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Povzetek: Glioblastoma GBM: Glioblastoma multiforme (GBM) remains one of the most lethal and treatment-resistant brain cancers, driven in part by the complexity of its tumour microenvironment (TME). While organ-on-chip (OoC) platforms offer more physiologically relevant models than traditional 2D or static 3D systems, their design remains largely empirical, lacking predictive control over flow conditions, biochemical gradients, and mechanical cues. Computational Fluid Dynamics (CFD) has emerged as a powerful tool to enhance the design, precision, and biological fidelity of OoC platforms. This comprehensive review highlights current limitations in replicating GBM’s biological complexity and technical constraints in device fabrication and maintenance, mapping them to specific CFD strategies. It synthesises current strategies into a structured workflow for integrating CFD into the design, optimisation, and validation of microfluidic tumour models—bridging engineering precision with biological complexity. In addition, validation frameworks reported in the literature are highlighted and mapped onto GBM-on-chip applications have been recommended, drawing on widely recognised international standards for engineering validation and regulatory modelling practices. Finally, this review positions CFD as a core component of GBM-on-chip development and explores how its integration with AI-based optimisation can advance the creation of more predictive, scalable, and biologically relevant in vitro tumour models.
Ključne besede: AI, computational fluid dynamics, glioblastoma, In silicosimulation, in vitro modelling, microfluidic perfusion, organ-on-chip, tumour microenvironment
Objavljeno v DiRROS: 13.02.2026; Ogledov: 358; Prenosov: 123
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Povzetek: Introduction: Glioblastoma (GBM) is a highly invasive brain tumor with limited treatment options and poor prognosis. Natural killer (NK) cells are key effectors of antitumor immunity, capable of eliminating cancer stem-like cells. However, GBM creates an immunosuppressive microenvironment that limits NK cell function. Here, we identify cystatin F as an immunosuppressive factor involved in regulating NK cell granule-mediated cytotoxicity. Methods: We analyzed cystatin F expression in GBM and its correlation with immune exhaustion markers. NK cell activity was compared between GBM patients and healthy donors. In vitro co-cultures of cystatin F-expressing microglial cells and glioblastoma stem-like cells were used to assess NK cell function. To block cystatin F activation from dimeric to active monomeric form, a small-molecule inhibitor of cathepsin V, the activating protease, was applied. Results: Cystatin F expression correlated with immune exhaustion and suppression markers in GBM. NK cells from patients showed reduced cytotoxicity compared to healthy donors. Co-cultures confirmed that cystatin F-expressing microglia impaired NK cell cytotoxicity, while inhibition of cathepsin V restored NK cell function in standard cytotoxicity assays, 3D spheroids, and microfluidic perfused models. Discussion: These results indicate that cystatin F mediates NK cell suppression in GBM. Targeting its activation enhances NK cell cytotoxicity, offering a potential strategy to improve NK-based immunotherapy for glioblastoma.
Ključne besede: glioblastoma, cystatin F, 3D models
Objavljeno v DiRROS: 26.11.2025; Ogledov: 928; Prenosov: 287
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Povzetek: Glioblastoma is the most aggressive and malignant primary brain tumor in adults and has a poor patient survival of only 20 months after diagnosis. This poor patient survival is at least partly caused by glioblastoma stem cells (GSCs), which are slowly-dividing and therefore therapy-resistant. GSCs are localized in protective hypoxic peri-arteriolar niches where these aforementioned stemness properties are maintained. We previously showed that hypoxic peri-arteriolar GSC niches in human glioblastoma are functionally similar to hypoxic peri-arteriolar hematopoietic stem cell (HSC) niches in human bone marrow. GSCs and HSCs express the receptor C-X-C receptor type 4 (CXCR4), which binds to the chemoattractant stromal-derived factor-1α (SDF-1α), which is highly expressed in GSC niches in glioblastoma and HSC niches in bone marrow. This receptor–ligand interaction retains the GSCs/HSCs in their niches and thereby maintains their slowly-dividing state. In acute myeloid leukemia (AML), leukemic cells use the SDF-1α–CXCR4 interaction to migrate to HSC niches and become slowly-dividing and therapy-resistant leukemic stem cells (LSCs). In this communication, we aim to elucidate how disruption of the SDF-1α–CXCR4 interaction using the FDA-approved CXCR4 inhibitor plerixafor (AMD3100) may be used to force slowly-dividing cancer stem cells out of their niches in glioblastoma and AML. Ultimately, this strategy aims to induce GSC and LSC differentiation and their sensitization to therapy.
