Cancer seriously threatens the lives and health of people worldwide, and exosomes seem to play an important role in managing cancer effectively, which has attracted extensive attention from researchers in recent years. This study aimed to scientifically visualize exosomes research in cancer (ERC) through bibliometric analysis, reviewing the past, summarizing the present, and predicting the future, with a view to providing valuable insights for scholars and policy makers. Researches search and data collection from Web of Science Core Collection and clinical trial.gov. Calculations and visualizations were performed using Microsoft Excel, VOSviewer, Bibliometrix R-package, and CiteSpace. As of December 1, 2024, and March 8, 2025, we identified 8,001 ERC-related publications and 107 ERC-related clinical trials, with an increasing trend in annual publications. Our findings supported that China, Nanjing Medical University, and International Journal of Molecular Sciences were the most productive countries, institutions, and journals, respectively. Whiteside, Theresa L. had the most publications, while Théry, C was the most co-cited scholar. In addition, Cancer Research was the most co-cited journal. Spatial and temporal distribution of clinical trials was the same as for publications. High-frequency keywords were "extracellular vesicle," "microRNA" and "biomarker." Additional, "surface functionalization," "plant," "machine learning," "nanomaterials," "promotes metastasis," "engineered exosomes," and "macrophage-derived exosomes" were promising research topics. Our study comprehensively and visually summarized the structure, hotspots, and evolutionary trends of ERC. It would inspire subsequent studies from a macroscopic perspective and provide a basis for rational allocation of resources and identification of collaborations among researchers.

The breast cancer is one of the most prevalent causes of cancer-related death globally. Preliminary diagnosis of breast cancer increases the patient's chances of survival. Breast cancer classification is a challenging problem due to dense tissue structures, subtle variations, cellular heterogeneity, artifacts, and variability. In this paper, we propose three hybrid deep-transfer learning models for breast cancer classification using histopathology images. These models use Xception model as a base model, and we add seven more layers to fine-tune the base model. We also performed an extensive comparative analysis of five prominent machine-learning classifiers, namely Random Forest Classifier (RFC), Logistic Regression (LR), Support Vector Classifier (SVC), K-Nearest Neighbors (KNN), and Ada-boost. We incorporate the best performing two classifiers, namely RFC and SVC, in the fine-tuned Xception model, and accordingly, they are named as Xception Random Forest (XRF) and Xception Support Vector (XSV), respectively. The fine-tuned Xception model with softmax classifier is termed as Multi-layer Xception Classifier (MXC). These three models are evaluated on the two publically available datasets: BreakHis and Breast Histopathology Images Database (BHID). Our all three models perform better than the state-of-the-art methods. The XRF provides the best performance at the 40 × magnification level on the BreakHis dataset, with an accuracy (ACC) of 94.44%, F1 score (F1) of 94.44%, area under the receiver operating characteristic curve (AUC) of 95.12%, Matthew's correlation coefficient (MCC) of 88.98%, kappa (K) of 88.88%, and classification success index (CSI) of 89.23%. The MXC provides the best performance on the BHID dataset, with an ACC of 88.50%, F1 of 88.50%, AUC of 95.12%, MCC of 77.03%, K of 77.00%, and CSI of 79.13%. Further, to validate our models, we performed fivefold cross-validation on both datasets and obtained similar results.

Metabolic processes are crucial in immune regulation, yet the impact of metabolic heterogeneity on immunological functions remains unclear. Integrating metabolomics into immunology allows the exploration of the interactions of multilayered features in the biological system and the molecular regulatory mechanism of these features. To elucidate such insight in lung squamous cell carcinoma (LUSC), we analyzed 106 LUSC tumor tissues. We performed high-resolution matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to obtain spatial metabolic profiles, and immunohistochemistry to detect tumor-infiltrating T lymphocytes (TILs). Unsupervised k-means clustering and Simpson's diversity index were employed to assess metabolic heterogeneity, identifying five distinct metabolic tumor subpopulations. Our findings revealed that TILs are specifically associated with metabolite distributions, not randomly distributed. Integrating a validation cohort, we found that heterogeneity-correlated metabolites interact with CD8+ TIL-associated genes, affecting survival. High metabolic heterogeneity was linked to worse survival and lower TIL levels. Pathway enrichment analyses highlighted distinct metabolic pathways in each subpopulation and their potential responses to chemotherapy. This study uncovers the significant impact of metabolic heterogeneity on immune functions in LUSC, providing a foundation for tailoring therapeutic strategies.

