Cisplatin is an effective chemotherapeutic drug, but is limited both by its toxicity and its tendency to induce drug resistance rapidly in some patients. Tissue transglutaminase 2 (TG2), which is overexpressed in various cancers, has two main isoforms: a long (TG2-L) and a short form (TG2-S). While TG2-L supports cell survival, conversely, TG2-S promotes cell death. Evidence increasingly suggests that TG2 may be a suitable target for combating chemoresistance in a variety of human cancers. Here, we show that cisplatin toxicity towards wild-type MCF-7 breast cancer cells is associated with reduced TG2-L and TG2-S expression, whereas approximately doubling the TG2-L expression through the retinoic acid pre-treatment of these cells induces survival in the presence of cisplatin at levels similar to those seen in long-term cisplatin-co-cultured cells, which have reduced sensitivity. The treatment of cisplatin-surviving cells with cisplatin alone did not significantly alter the levels of either TG2 isoform, whereas the cisplatin challenge of cisplatin-surviving MCF-7 cells following 20 µM retinoic acid pre-treatment resulted in increased levels of TG2-L, increased TG2 enzyme activity, and no significant change in TG2-S levels, with increased cell survival. These findings suggest a subtype-specific regulatory effect of RA in cisplatin-surviving MCF-7 cells, with TG2-L upregulated at higher RA concentrations, potentially contributing to altered cisplatin sensitivity. Anti-TG2 siRNA silencing reduced cisplatin IC50 to base levels in both wild-type and cisplatin-surviving MCF-7 cells, supporting the notion that the modulation of TG2 expression could offer a significant benefit to cisplatin efficacy. Preventing excessive retinoic acid exposure may also be a mechanism for maximising cisplatin efficacy, considering TG2 modulation.

Upon transferal from plastic to Matrigel, melanoma cells demonstrate growth in three dimensions and form de novo vascular networks-known as vasculogenic mimicry-that are characteristic of the stemness phenotype of aggressive tumors. It has been reported that during malignant transformation, stress, or differentiation, the long-range inter-chromosomal interactions between numerous developmental genes and nucleoli are changed. The aim of this work was to study the potential mechanisms behind the development of the vasculogenic mimicry phenotype in melanoma cells and whether the formation of these 3D structures is connected with the reorganization of inter-chromosomal contacts of rDNA clusters. Here, we show that after 15 h of growth on Matrigel, and following the formation of the vasculogenic mimicry phenotype, dramatic changes occur in Mel Z cells in rDNA contacts with different genomic regions that possess mainly developmental genes. Approximately 400 genes that retained stable contacts with nucleoli were co-expressed with different lincRNAs and were highly associated with H3K27me3 marks and simultaneously regulated by different transcription factors. These genes are involved in development and cell adhesion and may control the basic stage of differentiation. The genes that acquired or increased contacts with rDNA clusters during growth on Matrigel are associated with cell morphogenesis, cell junctions, and the cytoskeleton. Here, we present the first evidence that nucleoli may be involved in both the activation and repression of particular groups of developmental rDNA-contacting genes in melanoma cells forming the vasculogenic mimicry phenotype. We conclude that the inter-chromosomal interactions between developmental genes and rDNA clusters are dynamic, and that nucleoli play an important role in the development of vasculogenic mimicry and stemness phenotypes in aggressive tumor genes.