Ključne besede: glioblastoma, glioblastoma stem cells, niches, acute myeloid leukemia, hematopoietic stem cells, bone marrow, C-X-C receptor type 4, stromal-derived factor-1 ▫$[alpha]$▫, plerixafor
Objavljeno v DiRROS: 06.08.2024; Ogledov: 1601; Prenosov: 1445
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Povzetek: Glioblastoma is the most lethal primary brain tumor and poor survival of glioblastoma patients is attributed to the presence of glioma stem cells (GSCs). These therapy-resistant, quiescent and pluripotent cells reside in GSC niches, which are specific microenvironments that protect GSCs against radiotherapy and chemotherapy. We previously showed the existence of hypoxic peri-arteriolar GSC niches in glioblastoma tumor samples. However, other studies have described peri-vascular niches, peri-hypoxic niches, peri-immune niches and extracellular matrix niches of GSCs. The aim of this review was to critically evaluate the literature on these five different types of GSC niches. In the present review, we describe that the five niche types are not distinct from one another, but should be considered to be parts of one integral GSC niche model, the hypoxic peri-arteriolar GSC niche. Moreover, hypoxic peri-arteriolar GSC niches are structural and functional look-alikes of hematopoietic stem cell (HSC) niches in the bone marrow. GSCs are maintained in peri-arteriolar niches by the same receptor-ligand interactions as HSCs in bone marrow. Our concept should be rigidly tested in the near future and applied to develop therapies to expel and keep GSCs out of their protective niches to render them more vulnerable to standard therapies.
Ključne besede: glioblastoma, glioma stem cells, niches, blood vessels, extracellular matrix, tumor microenvironment, hypoxia, therapy resistance, vasculature
Objavljeno v DiRROS: 06.08.2024; Ogledov: 1276; Prenosov: 916
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Povzetek: Brain, the major organ of the central nervous system controls and processes most of body activities. Therefore, the most aggressive brain tumor – glioblastoma and metastases from other organs to the brain are lethal leaving the patients with very short time of survival. The brain tissue landscape is very different from any other tissues and the specific microenvironment, comprising stem cells niches and blood-brain barrier, significantly influences the low rate of glioblastoma metastasis out of the brain, but better accommodates brain-invading cancer. In contrast to low frequency (0.5%) of all glioblastoma metastases, 10%–45% of other primary cancers do metastasize to the brain. This review addresses general cellular and molecular pathways that are to some extent similar in both types of metastases, involving circulating tumor cells (CTCs) with cancer stem cells (CSCs) characteristics, and metastatic niches. The invasion is a dynamic process involving reversible epithelial-to-mesenchymal (EMT) cell process, creating a transient gradient state that is inter-connected with epigenetic plasticity of the metastasizing (m)CSCs. These cells can switch between stationary, low proliferating/dormant state to a migratory, mesenchymal-like state. Settling in their respective niches as dormant CSCs in the secondary organ is a common feature in all types of metastases. In glioblastoma metastasis, the malignant mGSC cells express markers of mesenchymal GSC subtype (MES-GSC), such as CD44 and YK-40 and their major obstacle seems to be propagating in the in various organs’ microenvironments, different from the niches that home GSCs in the primary glioblastoma. Focusing on one stromal component in the glioblastoma niches, the mesenchymal stem cells (MSCs), we report herein on their differential effects on glioblastoma cells, highly depending on their genetic subtype. On the other hand, in brain metastases, the major hindrance to metastatic progression of mCSCs seem to be crossing the blood-brain-barrier. Novel therapeutic approaches for brain metastases from various cancer types are advancing slowly, and the general trends involve targeting metastatic sub-clones and selective determinants of their niches. The update on the four most common brain metastases from lung, breast, melanoma and colorectal carcinoma is presented.
Ključne besede: glioblastoma, cancer stem cells, invasion, metastasis, tumor microenvironment
Objavljeno v DiRROS: 06.08.2024; Ogledov: 1670; Prenosov: 775
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