1. Gut microbiome in cancer : the next big opportunity for better patient outcomes?Jure Povšin, Timotej Sotošek, Metka Novak, Barbara Breznik, 2025, review article Abstract: The gut microbiome, a diverse community of microorganisms in the human body, plays an important role in maintaining health and influences various processes such as digestion, immunity, and protection against pathogens. A person's unique gut microbiome, shaped by factors such as birth method, diet, antibiotics, and lifestyle, contributes to bodily functions such as nutrient metabolism, drug processing, and im-mune regulation. Changes in the gut microbiome are associated with a predisposition to cancer and can influence the effectiveness of cancer treatments. Dysbiosis in the gut microbiome can lead to inflammation, tumor development, and metastasis, highlight-ing its importance in cancer research and prevention. The gut microbiota significantly influences cancer development and treatment outcomes. Certain bacteria enhance the effects of therapies such as cyclophosphamide and contribute to the body's im-mune response against tumors. Microbes produce anti-cancer molecules and probiotic compounds, making them potential tools in cancer prevention and treatment. Future research aims to develop targeted antibiotics and explore fecal microbiota transfer to selectively manipulate the microbiota for improved cancer treatment. Due to genetic and physiological similarities, mouse models are invaluable in biomedical research. However, because the gut microbiome of humans and mice and the composition of the tumor microenvironment differ, direct comparison between these two models can be challenging in research. Bridging these gaps is crucial for comparative medicine, especially in cancer research where the microbiome plays an important role in treat-ment outcomes. One important area where the gut microbiome could offer potential new treatment options is in primary brain tumors such as gliomas. To date, there are no long-lasting effective treatments for this type of cancer, but research in mouse models shows a link between tumor progression and response to treatment with changes in the gut microbiome. Overall, the gut microbiome and its modulation represent an opportu-nity for more efficient future cancer treatment.
Keywords: gut microbiome, cancer, treatment outcome, tumor models, glioma
Published in DiRROS: 03.04.2025; Views: 210; Downloads: 102
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3. The Slovenian translational platform GlioBank for brain tumour research : identification of molecular signatures of glioblastoma progressionMetka Novak, Bernarda Majc, Marta Malavolta, Andrej Porčnik, Jernej Mlakar, Matjaž Hren, Anamarija Habič, Mateja Mlinar, Ivana Jovchevska, Neja Šamec, Alja Zottel, Marija Skoblar Vidmar, Tina Vipotnik-Vesnaver, Andrej Zupan, Alenka Matjašič, Saša Trkov, Dejan Georgiev, Aleksander Sadikov, Roman Bošnjak, Borut Prestor, Radovan Komel, Tamara Lah Turnšek, Barbara Breznik, 2025, original scientific article Keywords: biobank, biomarker, glioblastoma, tumour models, oncology
Published in DiRROS: 28.01.2025; Views: 210; Downloads: 107
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4. Patient-derived tumor organoids mimic treatment-induced DNA damage response in glioblastomaBernarda Majc, Anamarija Habič, Marta Malavolta, Miloš Vittori, Andrej Porčnik, Roman Bošnjak, Jernej Mlakar, Alenka Matjašič, Andrej Zupan, Marija Skoblar Vidmar, Tamara Lah Turnšek, Aleksander Sadikov, Barbara Breznik, Metka Novak, 2024, original scientific article Abstract: Glioblastoma (GB) is the most common primary malignant brain tumor, characterized by resistance to therapy. Despite aggressive treatment options, GB remains an incurable disease. Invasiveness and heterogeneity are key GB features that cannot be studied in preclinical in vitro models. In this study, we investigated the effects of standard therapy using patient-derived GB organoids (GBOs). GBOs reflect the complexity and heterogeneity of the original tumor tissue. No significant effect on GBO viability or invasion was observed after irradiation and temozolomide treatment. E3 ubiquitin-protein ligase (MDM2), cyclin-dependent kinase inhibitor 1A (CDKN1A), and the serine/threonine kinases ATM and ATR were upregulated at the gene and protein levels after treatment. Our results show that the p53 pathway and DNA-damage response mechanisms were triggered, suggesting that GBOs recapitulate GB therapy resistance. GBOs thus provide a highly efficient platform to assess the specific responses of GB patients to therapy and to further explore therapy resistance.