UDP-Gal-β-1,4 galactosyltransferase-V (GalT-V) is a member of a large family of galactosyltransferases whose function is to transfer galactose from the nucleotide sugar UDP-galactose to a glycosphingolipid glucosylceramide, to generate lactosylceramide (LacCer). It also causes the N and O glycosylation of proteins in the Trans Golgi area. LacCer is a bioactive lipid second messenger that activates an "oxidative stress pathway", leading to critical phenotypes, e.g., cell proliferation, migration angiogenesis, autophagy, and apoptosis. It also activates an "inflammatory pathway" that contributes to the progression of disease pathology. β-1,4-GalT-V gene expression is regulated by the binding of the transcription factor Sp-1, one of the most O-GlcNAcylated nuclear factors. This review elaborates the role of the Sp-1/GalT-V axis in disease phenotypes and therapeutic approaches targeting not only Sp-1 but also Notch-1, Wnt-1 frizzled, hedgehog, and β-catenin. Recent evidence suggests that β-1,4GalT-V may glycosylate Notch-1 and, thus, regulate a VEGF-independent angiogenic pathway, promoting glioma-like stem cell differentiation into endothelial cells, thus contributing to angiogenesis. These findings have significant implications for cancer and cardiovascular disease, as tumor vascularization often resumes aggressively following anti-VEGF therapy. Moreover, LacCer can induce angiogenesis independent of VEGF and its level are reported to be high in tumor tissues. Thus, targeting both VEGF-dependent and VEGF-independent pathways may offer novel therapeutic strategies. This review also presents an up-to-date therapeutic approach targeting the β-1,4-GalT-V interactome. In summary, the β-1,4-GalT-V interactome orchestrates a broad network of signaling pathways essential for maintaining cellular homeostasis. Conversely, its dysregulation can promote unchecked proliferation, angiogenesis, and inflammation, contributing to the initiation and progression of multiple diseases. Environmental factors and smoking can influence β-1,4-GalT-V expression and its interactome, whereas elevated β-1,4-GalT-V expression may serve as a diagnostic biomarker of colorectal cancer, inflammation-exacerbated by factors that may worsen pre-existing cancer malignancies, such as smoking and a Western diet-and atherosclerosis, amplifying disease progression. Increased β-1,4-GalT-V expression is frequently associated with tumor aggressiveness and chronic inflammation, underscoring its potential as both a biomarker and therapeutic target in colorectal and other β-1,4-GalT-V-driven cancers, as well as in cardiovascular and inflammatory diseases.

Immune checkpoint inhibitors (ICIs) are a key treatment for advanced non-small cell lung cancer (NSCLC), but most patients will ultimately experience disease progression due to acquired resistance to ICI. Clinically, it is relevant to differentiate between systemic progression (SP) and oligoprogression (OP). Following SP, ICI treatment is usually discontinued, while in OP, patients are preferably treated with local ablative treatment with continuation of the ICI treatment. However, with progressive disease, it remains difficult to differentiate between true OP or SP. Circulating tumor DNA (ctDNA) analysis provides an accurate real-time reflection of the tumor burden. It remains elusive if ctDNA abundance and/or dynamics can discriminate between OP and SP. Therefore, the aim of this exploratory cohort study is to evaluate whether the sequential molecular tumor profiling of ctDNA is suitable for discriminating between true OP and SP in advanced NSCLC. Patients with stage III/IV NSCLC showing progression after ≥3 months of ICI were included. OP was defined retrospectively by RECIST response ≥ 6 months after local treatment and continued ICIs. Serial plasma samples were analyzed using the AVENIO ctDNA Expanded NGS assay targeting 77 cancer-related genes. Twenty patients (6 OP, 14 SP) were included. Somatic alterations were detected in 16 patients (median 4 mutations). No significant differences in baseline ctDNA levels, changes at progression, or mutation patterns were observed between OP and SP. Although ctDNA levels generally decreased early after the start of ICI treatment, and were increased at disease progression, mutational profiles of the 77 genes using the AVENIO Expanded ctDNA panel did not distinguish OP from SP.

The apoptotic mechanism is complex and involves many pathways. Defects can occur at any time along these pathways, resulting in malignant cell transformation and resistance to anticancer drugs. Collective efforts have made great progress in the implementation of natural products in clinical use and in discovering new therapeutic opportunities. This study aimed to screen volatile compounds of Warburgia salutaris leaf extracts and investigate their pro-apoptotic effects on MCF-7 cells. The approach was mainly based on determining cell viability using MTT and scratch assays, and DNA synthesis and damage using BrdU and comet assays, respectively. DAPI/PI stains were used for morphological analysis and expression was determined by RT-PCR and human apoptotic proteome profiler. Warburgia salutaris extracts exhibited antiproliferative effects on MCF-7 cells in a time- and dose-dependent manner. Acetone and methanol extracts exhibited low IC50 at 24, 48 and 72 h. Furthermore, the scratch test revealed that MCF-7 does not metastasise when treated with IC50. Expression showed upregulation of pro-apoptotic proteins and executioner caspases. Taken together, these findings suggest that leaves can promote apoptosis through the intrinsic apoptotic pathway, as observed by upregulation of the Bax and caspase 3 proteins. This paper provides new insights into the mechanisms of action of W. salutaris leaf extracts in the development of anticancer drugs.

