1. CXCR4 antagonists as stem cell mobilizers and therapy sensitizers for acute myeloid leukemia and glioblastoma?Vashendriya V. V. Hira, Cornelis J. F. van Noorden, Remco J. Molenaar, 2020, drugi znanstveni članki 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: 306; Prenosov: 398 Celotno besedilo (1,51 MB) Gradivo ima več datotek! Več... |
2. Proteases and cytokines as mediators of interactions between cancer and stromal cells in tumoursBarbara Breznik, Helena Motaln, Tamara Lah Turnšek, 2017, pregledni znanstveni članek Povzetek: Proteolytic enzymes are highly relevant in different processes of cancer progression. Their interplay with other signalling molecules such as cytokines represents important regulation of multicellular cross-talk. In this review, we discuss protease regulation mechanisms of cytokine signalling in various types of cancer. Additionally, we highlight the reverse whereby cytokines have an impact on protease expression in an autocrine and paracrine manner, representing complex feedback mechanisms among multiple members of these two protein families. The relevance of the protease-cytokine axis is illustrated in glioblastoma, where interactions between normal mesenchymal stem cells and cancer cells play an important role in this very malignant form of brain cancer. Ključne besede: cellular cross-talk, glioblastoma, invasion, mesenchymal stem cells, protease-cytokine signalling Objavljeno v DiRROS: 06.08.2024; Ogledov: 268; Prenosov: 178 Celotno besedilo (781,03 KB) Gradivo ima več datotek! Več... |
3. The hypoxic peri-arteriolar glioma stem cell niche, an integrated concept of five types of niches in human glioblastomaDiana A. Aderetti, Vashendriya V. V. Hira, Remco J. Molenaar, Cornelis J. F. van Noorden, 2018, pregledni znanstveni članek 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: 368; Prenosov: 219 Celotno besedilo (966,30 KB) Gradivo ima več datotek! Več... |
4. Cytokine CCL5 and receptor CCR5 axis in glioblastoma multiformeMiha Koprivnikar Krajnc, Metka Novak, Richard G. Pestell, Tamara Lah Turnšek, 2019, pregledni znanstveni članek Povzetek: Background
Glioblastoma is the most frequent and aggressive brain tumour in humans with median survival from 12 to 15 months after the diagnosis. This is mostly due to therapy resistant glioblastoma stem cells in addition to intertumour heterogeneity that is due to infiltration of a plethora of host cells. Besides endothelial cells, mesenchymal stem cells and their differentiated progenies, immune cells of various differentiation states, including monocytes, comprise resident, brain tumour microenvironment. There are compelling evidence for CCL5/CCR5 in the invasive and metastatic behaviour of many cancer types. CCR5, a G-protein coupled receptor, known to function as an essential co-receptor for HIV entry, is now known to participate in driving tumour heterogeneity, the formation of cancer stem cells and the promotion of cancer invasion and metastasis. Clinical trials have recently opened targeting CCR5 using a humanized monoclonal antibody (leronlimab) for metastatic triple negative breast cancer (TNBC) or a small molecule inhibitor (maraviroc) for metastatic colon cancer. There are important CCL5 and CCR5 structure and signalling mechanisms in glioblastoma. In addition, the CCL5/CCR5 axis directs infiltration and interactions with monocytes/macrophages and mesenchymal stem cells, comprising glioblastoma stem cell niches.
Conclusions
CCR5 is highly expressed in glioblastoma and is associated with poor prognosis of patients. CCL5/CCR5 is suggested to be an excellent new target for glioblastoma therapy. The molecular mechanisms, by which chemoattractant and receptor respond within the complex tissue microenvironment to promote cancer stem cells and tumour heterogeneity, should be considered in forthcoming studies. Ključne besede: cytokines, CCL5-RANTES, glioblastoma, tumour microenvironment, mesenchymal stem cells, signalling Objavljeno v DiRROS: 06.08.2024; Ogledov: 284; Prenosov: 146 Celotno besedilo (914,27 KB) Gradivo ima več datotek! Več... |
5. Brain malignancies : glioblastoma and brain metastasesTamara Lah Turnšek, Metka Novak, Barbara Breznik, 2020, pregledni znanstveni članek 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: 377; Prenosov: 250 Celotno besedilo (1,83 MB) Gradivo ima več datotek! Več... |
6. Energy metabolism in IDH1 wild-type and IDH1-mutated glioblastoma stem cells : a novel target for therapy?Cornelis J. F. van Noorden, Vashendriya V. V. Hira, Amber J. van Dijck, Metka Novak, Barbara Breznik, Remco J. Molenaar, 2021, pregledni znanstveni članek Povzetek: Cancer is a redox disease. Low levels of reactive oxygen species (ROS) are beneficial for cells and have anti-cancer effects. ROS are produced in the mitochondria during ATP production by oxidative phosphorylation (OXPHOS). In the present review, we describe ATP production in primary brain tumors, glioblastoma, in relation to ROS production. Differentiated glioblastoma cells mainly use glycolysis for ATP production (aerobic glycolysis) without ROS production, whereas glioblastoma stem cells (GSCs) in hypoxic periarteriolar niches use OXPHOS for ATP and ROS production, which is modest because of