This study investigated the role of long-chain acyl-CoA dehydrogenase (ACADL) in lung adenocarcinoma (LUAD). ACADL was significantly downregulated in human LUAD tissues compared to normal lung tissues. In vitro, ectopic expression of ACADL in murine LLC cells decreased cell viability, migration, and invasion, while ACADL knockdown exhibited the opposite effect. In vivo, ACADL overexpression impeded tumor growth and metastasis. Mechanistically, ACADL hindered tumor progression by inducing cell cycle arrest, promoting apoptosis, and suppressing the epithelial-mesenchymal transition (EMT) process. These findings suggest ACADL acts as a tumor suppressor in LUAD progression.

From tumorigenesis to the establishment of local or metastatic high-grade tumours, an integral part of the cellular lifespan relies on various signalling pathways. Particular pathways that allow cells to proliferate by creating a network of new blood vessels have been documented, whereas other pathways are primarily involved with a migration to distant body parts, partially through the process of epithelial-mesenchymal transition (EMT). This review will discuss the different signalling pathways, such as TGF-β, Cripto-1, Wnt pathways, Hedgehog, Notch and NF-κB pathways, and how they promote tumour initiation and progression by influencing diverse cellular processes and EMT in general and in benign and malignant prostate tumours. This review will discuss only the critical pathways. Therefore, many other types of signalling pathways which are related to prostate cancer will not be discussed. Possibilities for further investigation will be mentioned, as many underlying mechanisms involved in these pathways have potential as targets in future tumour therapy. This review will also introduce some novel clinical trials relating to the inhibition of signalling pathways and their clinical outcomes.

A previous RNA-Seq study revealed that the transcript abundance of specificity protein 1 (SP1) was significantly higher in Day 7 bovine blastocysts compared to conceptuses on Days 10, 13, 16, and 19, suggesting a stage-specific role in early bovine embryo development. The present study aimed to characterize the mRNA expression of SP1 and associated candidate genes (ACSS1, C1QBP, ATF3, MAT2A, and POLD1) during early bovine embryo development from the 2-cell to blastocyst stage. Further, the effects of SP1 inhibition on embryo development were evaluated by culturing embryos with the SP1 inhibitor, mithramycin A (MT) at varying concentrations (0, 25, 50, 100, and 1000 nM). As further validation, we examined expression of SP1 and associated genes by interrogating transcriptomic data from Day 4 (16-cell stage) embryos cultured in vitro or in vivo in the oviducts of lactating or nonlactating dairy cows. The relative abundance of SP1 peaked at the time of embryonic genome activation, being higher (P < 0.05) in 8- and 16-cell embryos compared to the 2-cell stage, and decreasing thereafter (at the morula and blastocyst stages). Similarly, transcript abundance for most of the selected candidate genes involved in the SP1 network were upregulated (P < 0.05) at the 8- and 16-cell stage, but not at other stages investigated. Inhibition of SP1 with MT did not affect embryo development up to the 8-cell stage but reduced (P < 0.05) the proportion of embryos reaching the 16-cell and blastocyst stages in a dose-dependent manner. Moreover, blastocysts produced in the presence of MT contained fewer (P < 0.05) cells than blastocysts developed without MT. Expression of SP1 and associated genes in 16-cell stage (Day 4) embryos produced either in vitro or in vivo was higher (P < 0.05) compared to in vitro-produced 2- to 4- cell stage (Day 2) embryos. These findings suggest an essential role of SP1 during early embryo development, particularly around the time of embryonic genomic activation.

Harnessing the modulation of redox homeostasis represents a promising anticancer strategy. Here, we design and evaluate Se-SN38, a prodrug of the camptothecin (CPT) derivative 7-ethyl-10-hydroxycamptothecin (SN38) with a cyclic five-membered diselenide moiety for redox-triggered activation. We demonstrate that Se-SN38 exhibits superior cytotoxicity in various cancer cell lines over the parent drug SN38 or the control prodrug S-SN38, a sulfur analogue of Se-SN38. This increased potency is attributed to the efficient release of SN38 and induction of oxidative stress, as demonstrated by a significant rise in reactive oxygen species production, along with a marked depletion of cellular total thiols and a decreased GSH/GSSG ratio. Furthermore, Se-SN38 treatment leads to inhibition of thioredoxin reductase activity, disruption of mitochondrial membrane potential, and induction of DNA damage, culminating in apoptosis. These findings suggest that Se-SN38 represents a promising strategy to enhance the therapeutic efficacy of CPT derivatives by exploiting the unique redox-active properties of cyclic five-membered diselenide to induce oxidative stress and apoptosis.

The ability to express replicative immortality is one of the hallmarks of cancer. Most of these cells attain this feature by expressing the enzyme telomerase. This enzyme is responsible for maintaining the telomeres, a repeating structure at the ends of chromosomes, protecting the chromosomes from degradation. The Paired Box (PAX) genes are a family of highly conserved genes involved in various functions, including the development of diseases like cancer, in which most of them express telomerase as the mechanism to maintain telomere length. This study seeks to investigate PAX genes as potential telomerase activators and explore emerging research areas. Related literature was retrieved from PubMed, Web of Science and Scopus databases using a keyword search, where 119 records were identified. However, upon further filtering, only four reports were relevant to this topic, which addresses the role of PAX5 and PAX8 genes and their proteins' role in telomerase regulation. More studies are needed to elucidate the complex mechanism of action between the PAX genes and telomerase regulation.