Colorectal cancer (CRC) remains a major cause of cancer-related mortality. Cetuximab improves survival by combining EGFR inhibition with immune activation. This study evaluated the influence of killer cell immunoglobulin-like receptor (KIR)-mediated immune responses on cetuximab efficacy in 124 metastatic CRC patients: 55 with wild-type (WT) KRAS and 69 with KRAS mutations. Peripheral blood was genotyped for 19 KIR genes and relevant HLA alleles, focusing on key KIR-HLA interactions (2DL1-C2, 3DL1-Bw4, 3DS1-Bw4). KRAS-WT patients showed better outcomes, receiving more treatment cycles (median: 17 vs. 4) and showing slower disease progression (60% vs. 92.8% at 12 months). WT patients had higher frequencies of inhibitory KIRs and the Bw4 allele, with KIR3DS1-Bw4 heterozygosity linked to longer survival (p = 0.013). In KRAS-mutant patients, heterozygous KIR genotypes (AB) and mixed A/B semi-haplotypes were associated with improved survival (p = 0.002). Multivariate analysis confirmed KIR3DS1-Bw4 as a favorable factor in WT patients and AB genotypes as beneficial in KRAS-mutants. In conclusion, KIR-HLA interactions significantly impact cetuximab efficacy in metastatic CRC, with distinct immunogenetic profiles in WT and KRAS-mutant patients. These results highlight the potential of KIR-HLA profiling to guide personalized treatment strategies.

The gut microbiota is recognized as one of the extrinsic factors that modulate the clinical outcomes of immune checkpoint inhibitors (ICIs), such as inhibitors targeting programmed cell death protein 1 (PD-1), in cancer patients. However, the link between intestinal barrier, which mutually interacts with the gut microbiota, and therapeutic effects has not been extensively studied so far. Therefore, the primary goal of this study was to investigate the relationship between intestinal barrier functionality and clinical outcomes of anti-PD-1 therapy in patients with advanced melanoma. Fecal samples were collected from 64 patients before and during anti-PD-1 therapy. The levels of zonulin, calprotectin, and secretory immunoglobulin A (SIgA), which reflect intestinal permeability, inflammation, and immunity, respectively, were measured in fecal samples (n = 115) using an Enzyme-Linked Immunosorbent Assay (ELISA). Moreover, the composition of the immunoglobulin (Ig)-bound (n = 108) and total stool microbiota (n = 117) was determined by the V3-V4 region of 16S rRNA gene sequencing. ELISA indicated a higher baseline concentration of fecal SIgA in patients with favorable clinical outcomes than those with unfavorable ones. Moreover, high baseline concentrations of intestinal barrier state biomarkers correlated with survival outcomes. In the cases of fecal zonulin and fecal SIgA, there was a positive correlation, while in the case of fecal calprotectin, there was a negative correlation. Furthermore, there were differences in the microbial profiles of the Ig-bound stool microbiota between patients with favorable and unfavorable clinical outcomes and their changes during treatment. Collectively, these findings indicate an association between intestinal barrier functionality and clinical outcomes of anti-PD-1 therapy in advanced melanoma patients.

