Radioresistance and Transcriptional Reprograming of Invasive Glioblastoma Cells

Tang, Zheng; Đokić, Ivana; Knoll, Maximilian; Ciamarone, Federica; Schwager, Christian; Klein, Carmen; Cebulla, G; Hoffmann, Dirk C.; Schlegel, J.; Seidel, Philipp; Rutenberg, Christiane; Brons, Stephan; Herold‐Mende, Christel; Wick, Wolfgang; Debus, Jürgen; Lemke, Dieter; Abdollahi, Amir

doi:10.1016/j.ijrobp.2021.09.017

Cited by 16 publications

(12 citation statements)

References 34 publications

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“…This could play a role in the context of radiation studies, as it has been shown that cells with greater migratory and invasive potential also show higher radioresistance. [60] Figure 4C shows the much larger cytoskeletal areas in 2D as compared to 3D which is expected with GBM cells in 2D presenting a spreadout morphology, when compared to the cells in 3D which show a more rounded morphology. [54] The immunofluorescence imaging of the co-culture samples was carried out using Hoechst (blue) for the nuclei, Phalloidin-TRITC conjugate (orange) for the cytoskeleton, and von-Willebrand factor-FITC conjugate (vWF, green), which is routinely employed for identifying blood vessels in tissue sections.…”

Section: Sem and 3d Immunofluorescence Characterization Of The U251 A...mentioning

confidence: 62%

Micro‐Vessels‐Like 3D Scaffolds for Studying the Proton Radiobiology of Glioblastoma‐Endothelial Cells Co‐Culture Models

Akolawala,

Keuning,

Rovituso

et al. 2023

Adv Healthcare Materials

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Glioblastoma (GBM) is a devastating cancer of the brain with an extremely poor prognosis. While X‐ray radiotherapy and chemotherapy remain the current standard, proton beam therapy is an appealing alternative as protons can damage cancer cells while sparing the surrounding healthy tissue. However, the effects of protons on in vitro GBM models at the cellular level, especially when co‐cultured with endothelial cells, the building blocks of brain micro‐vessels, are still unexplored. In this work, novel 3D‐engineered scaffolds inspired by the geometry of brain microvasculature are designed, where GBM cells cluster and proliferate. The architectures are fabricated by two‐photon polymerization (2PP), pre‐cultured with endothelial cells (HUVECs), and then cultured with a human GBM cell line (U251). The micro‐vessel structures enable GBM in vivo‐like morphologies, and the results show a higher DNA double‐strand breakage in GBM monoculture samples when compared to the U251/HUVECs co‐culture, with cells in 2D featuring a larger number of DNA damage foci when compared to cells in 3D. The discrepancy in terms of proton radiation response indicates a difference in the radioresistance of the GBM cells mediated by the presence of HUVECs and the possible induction of stemness features that contribute to radioresistance and improved DNA repair.

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Section: Sem and 3d Immunofluorescence Characterization Of The U251 A...mentioning

confidence: 62%

Micro‐Vessels‐Like 3D Scaffolds for Studying the Proton Radiobiology of Glioblastoma‐Endothelial Cells Co‐Culture Models

Akolawala,

Keuning,

Rovituso

et al. 2023

Adv Healthcare Materials

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“…Of note, PEF-5 treatment alone was significantly more effective in decreasing cell migration and invasion than radiation exposure in both U87 ML and NS cells independently of the delivered dose. A possible explanation of this radio resistance observed for cell invasion may come from transcriptomic analysis where the activation of hypoxia and NF-kB pathways, validated by the COX2 , CCL20 and iNOS downstream genes, may induce a radio-resistance mechanism after PEF-5 exposure [ 88 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Ultra-Short Pulsed Electric Field Exposure on Glioblastoma Cells