the hypoxia and quiescence of GSCs. In a significant proportion of glioblastoma, isocitrate dehydrogenase 1 (IDH1) is mutated, causing metabolic rewiring, and all cancer cells use OXPHOS for ATP and ROS production. Systemic therapeutic inhibition of glycolysis is not an option as clinical trials have shown ineffectiveness or unwanted side effects. We argue that systemic therapeutic inhibition of OXPHOS is not an option either because the anti-cancer effects of ROS production in healthy cells is inhibited as well. Therefore, we advocate to remove GSCs out of their hypoxic niches by the inhibition of their binding to niches to enable their differentiation and thus increase their sensitivity to radiotherapy and/or chemotherapy. Ključne besede: glioblastoma stem cells, IDH1-mutation, energy metabolism Objavljeno v DiRROS: 05.08.2024; Ogledov: 363; Prenosov: 275 Celotno besedilo (3,87 MB) Gradivo ima več datotek! Več... |
7. Identification of plasma biomarker candidates in glioblastoma using an antibody-array-based proteomic approachKlemen Zupančič, Marjan Koršič, Urška Verbovšek, Primož Rožman, Tamara Lah Turnšek, Andrej Blejec, Kristina Gruden, Helena Motaln, Miomir Knežević, Matija Veber, Ana Herman, 2014, izvirni znanstveni članek Povzetek: Background. Glioblastoma multiforme (GBM) is a brain tumour with a very high patient mortality rate, with a median survival of 47 weeks. This might be improved by the identification of novel diagnostic, prognostic and predictive
therapy-response biomarkers, preferentially through the monitoring of the patient blood. The aim of this study was to define the impact of GBM in terms of alterations of the plasma protein levels in these patients.
Materials and methods. We used a commercially available antibody array that includes 656 antibodies to analyse
blood plasma samples from 17 healthy volunteers in comparison with 17 blood plasma samples from patients with
GBM.
Results. We identified 11 plasma proteins that are statistically most strongly associated with the presence of GBM.
These proteins belong to three functional signalling pathways: T-cell signalling and immune responses; cell adhesion and migration; and cell-cycle control and apoptosis. Thus, we can consider this identified set of proteins as potential diagnostic biomarker candidates for GBM. In addition, a set of 16 plasma proteins were significantly associated with the overall survival of these patients with GBM. Guanine nucleotide binding protein alpha (GNAO1) was associated with both GBM presence and survival of patients with GBM.
Conclusions. Antibody array analysis represents a useful tool for the screening of plasma samples for potential cancer biomarker candidates in small-scale exploratory experiments; however, clinical validation of these candidates requires their further evaluation in a larger study on an independent cohort of patients. Ključne besede: glioblastoma, proteomics, biomarker Objavljeno v DiRROS: 02.08.2024; Ogledov: 320; Prenosov: 241 Povezava na celotno besedilo Gradivo ima več datotek! Več... |
8. Expression analysis of all protease genes reveals cathepsin K to be overexpressed in glioblastomaUrška Verbovšek, Helena Motaln, Ana Rotter, Nadia A. Atai, Kristina Gruden, Cornelis J. F. van Noorden, Tamara Lah Turnšek, 2014, izvirni znanstveni članek Povzetek: Background
Cancer genome and transcriptome analyses advanced our understanding of cancer biology. We performed transcriptome analysis of all known genes of peptidases also called proteases and their endogenous inhibitors in glioblastoma multiforme (GBM), which is one of the most aggressive and deadly types of brain cancers, where unbalanced proteolysis is associated with tumor progression.
Methods
Comparisons were performed between the transcriptomics of primary GBM tumors and unmatched non-malignant brain tissue, and between GBM cell lines (U87-MG and U373) and a control human astrocyte cell line (NHA). Publicly-available data sets and our own datasets were integrated and normalized using bioinformatics tools to reveal protease and protease inhibitor genes with deregulated expression in both malignant versus non-malignant tissues and cells.
Results
Of the 311 protease genes identified to be differentially expressed in both GBM tissues and cells, 5 genes were highly overexpressed, 2 genes coding for non-peptidase homologues transferrin receptor (TFRC) and G protein-coupled receptor 56 (GPR56), as well as 3 genes coding for the proteases endoplasmic reticulum aminopeptidase 2 (ERAP2), glutamine-fructose-6-phosphate transaminase 2 (GFPT2) and cathepsin K (CTSK), whereas one gene, that of the serine protease carboxypeptidase E (CPE) was strongly reduced in expression. Seventy five protease inhibitor genes were differentially expressed, of which 3 genes were highly overexpressed, the genes coding for stefin B (CSTB), peptidase inhibitor 3 (PI3 also named elafin) and CD74. Seven out of 8 genes (except CSTB) were validated using RT-qPCR in GBM cell lines. CTSK overexpression was validated using RT-qPCR in GBM tissues as well. Cathepsin K immunohistochemical staining and western blotting showed that only proteolytically inactive proforms of cathepsin K were overexpressed in GBM tissues and cells.