STK26 is highly expressed in colorectal cancer (CRC) and linked to tumorigenesis. Although implicated in unfolded protein response (UPR)-related oxidative stress, whether STK26 regulates CRC occurrence via the ATF6 pathway-a classic UPR branch governing proteostasis and cell survival-remains unestablished. In our research, we found that STK26 expression aberrantly upregulated in CRC is closely associated with poor prognosis. In vitro, tumor phenotype assays showed that STK26 drives CRC cell growth, proliferation, and migration. These effects were reversed by the ATF6 inhibitor Ceapin-A7, demonstrating that STK26's oncogenic function depends on ATF6. Moreover, transcriptome sequencing revealed that STK26 is associated with the protein folding, sorting, and degradation pathway, and a luciferase reporter assay showed that STK26 activated the ATF6 signal pathway. Furthermore STK26 interacted with p50ATF6 and enhanced its protein stabilization. In vivo studies demonstrated that the administration of the STK26 inhibitor Hesperadin significantly suppressed CRC growth, suggesting a tumor-promoting role for STK26 in CRC pathogenesis. In summary, our research reveals that STK26 is a novel regulator that promotes the growth, proliferation, and migration of CRC cells by activating the ATF6 signaling pathway and stabilizing p50ATF6. Hence, the STK26-ATF6 axis has the potential to become a new target for treating colorectal cancer.

Therapeutic resistance remains a critical barrier in effective cancer treatment, contributing to disease recurrence, progression, and reduced patient survival. In recent years, natural bioactive compounds have emerged as promising adjuncts in oncology due to their ability to modulate multiple biological processes involved in resistance. This review explores current evidence on the role of natural compounds in influencing cancer cell behavior and their interactions with the tumor microenvironment. By organizing these compounds into chemical families, we provide a structured overview of their potential to enhance the efficacy of standard chemotherapy and reduce resistance-related mechanisms. We also highlight innovative strategies, including combination therapies and advanced drug delivery systems, that aim to improve their clinical applicability. Overall, this work underscores the relevance of integrating natural bioactives into modern cancer therapy and calls for further translational research to bridge preclinical findings with clinical implementation.

Honokiol (HON) and magnolol (MAG), structural isomers from Magnolia officinalis, exhibit notable anticancer activity, particularly against head and neck squamous cell carcinoma (HNSCC). However, due to their high lipophilicity, their intravenous administration is challenging. This study aimed to develop HON- and MAG-loaded intravenous (IV) nanoemulsions using commercial lipid preparations with varying fatty acid compositions. The formulations were physicochemically characterized and evaluated in vitro using FaDu and SCC-040 HNSCC cell lines. HON and MAG were sterilized via ionizing radiation at doses of 25, 100, and 400 kGy. Their suitability for IV use was assessed through PXRD, DSC, TGA, EPR, FT-IR, NMR, and HPLC analyses. All formulations met safety criteria for IV administration, with mean droplet diameters below 241 nm and encapsulation efficiencies exceeding 95%. They significantly reduced cancer cell viability, with a synergistic effect observed in combined HON and MAG formulations compared to single-compound nanoemulsions. Clinoleic-based formulations showed enhanced anticancer efficacy, likely due to the pro-apoptotic properties of oleic acid. Notably, radiation sterilization at the standard 25 kGy dose preserved the thermal, crystalline, and structural stability of HON and MAG, whereas higher doses (400 kGy) induced degradation. Although free radicals were detected via EPR, their transient nature and rapid decay confirmed the method's safety. HON/MAG-loaded nanoemulsions exhibited strong anticancer potential, while radiation sterilization at 25 kGy ensured sterility without compromising stability. These findings provide a preliminary in vitro basis for future in vivo studies investigating HON and MAG as potential adjuvant therapies for HNSCC.

Calprotectin, a heterodimer of the S100A8 and S100A9 proteins, has been implicated in cancer-related inflammation and metastasis. Its role in melanoma progression, particularly in organ-specific metastasis, remains underexplored. In this retrospective study, plasma calprotectin levels were measured in 201 individuals, including healthy controls (n = 22), melanoma patients without evidence of metastasis (n = 71), and patients with metastatic melanoma (n = 108). Calprotectin concentrations were determined using the ELISA assay. Receiver operating characteristic (ROC) curve analyses were used to evaluate its diagnostic value, both alone and in combination with established biomarkers S100B and LDH. Plasma calprotectin levels were significantly elevated in patients with metastatic melanoma compared to non-metastatic patients (p < 0.001). Calprotectin showed moderate diagnostic value (AUC = 0.672), which improved to 0.755 when combined with S100B and LDH. Organ-specific analysis revealed that patients with liver metastases exhibited the highest calprotectin concentrations, with good discriminatory power (AUC = 0.710). No significant association was found between calprotectin levels and the type of metastasis identified (lymphatic vs. hematogenous). Logistic regression analysis showed that calprotectin levels above 2728 ng/mL were associated with a 7.4-fold increased risk of liver metastasis. Calprotectin is a promising blood-based biomarker that may enhance the detection of metastatic melanoma, particularly in cases with liver involvement. These findings suggest that calprotectin could be integrated into multivariable prediction models to improve risk stratification in clinical practice.

