1. Complementary detection strategies for circulating tumor cells in breast cancer: clinical implications of combining immunofluorescence and cytopathological stainingTanja Jesenko, Cvetka Grašič-Kuhar, Živa Pišljar, Simona Miceska, Veronika Kloboves-Prevodnik, Maja Čemažar, 2025, izvirni znanstveni članek Povzetek: Background: Circulating Tumor Cells (CTCs) serve as important biomarkers for disease monitoring and treatment response in patients with metastatic breast cancer. Their detection remains challenging because of their low abundance, phenotypic diversity and non-standardized mode of detection. Cytopathological Giemsa and Immunofluorescence (IF) staining can offer complementary approaches for CTC characterization. Giemsa staining enables assessment of cellular morphology, while IF allows for marker-specific identification, together providing a more comprehensive and accurate evaluation of CTCs. Methods: We developed an IF staining protocol with antibodies against Cytokeratin (CK), vimentin (VIM), and Cluster of Differentiation 45 (CD45) to distinguish epithelial, mesenchymal, hybrid and hematopoietic cells for CTC detection and characterization and compared it with cytopathologic method of detection via Giemsa staining with regard to CTC detection rates and morphological detail. Results: Study was performed on the samples of 29 heavily pretreated patients with metastatic breast cancer (median duration of metastatic disease 19.4 months). Giemsa staining enabled the detection of a higher number of CTCs compared to our IF protocol. Lower detection rate was potentially due to the loss of fragile or loosely adherent cells during methanol fixation and IF staining. Additionally, in IF-stained samples, some CTCs presented faint nuclear signals, potentially impairing their recognition. The IF staining supported the identity of CTCs detected on Giemsa-stained slides by employing a three-color antibody panel-based approach and allowed detailed phenotypic discrimination and structural analysis of CTCs, including the identification of a distinctive CK polarization pattern suggestive of a transitional state during intravasation. Conclusion: Giemsa and IF may thus be complementary rather than mutually exclusive and relying on a single detection approach could underestimate the true CTC burden. An integrative strategy combining both techniques may offer a more comprehensive view of CTC populations in metastatic breast cancer, thereby enhancing diagnostic precision.
Ključne besede: biomarkers, breast cancer, circulating tumor cells, cytopathological detection
Objavljeno v DiRROS: 05.12.2025; Ogledov: 50; Prenosov: 15
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2. PET/CT and MR improve interobserver agreement in primary tumor determination for radiotherapy in esophageal squamous cell cancerAjra Šečerov Ermenc, Primož Peterlin, Vaneja Velenik, Ana Jeromen, Jasna But-Hadžić, Franc Anderluh, Barbara Šegedin, 2025, izvirni znanstveni članek Povzetek: The aim of the study was to evaluate interobserver variability in the determination of the primary tumor for radiotherapy treatment planning in esophageal squamous cell carcinoma (ESCC). Methods: Sixteen patients with locally advanced ESCC were included in the analysis. In all patients positron emission tomography with computed tomography (PETC/CT) and magnetic resonance (MR) scans for radiotherapy planning were performed. Five experienced radiation oncologists delineated the primary tumor based on CT alone, MR alone, PET/CT, CT with fused MR and PET/CT with fused MR. Mean tumor volumes were calculated for each patient and imaging modality. The generalized conformity index (CIgen) was calculated to assess agreement in tumor determination. Results: The mean tumor volumes and CIgen for CT alone, MR alone, PET/CT, CT with fused MR and PET/CT with fused MR were 33.1 cm3, 30.2 cm3, 38.1 cm3, 31.9 cm3, 36.2 cm3 and 0.59, 0.64, 0.66, 0.63, 0.71, respectively. CIgen was significantly higher using PET/CT with fused MR compared to CT (p < 0.001) and PET/CT (p = 0.002) and using PET/CT compared to CT (alone) (p = 0.003). Conclusions: Our study showed higher agreement in primary tumor determination in ESCC using PET/CT compared to CT alone. Higher agreement was also found using PET/CT with fused MR compared to CT alone and PET/CT.