Conclusions
The presence of high levels of inactive proforms of cathepsin K in GBM tissues and cells indicate that in GBM the proteolytic/collagenolytic role is not its primary function but it plays rather a different yet unknown role. Ključne besede: glioblastoma multiforme, genes Objavljeno v DiRROS: 02.08.2024; Ogledov: 379; Prenosov: 220 Celotno besedilo (1,38 MB) Gradivo ima več datotek! Več... |
9. Heterogeneous glioblastoma cell cross-talk promotes phenotype alterations and enhanced drug resistanceAna Koren, Helena Motaln, Živa Ramšak, Kristina Gruden, Christian Schichor, Tamara Lah Turnšek, 2015, izvirni znanstveni članek Povzetek: Glioblastoma multiforme is the most lethal of brain cancer, and it comprises a heterogeneous mixture of functionally distinct cancer cells that affect tumor progression. We examined the U87, U251, and U373 malignant cell lines as in vitro models to determine the impact of cellular cross-talk on their phenotypic alterations in co-cultures. These cells were also studied at the transcriptome level, to define the mechanisms of their observed mutually affected genomic stability, proliferation, invasion and resistance to temozolomide. This is the first direct demonstration of the neural and mesenchymal molecular fingerprints of U87 and U373 cells, respectively. U87-cell conditioned medium lowered the genomic stability of U373 (U251) cells, without affecting cell proliferation. In contrast, upon exposure of U87 cells to U373 (U251) conditioned medium, U87 cells showed increased genomic stability, decreased proliferation rates and increased invasion, due to a plethora of produced cytokines identified in the co-culture media. This cross talk altered the expression 264 genes in U87 cells that are associated with proliferation, inflammation, migration, and adhesion, and 221 genes in U373 cells that are associated with apoptosis, the cell cycle, cell differentiation and migration. Indirect and direct co-culturing of U87 and U373 cells showed mutually opposite effects on temozolomide resistance. In conclusion, definition of transcriptional alterations of distinct glioblastoma cells upon co-culturing provides better understanding of the mechanisms of glioblastoma heterogeneity, which will provide the basis for more informed glioma treatment in the future. Ključne besede: glioblastoma heterogeneity, U87 cells, temozolomide resistance, cellular cross-talk, transcriptomics Objavljeno v DiRROS: 29.07.2024; Ogledov: 303; Prenosov: 239 Povezava na celotno besedilo Gradivo ima več datotek! Več... |
10. Analysis of glioblastoma patients' plasma revealed the presence of microRNAs with a prognostic impact on survival and those of viral originKlemen Zupančič, Helena Motaln, Miomir Knežević, Urška Verbovšek, Marjan Koršič, Tamara Lah Turnšek, Primož Rožman, Matjaž Jeras, Matjaž Hren, Kristina Gruden, Andrej Blejec, Matija Veber, Ana Herman, Andrej Porčnik, Vid Podpečan, 2015, izvirni znanstveni članek Povzetek: Background
Glioblastoma multiforme (GBM) is among the most aggressive cancers with a poor prognosis in spite of a plethora of established diagnostic and prognostic biomarkers and treatment modalities. Therefore, the current goal is the detection of novel biomarkers, possibly detectable in the blood of GBM patients that may enable an early diagnosis and are potential therapeutic targets, leading to more efficient interventions.
Experimental Procedures
MicroRNA profiling of 734 human and human-associated viral miRNAs was performed on blood plasma samples from 16 healthy individuals and 16 patients with GBM, using the nCounter miRNA Expression Assay Kits.
Results
We identified 19 miRNAs with significantly different plasma levels in GBM patients, compared to the healthy individuals group with the difference limited by a factor of 2. Additionally, 11 viral miRNAs were found differentially expressed in plasma of GBM patients and 24 miRNA levels significantly correlated with the patients’ survival. Moreover, the overlap between the group of candidate miRNAs for diagnostic biomarkers and the group of miRNAs associated with survival, consisted of ten miRNAs, showing both diagnostic and prognostic potential. Among them, hsa miR 592 and hsa miR 514a 3p have not been previously described in GBM and represent novel candidates for selective biomarkers. The possible signalling, induced by the revealed miRNAs is discussed, including those of viral origin, and in particular those related to the impaired immune response in the progression of GBM.
Conclusion
The GBM burden is reflected in the alteration of the plasma miRNAs pattern, including viral miRNAs, representing the potential for future clinical application. Therefore proposed biomarker candidate miRNAs should be validated in a larger study of an independent cohort of patients Ključne besede: microRNAs, glioblastoma multiforme, biomarkers, RNA extraction, viral disease diagnosis Objavljeno v DiRROS: 26.07.2024; Ogledov: 358; Prenosov: 161 Povezava na celotno besedilo Gradivo ima več datotek! Več... |