An oxysterol, 25-Hydroxycholesterol (25OHChol), is produced through cholesterol oxidation and is involved in various cellular processes, including apoptosis. However, the precise mechanisms underlying 25OHChol-induced apoptosis in neuroblastoma cells remain unclear. The aim of this study was to elucidate the detailed molecular mechanisms by which 25OHChol induces apoptosis in human neuroblastoma cells. This study explores the apoptotic effects of 25OHChol and the associated signaling pathways in BE(2)-C cells, a widely used human neuroblastoma cell model for neuronal differentiation and cancer research. To evaluate the cytotoxicity of 25OHChol, cell viability was assessed using the CCK-8 assay, which demonstrated a concentration-dependent decline, indicating a potential induction of cell death. Morphological changes characteristic of apoptosis, such as nuclear condensation and fragmentation, were confirmed via DAPI staining. Additionally, Annexin V/PI flow cytometry analysis revealed an increase in late apoptotic cell populations, further corroborating apoptosis induction. To investigate the molecular mechanisms, we analyzed the expression of Bcl-2 family proteins via Western blotting. The results showed an elevated Bax/Bcl-2 ratio, suggesting activation of the intrinsic mitochondrial apoptotic pathway. This was further supported by a reduction in mitochondrial membrane potential (MMP), as measured by flow cytometry. Increased caspase-9 and caspase-3/7 activity provided additional evidence for caspase-mediated apoptosis. Moreover, treatment with the pan-caspase inhibitor Z-VAD-FMK led to a dose-dependent increase in cell viability, confirming the essential role of caspases in 25OHChol-induced apoptosis. In conclusion, this study demonstrates that 25OHChol triggers apoptosis in BE(2)-C neuroblastoma cells through activation of the intrinsic mitochondrial apoptotic pathway. These findings provide new insights into the cytotoxic effects of 25OHChol and its potential role in neuroblastoma cell death.

Artificial intelligence (AI) and its machine learning and deep learning algorithms have shown promise in oncological practice. Spatial information analysis in the context of cancer is crucial for its diagnosis and treatment because it can provide an understanding of tumor-microenvironment interactions and reveal insights into response to treatment. AI tools can analyze spatial information at multiple scales, highlighting key disease, clinical, and genetic phenotypes that may reveal underlying mechanisms and molecular markers of response and resistance within the tumor and its microenvironment. By examining tumor interactions at macroscopic (diagnostic imaging) and microscopic (pathology slides and spatial biology) levels, AI can assist in making important diagnostic and prognostic decisions. In this review, we first present an overview of AI and the need for multiscale spatial information in oncology. Then, we examine growing AI applications in the analysis of such information, focusing on diagnostic imaging, digital pathology, and spatial molecular biology. We also discuss applications of large-scale foundation models and task-oriented agentic AI in these fields as emergent technologies. Then, we discuss current limitations for the clinical translation of AI into regular utilization in cancer care and discovery.

Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with a growing incidence and significant molecular heterogeneity that challenges traditional diagnostic and management paradigms. While histopathological assessment remains the gold standard for diagnosis, emerging liquid biopsy technologies provide promising non-invasive alternatives for tumor detection, molecular profiling, and disease monitoring. This review comprehensively explores the current landscape and clinical utility of liquid biopsy analytes-including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), extracellular RNAs, and exosomes-in the context of EC. We discuss the evolving role of pathologists in integrating molecular data with histomorphological features to enhance diagnostic precision, prognostic stratification, and therapeutic decision-making. Novel technologies such as methylation-based assays, tumor-informed ctDNA sequencing, and tumor-educated platelets (TEPs) are highlighted for their diagnostic accuracy and potential for early detection. Furthermore, we summarize key clinical trials and future directions aimed at validating liquid biopsy platforms for routine clinical implementation. As EC care transitions toward a precision oncology model, the integration of liquid biopsy with traditional surgical pathology offers a transformative approach to individualized and personalized patient management.