Keywords: cellular physiology, cellular toxicology, in vitro toxicology including 3D culture, technical aspects of cell biology, cancer
Published in DiRROS: 09.09.2024; Views: 579; Downloads: 234
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6. Editorial : brain cancer pathogenesis and data integrationAndrea Comba, Xinzhong Li, Barbara Breznik, 2023, other scientific articles Abstract: Brain tumors are one of the most aggressive malignancies in humans. They can be classified as primary tumors, which arise in the brain, or secondary tumors, which arise elsewhere in the body and initially metastaze the brain. The morbidity and mortality of brain tumors is one of the highest among cancers (Siegel et al., 2023). Of particular concern is that mortality and incidence of brain tumors are increasing, especially in the population under 44 years of age. Brain tumor mortality in this population is 13.4%. For example, primary brain tumors are the most common cancer in children and the leading cause of death in pediatric cancer patients (Gould, 2018). Considering the low survival rate of adult and pediatric brain tumor patients and the detrimental impact on patient quality of life, economic costs, and mortality rates, there is an urgent need to develop more effective therapeutic approaches. Despite major research efforts, there are currently no effective treatment modalities or prevention strategies that would significantly improve the quality of life and disease outcome of brain tumor patients.
Keywords: brain tumor, data integration, therapeutic resistance, biomarkers, liquid biopsies
Published in DiRROS: 06.08.2024; Views: 476; Downloads: 243
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7. Proteases and cytokines as mediators of interactions between cancer and stromal cells in tumoursBarbara Breznik, Helena Motaln, Tamara Lah Turnšek, 2017, review article Abstract: 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.
Keywords: cellular cross-talk, glioblastoma, invasion, mesenchymal stem cells, protease-cytokine signalling
Published in DiRROS: 06.08.2024; Views: 480; Downloads: 278
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8. Epithelial-to-mesenchymal transition as the driver of changing carcinoma and glioblastoma microenvironmentBernarda Majc, Tilen Sever, Miki Zarić, Barbara Breznik, Boris Turk, Tamara Lah Turnšek, 2020, review article Abstract: Epithelial-to-mesenchymal transition (EMT) is an essential molecular and cellular process that is part of normal embryogenesis and wound healing, and also has a ubiquitous role in various types of carcinoma and glioblastoma. EMT is activated and regulated by specific microenvironmental endogenous triggers and a complex network of signalling pathways. These mostly include epigenetic events that affect protein translation-controlling factors and proteases, altogether orchestrated by the switching on and off of oncogenes and tumour-suppressor genes in cancer cells. The hallmark of cancer-linked EMT is that the process is incomplete, as it is opposed by the reverse process of mesenchymal-to-epithelial transition, which results in a hybrid epithelial/mesenchymal phenotype that shows notable cell plasticity. This is a characteristic of cancer stem cells (CSCs), and it is of the utmost importance in their niche microenvironment, where it governs CSC migratory and invasive properties, thereby creating metastatic CSCs. These cells have high resistance to therapeutic treatments, in particular in glioblastoma.
Keywords: carcinomas, cancer stem cellsInvasion, proteases, tumour microenvironment
Published in DiRROS: 06.08.2024; Views: 569; Downloads: 508
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9. Brain malignancies : glioblastoma and brain metastasesTamara Lah Turnšek, Metka Novak, Barbara Breznik, 2020, review article Abstract: 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.
Keywords: glioblastoma, cancer stem cells, invasion, metastasis, tumor microenvironment
Published in DiRROS: 06.08.2024; Views: 619; Downloads: 343
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10. 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, review article Abstract: 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.
Keywords: glioblastoma stem cells, IDH1-mutation, energy metabolism
Published in DiRROS: 05.08.2024; Views: 625; Downloads: 423
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