Ključne besede: magnetic resonance, positron emission tomography, squamous cell carcinoma, primary tumor
Objavljeno v DiRROS: 26.11.2025; Ogledov: 99; Prenosov: 40
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3. Electrochemotherapy with bleomycin, oxaliplatin, or cisplatin in mouse tumor models, from tumor ablation to in situ vaccinationKatja Uršič Valentinuzzi, Urška Kamenšek, Simona Kranjc Brezar, Chloe Heranney, Tilen Komel, Simon Buček, Maja Čemažar, Gregor Serša, 2025, izvirni znanstveni članek Povzetek: Introduction: In addition to its direct cytotoxic effects, ablative therapies as electrochemotherapy (ECT) can elicit indirect antitumor effects by triggering immune system responses. Here, we comprehensively analyzed this dual effectiveness of intratumoral ECT with chemotherapeutic drugs bleomycin (BLM), oxaliplatin (OXA), and cisplatin (CDDP). Our aim was to determine if ECT can act as in situ vaccination and thereby induce an abscopal effect. By evaluating ECT’s potential for in situ vaccination, our goal was to pave the way for future advancements for its combination with emerging (immuno)therapies, leading to enhanced responses and outcomes. Methods: We employed two mouse tumor models, the immunologically cold B16F10 melanoma and 4T1 mammary carcinoma, to explore both local and systemic (i.e., abscopal) antitumor effects following equieffective intratumoral ECT with BLM, OXA, and CDDP. Through histological analyses and the use of immunodeficient and metastatic (for abscopal effect) mouse models, we identified and compared both the cytotoxic and immunological components of ECT’s antitumor efficiency, such as immunologically recognizable cell deaths (immunogenic cell death and necrosis) and immune infiltrate (CD11+, CD4+, CD8+, GrB+). Results: Differences in immunological involvement after equieffective intratumoral ECT were highlighted by variable kinetics of immunologically recognizable cell deaths and immune infiltrate across the studied tumor models. Particularly, the 4T1 tumor model exhibited a more pronounced involvement of the immune component compared to the B16F10 tumor model. Variances in the antitumor (immune) response were also detected based on the chemotherapeutic drug used in ECT. Collectively, ECT demonstrated effectiveness in inducing in situ vaccination in both tumor models; however, an abscopal effect was observed in the 4T1 tumor model only. Conclusions: This is the first preclinical study systematically comparing the immune involvement in intratumoral ECT’s efficiency using three distinct chemotherapeutic drugs in mouse tumor models. The demonstrated variability in immune response to ECT across different tumor models and chemotherapeutic drugs provides a basis for future investigations aimed at enhancing the effectiveness of combined treatments.
Ključne besede: electroporation, chemotherapeutic drugs, mouse tumor models
Objavljeno v DiRROS: 19.11.2025; Ogledov: 149; Prenosov: 69
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4. Melanoma antigens in pediatric medulloblastoma contribute to tumor heterogeneity and species-specificity of group 3 tumorsRebecca R. J. Collins, Rebecca R. Florke Gee, Sima Tozandehjani, Tara Bayat, Maria Camila Hoyos Sanchez, Juan Sebastian Solano Gutierrez, Barbara Breznik, Anna K. Lee, Klementina Fon Tacer, 2025, izvirni znanstveni članek Povzetek: Medulloblastoma (MB) is the most malignant childhood brain cancer. Group 3 MB (G3 MB) subtype accounts for about 25% of MB and is associated with the worst outcomes. Herein, we report that more than half of G3 MB tumors express melanoma antigens (MAGEs), which are potential prognostic and therapeutic markers. MAGEs are cancer‑testis antigens, aberrantly expressed in several adult cancers, and associated with poorer prognosis and therapy resistance; however, their role in pediatric cancers is mostly unknown. This study aimed to determine whether MAGEs are activated and important in pediatric MB. We obtained formalin‑fixed paraffin‑embedded tumor samples of 34 patients, collected between 2008 and 2015 at the Children’s Medical Center in Dallas and applied our validated reverse transcription quantitative PCR (RT‑qPCR) assay to measure the expression of 23 MAGE genes. To validate our data, we analyzed