Telomerase reverse transcriptase is a ribonucleoprotein complex that maintains telomere length in rapidly dividing cells, thus enabling cellular immortality. Despite being recognized as an important cancer target for decades, no small molecule telomerase inhibitors have been approved as anticancer therapeutics to date. Several limitations, including the absence of high-throughput screening tools, have posed challenges to the telomerase drug discovery field. Here, we describe a high-throughput, fluorescently coupled screening methodemploying a chemically modified reporter nucleotide. We utilize the Tribolium castaneum telomerase as a surrogate model as it shares a high degree of active site homology with the human enzyme . We piloted this tool by screening a chemical library of ∼3600 nucleoside mimetics todemonstrate excellent assay quality, and identified 2 compounds with inhibitory activity that were further validated in a direct enzymatic assay. Our work introduces a method that has the potential to uncover novel telomerase inhibitors for further drug discovery efforts.

Immunotherapy has had a tremendous impact on cancer treatments. Although frequently used inside the clinics, the application of immunomodulating compounds remains restricted due to the immunosuppressive tumor microenvironment. Among the promising methods, the activation of the stimulator of interferon genes (STING) pathway has emerged as a next-generation immunotherapeutic target. Despite promising preliminary results, the application of STING activating agents is strongly limited due to poor tumor selectivity and poor bioavailability. To overcome these limitations, herein, the first example of a cobalt(III) cyclam prodrug capable of inducing a chemotherapeutic effect and activating the STING pathway is reported. The cobalt(III) complex was found to be stable under physiological conditions, but released its axial ligands within the reducing cancerous microenvironment. While the reduced metal complex triggered a strong cytotoxic response by chemotherapy, the released organic ligands induced a strong immune response using the STING pathway, resulting in a multimodal treatment. To further enhance the pharmacological properties and provide tumor selectivity, the metal complex was encapsulated in polymeric nanoparticles. Upon injection into the blood stream, the nanoparticles accumulated in the triple-negative breast cancer tumor of the mouse model, activated the immune response inside the animal, and caused a nearly complete eradication of the tumor.

Per- and polyfluoroalkyl substances (PFAS) are "forever chemicals" and pervasive environmental contaminants associated with cancer. Epidemiological studies found that an increased incidence of hormone-sensitive breast cancer is correlated with PFAS exposure. Cell-based assays provide a well-controlled experimental platform to quantify cellular responses as a function of exposure. Given the nearly 15,000 known PFAS on the Environmental Protection Agency's toxicity database (DSSTox), in vitro models are the only feasible approach to screen this large molecular library. One of the hallmarks of cancer is increased migration and invasion, processes that are the gateway to metastasis. Using a paper-based invasion assay developed in our lab, we compared the invasion of the MCF7 and M231 cell lines after acute and prolonged exposures to 2 legacy PFAS compounds, individually and in an equimolar mixture: perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS). The acute exposures quantified cellular movement after a 24-h period in the presence of the molecule of interest. The prolonged exposures in this work exposed 5 consecutive cell passages to the PFAS. We hypothesized that prolonged PFAS exposures would select for invasive subpopulations. These prolonged exposures increased the invasion of MCF7 and M231 cells compared to acute exposures of the same PFAS concentration (10 µM). The prolonged exposures to PFOA and PFOS at environmentally relevant concentrations (10 nM) did not increase invasion. Our results highlight the need to assess different exposure durations in vitro and that the paper-based invasion assay is a reasonable screening tool.

Significance: Growing evidence indicates the importance of redox reactions homeostasis, mediated predominantly by reactive oxygen species (ROS) in influencing the development, differentiation, progression, metastasis, programmed cell death, tumor microenvironment, and therapeutic resistance of cancer. Therefore, reviewing the ROS-linked epigenetic changes in cancer is fundamental to understanding the progression and prevention of cancer. Recent Advances: We review in depth the molecular mechanisms involved in ROS-mediated epigenetic changes that lead to alteration of gene expression by altering DNA, modifying histones, and remodeling chromatin and noncoding RNA. Critical Issues: In cancerous cells, alterations of the gene-expression regulatory elements could be generated by the virtue of imbalance in tumor microenvironment. Various oxidizing agents and mitochondrial electron transport chain are the major pathways that generate ROS. ROS plays a key role in carcinogenesis by activating pro-inflammatory signaling pathways and DNA damage. This loss of ROS-mediated epigenetic regulation of the signaling pathways may promote tumorigenesis. We address all such aspects in this review. Future Directions: Developments in this growing field of epigenetics are expected to contribute to further our understanding of human health and diseases such as cancer and to test the clinical applications of redox-based therapy. Recent studies of the cancer-epigenetic landscape have revealed pervasive deregulation of the epigenetic factors in cancer. Thus, the study of interaction between ROS and epigenetic factors in cancer holds a great promise in the development of effective and targeted treatment modalities. Antioxid. Redox Signal. 42, 848-867.