Casciati

Tanori

Gianlorenzi

et al. 2022

IJMS

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Glioblastoma multiforme (GBM) is the most common brain cancer in adults. GBM starts from a small fraction of poorly differentiated and aggressive cancer stem cells (CSCs) responsible for aberrant proliferation and invasion. Due to extreme tumor heterogeneity, actual therapies provide poor positive outcomes, and cancers usually recur. Therefore, alternative approaches, possibly targeting CSCs, are necessary against GBM. Among emerging therapies, high intensity ultra-short pulsed electric fields (PEFs) are considered extremely promising and our previous results demonstrated the ability of a specific electric pulse protocol to selectively affect medulloblastoma CSCs preserving normal cells. Here, we tested the same exposure protocol to investigate the response of U87 GBM cells and U87-derived neurospheres. By analyzing different in vitro biological endpoints and taking advantage of transcriptomic and bioinformatics analyses, we found that, independent of CSC content, PEF exposure affected cell proliferation and differentially regulated hypoxia, inflammation and P53/cell cycle checkpoints. PEF exposure also significantly reduced the ability to form new neurospheres and inhibited the invasion potential. Importantly, exclusively in U87 neurospheres, PEF exposure changed the expression of stem-ness/differentiation genes. Our results confirm this physical stimulus as a promising treatment to destabilize GBM, opening up the possibility of developing effective PEF-mediated therapies.

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“…Moreover, its upregulation by photon irradiation was also linked to induced migration and acquisition of stemness, leading to radioresistance and failure of therapy [ 16 , 18 , 36 ]. In gliomas, photon irradiation is reported to significantly enhance migration, invasion [ 37 ], and stemness [ 38 ], while CII was found to reduce the migration [ 28 ], invasion [ 17 ] and stemness [ 27 ]. Our results are in line with these observations and implicate a role for Notch signaling in the differential response between photon irradiation and CII.…”

Section: Discussionmentioning

confidence: 99%

“…Conventional radiotherapy, which is the major therapeutic strategy for treating glioblastoma, often upregulates Notch signaling, especially in glioma stem cells [ 16 ]. Furthermore, it was recently shown that the Notch signaling pathway is enriched in the invasive tumor cells that constitute a phenotypically distinct and highly radio-resistant GBM subpopulation with poor prognosis [ 17 ]. All of these form the major contributing factors in radioresistance that limit the efficacy of conventional radiotherapy.…”

Section: Introductionmentioning

confidence: 99%

Carbon Ion Irradiation Downregulates Notch Signaling in Glioma Cell Lines, Impacting Cell Migration and Spheroid Formation

Kumar

Vashishta

Kong

et al. 2022

Cells

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Photon-based radiotherapy upregulates Notch signaling in cancer, leading to the acquisition of the stem cell phenotype and induction of invasion/migration, which contributes to the development of resistance to therapy. However, the effect of carbon ion radiotherapy (CIRT) on Notch signaling in glioma and its impact on stemness and migration is not explored yet. Human glioma cell lines (LN229 and U251), stable Notch1 intracellular domain (N1ICD) overexpressing phenotype of LN229 cells, and Notch inhibitor resistant LN229 cells (LN229R) were irradiated with either photon (X-rays) or (carbon ion irradiation) CII, and expressions of Notch signaling components were accessed by RT-PCR, Western blotting, and enzymatic assays and flow cytometry. Spheroid forming ability, cell migration, and clonogenic assay were used to evaluate the effect of modulated Notch signaling by irradiation. Our results show that X-ray irradiation induced the expression of Notch signaling components such as Notch receptors, target genes, and ADAM17 activity, while CII reduced it in glioma cell lines. The differential modulation of ADAM17 activity by CII and X-rays affected the cell surface levels of NOTCH1 and NOTCH2 receptors, as they were reduced by X-ray irradiation but increased in response to CII. Functionally, CII reduced the spheroid formation and migration of glioma cells, possibly by downregulating the N1ICD, as stable overexpression of N1ICD rescued these inhibitory effects of CII. Moreover, LN229R that are less reliant on Notch signaling for their survival showed less response to CII. Therefore, downregulation of Notch signaling resulting in the suppression of stemness and impaired cell migration by CII seen here may reduce tumor regrowth and disease dissemination, in addition to the well-established cytotoxic effects.

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Radioresistance and Transcriptional Reprograming of Invasive Glioblastoma Cells

Cited by 16 publications

References 34 publications

Micro‐Vessels‐Like 3D Scaffolds for Studying the Proton Radiobiology of Glioblastoma‐Endothelial Cells Co‐Culture Models

Micro‐Vessels‐Like 3D Scaffolds for Studying the Proton Radiobiology of Glioblastoma‐Endothelial Cells Co‐Culture Models

Effects of Ultra-Short Pulsed Electric Field Exposure on Glioblastoma Cells

Carbon Ion Irradiation Downregulates Notch Signaling in Glioma Cell Lines, Impacting Cell Migration and Spheroid Formation

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