published datasets from pediatric MB tumors and patient‑derived orthotopic xenografts, totaling 949 patients. Our RT‑qPCR analysis suggested that MAGEs were expressed in G3/4MB. Further mining of bulk and single‑cell RNA‑sequencing datasets confirmed that 50–75% of G3 tumors activate several MAGEs. Intriguingly, single‑cell data analysis showed that MAGEs are expressed in distinct subsets of cells in MAGE‑positive tumors and are not activated in mouse genetic models, suggesting they contribute to the tumor heterogeneity and species‑specificity of G3 MB. We then examined how MAGE expression affects the growth and oncogenic potential by CRISPR‑Cas9‑ and siRNA‑mediated gene depletion. Depletion of MAGEAs, ‑B2, and ‑Cs altered cell survival, viability, and clonogenic growth due to decreased proliferation and increased apoptosis of MAGE‑positive MB cells. These findings suggested that targeting MAGEs could represent a viable therapeutic strategy for G3 MB. A deeper understanding of MAGE regulation and function is warranted and could aid in improving prognostic and therapeutic approaches for this poorly characterized subgroup of pediatric brain tumors.
Ključne besede: medulloblastoma, tumor antigens, MAGE, pediatric cancer, cancer‑testis antigens
Objavljeno v DiRROS: 19.09.2025; Ogledov: 300; Prenosov: 135
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6. Gut microbiome in cancer : the next big opportunity for better patient outcomes?Jure Povšin, Timotej Sotošek, Metka Novak, Barbara Breznik, 2025, pregledni znanstveni članek Povzetek: 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.
Ključne besede: gut microbiome, cancer, treatment outcome, tumor models, glioma
Objavljeno v DiRROS: 03.04.2025; Ogledov: 755; Prenosov: 353
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7. Editorial : brain cancer pathogenesis and data integrationAndrea Comba, Xinzhong Li, Barbara Breznik, 2023, drugi znanstveni članki Povzetek: 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.
Ključne besede: brain tumor, data integration, therapeutic resistance, biomarkers, liquid biopsies
Objavljeno v DiRROS: 06.08.2024; Ogledov: 1032; Prenosov: 514
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8. 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: 1003; Prenosov: 716
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9. 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: 1252; Prenosov: 645
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10. Angiogenesis in gynecological cancers and the options for anti-angiogenesis therapyBahar Yetkin-Arik, Arnoud W. Kastelein, Ingeborg Klaassen, Charlotte H. J. R. Jansen, Yani P. Latul, Miloš Vittori, Aydan Biri, Korhan Kahraman, Arjan W. Griffioen, Frederic Amant, Christianne A. R. Lok, Reinier O. Schlingemann, Cornelis J. F. van Noorden, 2021, pregledni znanstveni članek Povzetek: Angiogenesis is required in cancer, including gynecological cancers, for the growth of primary tumors and secondary metastases. Development of anti-angiogenesis therapy in gynecological cancers and improvement of its efficacy have been a major focus of fundamental and clinical research. However, survival benefits of current anti-angiogenic agents, such as bevacizumab, in patients with gynecological cancer, are modest. Therefore, a better understanding of angiogenesis and the tumor microenvironment in gynecological cancers is urgently needed to develop more effective anti-angiogenic therapies, either or not in combination with other therapeutic approaches. We describe the molecular aspects of (tumor) blood vessel formation and the tumor microenvironment and provide an extensive clinical overview of current anti-angiogenic therapies for gynecological cancers. We discuss the different phenotypes of angiogenic endothelial cells as potential therapeutic targets, strategies aimed at intervention in their metabolism, and approaches targeting their (inflammatory) tumor microenvironment.
Ključne besede: angiogenesis, anti-angiogenic therapy, endothelial cells, endothelial cell metabolism, gynecological cancer, non-tip cells, tip cells, tumor microenvironment, vascular disrupting agents
Objavljeno v DiRROS: 05.08.2024; Ogledov: 922; Prenosov: 566
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