Gray hair, widely regarded as a hallmark of aging. While gray hair is associated with aging, reversing this trait through gene targeting does not alter the fundamental biological processes of aging. Similarly, certain oncogenes (such as CXCR4, MMP-related genes, etc.) can serve as markers of tumor behavior, such as malignancy or prognosis, but targeting these genes alone may not lead to tumor regression. We pioneered the name of this class of genes as "phenotypic genes". Historically, cancer genetics research has focused on tumor driver genes, while genes influencing cancer phenotypes have been relatively overlooked. This review explores the critical distinction between driver genes and phenotypic genes in cancer, using the MAPK and PI3K/AKT/mTOR pathways as key examples. We also discuss current research techniques for identifying driver and phenotypic genes, such as whole-genome sequencing (WGS), RNA sequencing (RNA-seq), RNA interference (RNAi), CRISPR-Cas9, and other genomic screening methods, alongside the concept of synthetic lethality in driver genes. The development of these technologies will help develop personalized treatment strategies and precision medicine based on the characteristics of relevant genes. By addressing the gap in discussions on phenotypic genes, this review significantly contributes to clarifying the roles of driver and phenotypic genes, aiming at advancing the field of targeted cancer therapy.

Potassium channel tetramerization domain-containing 1 (KCTD1) plays a critical role in transcriptional regulation and adipogenesis, but its significance in hepatocellular cancer (HCC) has not been reported.

Immunohistochemistry, Western blotting and quantitative real-time PCR analysis were performed to assess the expression of KCTD1 and related genes in HCC cells. MTT assays, colony formation, cell migration, invasion and the in-vivo mouse models were utilized to evaluate the function of KCTD1 in HCC progression. Co-immunoprecipitation, chromatin immunoprecipitation and luciferase reporter assays were conducted to elucidate the molecular mechanisms of KCTD1 in HCC.

KCTD1 expression was increased in human HCC tissues and closely associated with advanced tumor stages. KCTD1 overexpression enhanced growth, migration, and invasion of Huh7 and HepG2 cells both in vitro and in vivo, while KCTD1 knockdown reversed these effects in MHCC97H cells. Mechanistically, KCTD1 interacted with hypoxia-inducible factor 1 alpha (HIF-1α) and enhanced HIF-1α protein stability with the inhibited prolyl-hydroxylases (PHD)/Von Hippel-Lindau (VHL) pathway, consequently activating the Vascular Endothelial Growth Factor (VEGF)/VEGFR2 pathway in HCC cells. Sorafenib and KCTD1 knockdown synergistically inhibited intrahepatic tumor growth following in situ injection of MHCC97H cells. miR-129-5p downregulated KCTD1 by binding to KCTD1 3'UTR. Finally, 45 µg exosomes from miR-129-5p-overexpressing MHCC97H cells combined with 25 mg/kg sorafenib to decrease HCC tumor size.

These results suggested that KCTD1 protects HIF-1α from degradation and activates the VEGF signaling cascade to enhance HCC progression. Therefore, KCTD1 may serve as a novel target of HCC and pave the way for an efficient combined therapy in advanced HCC.

In recent years, energy metabolism in cancer has received increasing attention as an important component of tumor biology, and the functions of transcription factors, mitochondria, reactive oxygen species (ROS) and the autophagy-lysosome system in which have been elucidated. G-quadruplex (G4) is a molecular switch that regulates gene transcription or translation. As an anticancer target, the effect of G4 on cancer cell proliferation, apoptosis, cycle and autophagy has been recognized. The energy metabolism system is a unified whole composed of transcription factors, metabolic regulators, metabolites and signaling pathways that run through the entire cancer process. However, the role of G4 in this complex metabolic network has not been systematically elucidated. In this review, we analyze the close correlation between G4 and transcription factors, mitochondria, ROS and the autophagy-lysosome system and suggest that G4 can exert a marked effect on cancer energy metabolism by regulating the above mentioned key regulatory elements. The anticancer effects of some G4 ligands through regulation of energy metabolism have also been summarized, confirming the clear involvement of G4 in energy metabolism. Although much more research is needed, we propose that G4 may play a critical role in the complex energy metabolism system of cancer, which is a promising target for anticancer strategies focusing on energy metabolism.

