial cells had little effect on 3D spheroid formation, while treatment with cannabinoids led to significantly larger spheroids. The addition of astrocytes blocked cannabinoid-induced effects. None of the interventions affected cell death. Furthermore, glial cell-conditioned media led to a significant slowdown in collective, but not single-cell migration speed. Taken together, glial cells in glioblastoma and brain metastasis micromilieu impact the tumor spheroid formation, cell spreading, and motility. Since the size of spheroid remained unaffected in glial cell tumor co-cultures, phytocannabinoids increased the size of spheroids without any effects on migration. This aspect might be of relevance since phytocannabinoids are frequently used in tumor therapy for side effects.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells11010147
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2661518-6
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  • 10
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    Data_Sheet_2.docx
    Frontiers Media SA ; 2022
    In:  Frontiers in Aging Neuroscience Vol. 14 ( 2022-4-29)
    Details
    In: Frontiers in Aging Neuroscience, Frontiers Media SA, Vol. 14 ( 2022-4-29)
    Abstract: Acute lesions of the central nervous system often lead to permanent limiting deficits. In addition to the initial primary damage, accompanying neuroinflammation is responsible for progression of damage. Mycophenolate mofetil (MMF) as a selective inhibitor of inosine 5-monophosphate dehydrogenase (IMPDH) was shown to modulate the inflammatory response and promote neuronal survival when applied in specific time windows after neuronal injury. The application of brain cytoprotective therapeutics early after neuronal damage is a fundamental requirement for a successful immunomodulation approach. This study was designed to evaluate whether MMF can still mediate brain cytoprotection when applied in predefined short time intervals following CNS injury. Furthermore, the role of microglia and changes in IMPDH2 protein expression were assessed. Organotypic hippocampal slice cultures (OHSC) were used as an in vitro model and excitotoxically lesioned with N -methyl-aspartate (NMDA). Clodronate (Clo) was used to deplete microglia and analyze MMF mediated microglia independent effects. The temporal expression of IMPDH2 was studied in primary glial cell cultures treated with lipopolysaccharide (LPS). In excitotoxically lesioned OHSC a significant brain cytoprotective effect was observed between 8 and 36 h but not within 8 and 24 h after the NMDA damage. MMF mediated effects were mainly microglia dependent at 24, 36, 48 h after injury. However, further targets like astrocytes seem to be involved in protective effects 72 h post-injury. IMPDH2 expression was detected in primary microglia and astrocyte cell cultures. Our data indicate that MMF treatment in OHSC should still be started no later than 8–12 h after injury and should continue at least until 36 h post-injury. Microglia seem to be an essential mediator of the observed brain cytoprotective effects. However, a microglia-independent effect was also found, indicating involvement of astrocytes.
    Type of Medium: Online Resource
    ISSN: 1663-4365
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fnagi.2022.863598
    DOI: 10.3389/fnagi.2022.863598.s001
    DOI: 10.3389/fnagi.2022.863598.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2558898-9
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