Glioblastoma (GBM) is a highly aggressive brain tumour characterised by a poor prognosis and resistance to anti-angiogenic treatments. Vasculogenic mimicry (VM), in which tumour cells form vessel-like structures independent of endothelial cells, has emerged as a key mechanism hindering the efficacy of anti-angiogenic therapies. Recent research highlights the central role of RNA-binding proteins (RBPs) in regulating VM through diverse post-transcriptional mechanisms, including mRNA decay induction and translational repression. Several oncogenic RBPs, such as HuR and HNRNPs, promote VM and tumour aggressiveness, while others, including RBMS3, act as suppressors of VM. Despite the prominent oncogenic roles of multiple RBPs, RBP-targeting compounds aimed at suppressing VM in GBM have remained at an early stage due to a number of limitations. This review summarises the role of VM in the treatment resistance of GBM, RBP regulation of VM, and the current landscape and future direction of RBP-targeted therapies aimed at overcoming VM-mediated treatment resistance in GBM.

In recent years, combination chemotherapy with therapeutic nucleic acids has emerged as a promising strategy to enhance the effectiveness of cancer therapy. However, developing an effective co-delivery system to simultaneously transport both chemotherapeutic drugs and nucleic acids remains challenging. Herein, we fabricated cholesterol-conjugated polyion complex nanoparticles (PCNs) for combination delivery of hydrophobic paclitaxel (PTX) and hydrophilic miR-34a. Cholesterol was conjugated to polyethylenimine (PEI) and hyaluronic acid (HA), producing C-PEI and C-HA, respectively. PTX was initially encapsulated within the hydrophobic core formed by the self-assembly of C-HA and C-PEI, yielding polyion complex nanoparticles (PTX@C-HA/C-PEI PCNs). Subsequently, the negatively charged miR-34a was electrostatically complexed with the cationic C-PEI moieties to generate miR-34a/PTX@C-HA/C-PEI PCNs. These PCNs exhibited a nanoscale structure with a uniform size distribution and demonstrated low cytotoxicity in colon cancer cells. Fluorescence microscopy confirmed efficient cytosolic delivery of C-HA/C-PEI PCNs in colon carcinoma cells. Furthermore, combination delivery of PTX and miR-34a using C-HA/C-PEI PCNs exhibited significantly enhanced transfection efficiency and cellular uptake for human colon cancer cells. Notably, PTX/miR-34a@C-HA/C-PEI PCNs effectively downregulated critical oncogenic targets, including Notch1, Snail1, and BCL-2, resulting in reduced cancer cell migration and proliferation. These findings indicate that PTX/miR-34a@C-HA/C-PEI PCNs hold significant potential as an innovative combination delivery platform, offering improved therapeutic efficacy for colon cancer therapy.

Papillary thyroid carcinoma (PTC), while often having a favorable prognosis, can progress to aggressive forms. Matrix metalloproteinases (MMPs) are crucial in extracellular matrix remodeling and are implicated in tumor invasion and metastasis. This study investigated MMP expression and activity in PTC and the efficacy of two selective MMP inhibitors in suppressing PTC cell migration and invasion. The analysis of RNA-seq data from the TCGA-THCA dataset highlighted the overexpression of MMP-14 in PTC, a key upstream activator of several MMPs, including MMP-2 and, indirectly, MMP-9. This elevation correlated with disease status and recurrence risk. Validation in a cell model, using PTC lines (K1 and BCPAP) and non-tumoral thyroid cells (Nthy-ori 3-1), showed markedly increased MMP-14 activity in PTC lines (6-fold in K1; 11-fold in BCPAP). MMP-9 activity was also substantially elevated (386-fold in K1; 131-fold in BCPAP), along with increased MMP-2 activity. We then tested selective inhibitors. NSC405020, an MMP-14 inhibitor, reduced K1 cell migration by 56.52% and invasion by 67.3%. Gallic acid, an MMP-2 and MMP-9 inhibitor, reduced K1 cell migration to 60.3% and invasion to 33.3% relative to the controls. These findings suggest that elevated MMP activity is a hallmark of aggressive PTC, underscoring MMPs' role in cancer progression. Targeting MMPs, particularly with agents like NSC405020 and gallic acid, presents a promising therapeutic strategy to disrupt PTC tumor progression.