Aberrant lipid metabolism is increasingly recognized as a hallmark of cancer, contributing to tumor growth, metastatic dissemination, and resistance to therapy. Cancer cells reprogram key metabolic pathways-including de novo lipogenesis, lipid uptake, and phospholipid remodeling-to sustain malignant progression and adapt to microenvironmental demands. This review summarizes current insights into the role of lipid metabolic reprogramming in oncogenesis and highlights recent advances in lipidomics that have revealed cancer type- and stage-specific lipid signatures with diagnostic and prognostic relevance. We emphasize the dual potential of lipid metabolic pathways-particularly those involving phospholipids-as sources of clinically relevant biomarkers and therapeutic targets. Enzymes and transporters involved in these pathways have emerged as promising candidates for both diagnostic applications and pharmacological intervention. We also examine persistent challenges hindering the clinical translation of lipid-based approaches, including analytical variability, insufficient biological validation, and the lack of standardized integration into clinical workflows. Furthermore, the review explores strategies to overcome these barriers, highlighting the importance of incorporating lipidomics into multi-omics frameworks, supported by advanced computational tools and AI-driven analytics, to decipher the complexity of tumor-associated metabolic networks. We discuss how such integrative approaches can facilitate the identification of actionable metabolic targets, improve the specificity and robustness of lipid-based biomarkers, and enhance patient stratification in the context of precision oncology.

Hepatocellular carcinoma (HCC) is a complex malignancy driven by the dysregulation of multiple cellular pathways. Survivin, a key member of the inhibitor of apoptosis (IAP) family, plays a central role in HCC tumorigenesis and progression. Despite significant research, a comprehensive understanding of the contributions of survivin to the hallmarks of cancer, its molecular network, and its potential as a therapeutic target remains incomplete. In this review, we integrated bioinformatics analysis with an extensive literature review to provide deeper insights into the role of survivin in HCC. Using bioinformatics tools such as the Human Protein Atlas, GEPIA, STRING, TIMER, and Metascape, we analyzed survivin expression and its functional associations and identified the top 20 coexpressed genes in HCC. These include TK1, SPC25, SGO2, PTTG1, PRR11, PLK1, NCAPH, KPNA2, KIF2C, KIF11, HJURP, GTSE1, FOXM1, CEP55, CENPA, CDCA3, CDC45, CCNB2, CCNB1 and CTD-2510F5.4. Our findings also revealed significant protein-protein interactions among these genes, which were enriched in pathways associated with the FOXM1 oncogenic signaling cascade, and biological processes such as cell cycle regulation, mitotic checkpoints, and diseases such as liver neoplasms. We also discussed the involvement of survivin in key oncogenic pathways, including the PI3K/AKT, WNT/β-catenin, Hippo, and JAK/STAT3 pathways, and its role in modulating cell cycle checkpoints, apoptosis, and autophagy. Furthermore, we explored its interactions with the tumor microenvironment, particularly its impact on immune modulation through myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and natural killer cell function in HCC. Additionally, we highlighted its involvement in alkylglycerone phosphate synthase (AGPS)-mediated lipid reprogramming and identified important gaps in the survivin network that warrant further investigation. This review also examined the role of survivin in cancer stemness, inflammation, and virally mediated hepatocarcinogenesis. We evaluated its potential as a diagnostic, prognostic, predictive, and pharmacodynamic biomarker in HCC, emphasizing its relevance in precision medicine. Finally, we summarized emerging survivin-targeted therapeutics and ongoing clinical trials, underscoring the need for novel strategies to effectively target survivin in HCC.

A scaffold hybridization approach was utilized to enhance the antitumor and carbonic anhydrase inhibitory activity of our oxindole and coumarin lead compounds (V and X). Two oxindole-coumarin hybrids 6c and 6e showed broad spectrum of anticancer activity with NCI full panel MG-MIDs of 5.01 and 6.31 µM, respectively. They revealed GI50 of a single digit micromolar concentration against 46 and 39 cell lines, respectively. An apoptosis dependent mechanism is suggested for the potent anticancer activity of compounds 6c and 6e via the increase in the BAX/BCL-2 ratio and enhancement of the expression levels of caspase-9 and the tumor suppressor p53. While this structure hybridization resulted in enhanced antitumor activity, it resulted in moderate CA IX and XII inhibitory activity. The potent anticancer compound 6e was among the most active inhibitors of the tumor associated CA IX and CA XII in this study (KI = 1.8 and 2.1 μM, respectively). As a result, even compound 6e's moderate CA IX/XII inhibitory activity may have synergistic effects contributing to its increased tumor growth suppression and proapoptotic activity. Moreover, compound 6e revealed a nonsignificant cytotoxicity toward the normal kidney epithelial Vero cell line and was totally inactive against the cytosolic isoforms CA I and CA II (KI = > 100 μM) which mitigate its side effect as chemotherapeutic agent and enforce its safety profile.

Single-cell RNA sequencing measures individual cell transcriptomes in a sample. In the past decade, this technology has motivated the development of hundreds of clustering methods. These methods attempt to group cells into populations by leveraging the similarity of their transcriptomes. Because each method relies on specific hypotheses, their predictions can vary drastically. To address this issue, ensemble algorithms detect cell populations by integrating multiple clustering methods, and minimizing the differences of their predictions. While this approach is sensible, it has yet to address some conceptual challenges in single-cell data science; namely, ensemble algorithms have yet to generate clustering results with uncertainty values and multiple resolutions. In this work, we present an original approach to ensemble clustering that addresses these challenges, by describing the differences between clustering results, rather than minimizing them. We present the scEVE algorithm, and we evaluate it on 15 experimental datasets, and up to 1200 synthetic datasets. Our results reveal that scEVE outperforms the state of the art, and addresses both conceptual challenges. We also highlight how biological downstream analyses will benefit from addressing these challenges. We expect that this work will provide an alternative direction for developing single-cell ensemble clustering algorithms.

The tumor suppressor protein p53 plays a key role in the cellular response to DNA damage. In response to DNA double-strand breaks (DSB), cultured cells exhibit oscillations of p53 levels, which impact gene expression and cell fate. The dynamics of p53 in vivo have only been studied in fixed tissues or using reporters for p53's transcriptional activity. Here we established breast tumors expressing a fluorescent reporter for p53 levels and employed intravital imaging to quantify its dynamics in response to DSB in vivo. Our findings revealed large heterogeneity among individual cells, with most cells exhibiting a single prolonged pulse. We then tested how p53 dynamics might change under high cell confluency, one factor that differs between cell culture and tissues. We revealed that highly confluent cultured breast cancer cells also show one broad p53 pulse instead of oscillations. Through mathematical modeling, sensitivity analysis, and live-cell imaging, we identified low levels of the phosphatase Wip1, a transcriptional target and negative regulator of p53, as a key contributor to these dynamics. Because high cell confluency better reflects the microenvironment of tissues, the impact of cell confluency on p53 dynamics may have important consequences for cancerous tissues responding to DNA damage-inducing therapies.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with ~7% 5-year overall survival reflecting early metastasis and rapid acquired chemoresistance. Immunotherapy briefly extends overall survival in ~15% cases, yet predictive biomarkers are lacking. Targeted therapies are beginning to show promise, with a recently approved delta-like ligand 3 (DLL3)-targeted therapy impacting the treatment landscape. The increased availability of patient-faithful models, accumulating human tumour biobanks and numerous comprehensive molecular profiling studies have collectively facilitated the mapping and understanding of substantial intertumoural and intratumoural heterogeneity. Beyond the almost ubiquitous loss of wild-type p53 and RB1, SCLC is characterized by heterogeneously mis-regulated expression of MYC family members, yes-associated protein 1 (YAP1), NOTCH pathway signalling, anti-apoptotic BCL2 and epigenetic regulators. Molecular subtypes are based on the neurogenic transcription factors achaete-scute homologue 1 (ASCL1) and neurogenic differentiation factor 1 (NEUROD1), the rarer non-neuroendocrine transcription factor POU class 2 homeobox 3 (POU2F3), and immune- and inflammation-related signatures. Furthermore, SCLC shows phenotypic plasticity, including neuroendocrine-to-non-neuroendocrine transition driven by NOTCH signalling, which is associated with disease progression, chemoresistance and immune modulation and, in mouse models, with metastasis. Although these features pose substantial challenges, understanding the molecular vulnerabilities of transcription factor subtypes, the functional relevance of plasticity and cell cooperation offer opportunities for personalized therapies informed by liquid and tissue biomarkers.

Mesenchymal stem cells (MSCs) are properties of self-renewal and differentiation potentials and thus are very appealing to regenerative medicine. Nevertheless, their therapeutic potential is frequently constrained by senescence, limited proliferation, and stress-induced apoptosis. The key role of the p53-p21 biology in MSC biology resides in safeguarding genomic stability while promoting senescence and limiting regenerative capacity upon over-activation demonstrated. This pathway is a key point for improving MSC function and exploiting the inherent limitations. Recent advances indicate that senescence can be delayed by targeting the p53-p21 signaling and improved MSC proliferation and differentiation capacity. PFT-α pharmacological agents transiently inhibit p53 from increasing proliferation and lineage-specific differentiation, while antioxidants such as hydrogen-rich saline and epigallocatechin 3 gallate (EGCG) suppress oxidative stress and attenuate p53 p21 signaling. Genetic tools like CRISPR-Cas9 and RNA interference also precisely modulate TP53 and CDKN1A expression to optimize MSC functionality. The interplay of p53-p21 with pathways like Wnt/β-catenin and MAPK further highlights opportunities for combinatorial therapies to enhance MSC resilience and regenerative outcomes. This review aims to offer a holistic view of how p53-p21 targeting can further the regenerative potential of MSCs, resolving senescence, proliferation, and stress resilience towards advanced therapeutics built on MSCs.