Renal cell carcinoma (RCC) has a well-established propensity to form grossly visible tumour thrombi; however a comprehensive understanding of the underlying mechanisms is still lacking. The epithelial-mesenchymal transition (EMT) has been implicated in the progression of many carcinomas, including RCC; however, its exact role in the formation of venous tumour thrombi remains unclear. This study aims to explore the involvement of the EMT in venous invasion in RCC. In 14 patients with WHO/ISUP grade 2/3 clear cell RCC with venous invasion, the expression of main EMT markers (the miR-200 family, miR-205, SNAI1/2, TWIST1, ZEB2, and CDH1) was analyzed by qPCR in the selected tumour regions-the tumour centre (TC), the tumour periphery (TP), the venous tumour thrombus (VTT)-and compared to the corresponding non-neoplastic kidney tissue (N). Expression of E-cadherin, N-cadherin, and ZEB2 was analyzed immunohistochemically. The miR-200 family was downregulated in all areas examined compared to the corresponding N. When comparing the VTT with the TC, upregulation of miR-200c and miR-429 was observed. CDH1 was downregulated when the TP was compared with N, while SNAI2 was downregulated in all tumour regions. There was a strong correlation between the expression of all members of the miR-200 family. Our results demonstrate the presence of distinct molecular signatures between the selected ccRCC regions. The upregulation of two miRNAs in the VTT compared to the TC and their correlation with CDH1 expression could indicate a reversal of the EMT towards a more epithelial cell state in the VTT.

Breast cancer is one of the most common cancers globally. Unfortunately, many patients with breast cancer develop resistance to chemotherapy and tumor recurrence, which is primarily driven by breast cancer stem cells (BCSCs). BCSCs behave like stem cells and can self-renew and differentiate into mature tumor cells, enabling the cancer to regrow and metastasize. Key markers like CD44 and aldehyde dehydrogenase-1 (ALDH1), along with pathways like Wingless-related integration site (Wnt), Notch, and Hedgehog, are critical to regulating this stem-like behavior of BCSCs and, thus, are being investigated as targets for various new therapies. This review summarizes marker-dependent strategies for targeting BCSCs and expands on the challenges for the development of anti-BCSC drugs. We explore cutting-edge approaches like artificial intelligence (AI)-driven drug discovery and urge readers to seriously consider biological clocks and chronotherapy as experimental variables in drug discovery. Collectively, the task of cancer researchers is to overcome the many hurdles targeting BCSCs if we hope to tangibly improve breast cancer treatment outcomes and reduce mortality.

(1) Polycystic ovary syndrome (PCOS) is one of the most common endocrinological disorders worldwide; its complex etiopathology remains poorly understood. PCOS is associated with a broad spectrum of abnormalities, including irregular menses, androgen excess, and increased risk of metabolic, endocrinological, and cardiovascular disorders. This narrative review focuses on structural and functional changes in the uterus associated with polycystic ovary syndrome and hyperandrogenism. (2) The review was performed by searching PubMed, Medline, Embase, Google Scholar, and Cochrane Library electronic databases on records published between 1964 and 2025. The authors included studies on (i) the uterus in clinical settings of PCOS patients, (ii) the uterus in PCOS models, and (iii) the pregnant uterus in patients with PCOS. Multiple animal and human studies describe a potential impact of PCOS on uterine blood flow, morphology, and thickness of the uterine muscle, indicating a possible functional impairment in pregnant and non-pregnant women. The scope of available knowledge regarding functional and structural uterine changes in PCOS is scarce; new studies are warranted. Future research should focus on hyperandrogenism associated with PCOS and explore the link between the morphology and function of the uterus.