Solid tumors (particularly the desmoplastic ones) usually harbor insurmountable mechanical barriers and formidable immunosuppressive tumor microenvironment (TME), which severely restricted nanomedicine-penetration and vastly crippled outcomes of numerous therapies. To overcome these barriers, a versatile nanoplatform orchestrated mechanotherapy with chemoimmunotherapy was developed here to simultaneously modulate tumor physical barriers and remodel TME for synergistically enhancing anticancer efficiency. Dexamethasone (DMS) and cis-aconityl-doxorubicin (CAD) were co-hitchhiked into phenylboronic acid functionalized polyethylenimine (PEI-PBA) carrier, and further in situ shielded by aldehyde-modified polyethylene glycol (PEG) to form CAD/DMS@PEG/PEI-PBA (CD@PB) nanoparticles (NPs). The CD@PB NPs exhibited multifunctionality: (1) Long in vivo circulation and acidic TME-responsive PEG deshielding for being efficiently internalized into cells. (2) Endosomal-pH triggered drug release and PEI-facilitated drug-escaping from endosome into cytoplasm. (3) DMS down-regulated thick stroma and weakened mechanical barriers for facilitating NP penetration. (4) DMS mediated nuclear pore dilation to promote more DOX entering nucleus and enhance treatment effects. (5) DOX induced potent immunogenic cell death (ICD), activated antitumor immunity and exerted chemoimmunotherapy. The versatile CD@PB NPs displayed excellent antitumor efficacy against 4T1 mouse breast cancer, which effectively remodeled immunosuppressive TME and orchestrated mechanotherapy with chemoimmunotherapy to synergistically enhance antitumor efficiency. The study provided an illuminating paradigm for multidimensional cancer therapy.

MicroRNAs, a class of small noncoding RNAs, have been identified as promising biomarkers for cancer identification and management by regulating gene expression and other cellular biological pathways. This review gathers findings for understanding the molecular basis and clinical importance of microRNA-216 (miR-216) in several cancers. Increased or decreased expression of miR-216 has been observed in a variety of cancers, including esophageal cancer, breast cancer, colorectal cancer, gastric cancer, pancreatic cancer, cervical cancer, brain tumor (glioma), prostate cancer, and acute myeloid leukemia, indicating its activity as an oncogene or tumor suppressor. Through this study, we proposed that miR-216 can potentially be a candidate as a prognostic marker for early detection of tumor development, progression, as well as metastasis in cancer patients.

Fumarate hydratase (FH) is a key enzyme in the Krebs cycle and cellular energy metabolism, playing a crucial role in tumorigenesis. It is considered a prognostic, diagnostic, and therapeutic target for many types of cancer. Therefore, FH is a popular scientific subject in cancer research. The current study aimed to identify cancer research in the WoS database and examine studies conducted on FH molecules using bibliometric indicators.

The keywords "fumarate hydratase" OR fumarase" AND "cancer OR tumor OR neoplasm" were used to search the WoS database. This search was performed using abstracts, titles, and keywords. The "Article" and "Review" options were used to access the data of papers published between 2002 and March 2024.

A total of 840 publications (616 articles and 224 reviews) were published by the end of March 2024. Research output on FH and cancer has significantly increased recently, with the highest number of publications in 2020 (n = 69, 8.214%). The most commonly used language was English (n = 823, 97.976%), and the USA led in productivity, contributing 306 studies (36.429%). The University of Helsinki is the most productive affiliation with 138 published articles. The researcher who conducted most studies (n = 58, 6.904%) was also the most-cited author, with 1562 citations. In the current bibliometric study, "hereditary leiomyomatosis", "mutations", and "renal-cell cancer" were frequently included in publications.

This bibliometric study provides a quantitative overview of FH research in oncology and presents the most recent FH status in cancer research.

Dysregulated cell death leading to uncontrolled cell proliferation is a hallmark of cancer. Chemotherapy-induced cell death is critical for the success of cancer treatment but this process is impaired by metabolic byproducts. How these byproducts interfere with anti-cancer therapy is unclear. Here, we show that the metabolic byproduct acrolein derived from polyamines, tobacco smoke or fuel combustion, induces ferroptosis independently of ZBP1, while suppressing necroptosis in cancer cells by inhibiting the oligomerization of the necroptosis effector MLKL. Loss of the enzyme SAT1, which contributes to intracellular acrolein production, sensitizes cells to necroptosis. In mice, administration of an acrolein-trapping agent relieves necroptosis blockade and enhances the anti-tumor efficacy of the chemotherapeutic drug cyclophosphamide. Human patients with cancer coupled with a higher cell death activity but a lower expression of genes controlling polyamine metabolism exhibit improved survival. These findings highlight that the removal of metabolic byproducts improves the success of certain chemotherapies.

Cholangiocarcinoma (CCA) is a rare but devastating liver cancer which is commonly diagnosed at a late stage and often resistant to chemotherapy. Bcl-2 family members, which control apoptotic cell death, are known to be involved in the chemoresistance of some cancer types. This study investigated the role of Bcl-2 family members in the chemoresistance of cholangiocarcinoma organoids (CCAOs) in both undifferentiated and matured branching phenotypes (BRCCAOs). Patient-derived CCAOs and BRCCAOs were cultured to assess chemoresistance to an FDA-approved anticancer drug panel by testing cell viability using ATP quantification and apoptotic cell death by cleaved caspase 3 staining. More specifically, sensitivity to the first-line drug gemcitabine was tested in combination with Bcl-2 family inhibitors or activators. We found that in gemcitabine-resistant CCAOs, inhibition of Bcl-xl could overcome gemcitabine resistance and induce apoptotic cell death. Although inhibition of Mcl-1 or activation of Bax induced spontaneous cell death, this could not overcome gemcitabine resistance. The BRCCAOs, which mimic tumor architecture better than CCAOs, show broader chemoresistance to anticancer drugs. Of note, in the resistant BRCCAOs, Bcl-xl inhibition could restore gemcitabine sensitivity. In conclusion, this study shows that targeting Bcl-xl can overcome chemoresistance to gemcitabine in CCA organoids. CCAOs and BRCCAOs provide good preclinical models for testing new drug combinations and assessing personalized therapeutic approaches.

Liquid biopsy has gained attention in oncology as a non-invasive diagnostic tool, offering valuable insights into tumor biology through the analysis of circulating nucleic acid (cfDNA and cfRNA), circulating tumor cells (CTCs), extracellular vesicles (EVs), and tumor-educated platelets (TEPs). In this review, we summarize the clinical use of liquid biopsies in cancer now and look forward to its future, with a particular emphasis on some the methods used to isolate the liquid biopsy analytes. This technique provides real-time information on tumor dynamics, treatment response, and disease progression, with the potential for early diagnosis and personalized treatment. Despite its advantages, liquid biopsy faces several challenges, particularly in detecting analytes in early-stage cancers and evaluating the tumor molecular fraction. Tumor burden, molecular fraction, and the presence of subclones can impact the sensitivity and specificity of the analysis. Recent advancements in artificial intelligence (AI) have enhanced the diagnostic accuracy of liquid biopsy by integrating data, and multimodal approaches that combine multiple biomarkers such as ctDNA, CTCs, EVs, and TEPs show promise in providing a more comprehensive view of tumor characteristics. Liquid biopsy has the potential to revolutionize cancer care by providing rapid, non-invasive, and cost-effective diagnostics, enabling timely interventions and personalized treatment strategies.

Targeting Hsp90 is an effective strategy for cancer therapy. TAS-116 has been approved for the treatment of gastrointestinal stromal tumors. Our previous studies identified a series of pyrazole derivatives as covalent Hsp90 inhibitors that allosterically disrupt the Hsp90-Cdc37 interaction. Here, through systematic structure-activity relationship (SAR) optimization, compound 39 (DDO-6691) with a new covalent warhead was developed, which demonstrates improved ADME properties and significantly enhanced antitumor activity. Notably, parental HCT-116 cells exhibited markedly greater sensitivity to compound 39 (IC50 > 50 μM) compared to their Cdc37-knockout counterparts. Importantly, compound 39 displayed potent tumor growth inhibition in HCT-116 xenograft mouse models. These collective findings underscore the therapeutic promise of covalent Hsp90-targeted disruption of the Hsp90-Cdc37 complex, offering a novel mechanistic approach to cancer treatment.

Cancer is a major burden of disease around the globe and one of the leading causes of premature death. The key to improve patient outcomes in modern clinical cancer research is to gain insights into dynamics underlying cancer evolution in order to facilitate the search for effective therapies. However, most cancer data analysis tools are designed for controlled trials and cannot leverage routine clinical data, which are available in far greater quantities. In addition, many cancer models focus on single disease processes in isolation, disregarding interaction. This work proposes a unified stochastic modelling framework for cancer progression that combines (stochastic) processes for tumour growth, metastatic seeding, and patient survival to provide a comprehensive understanding of cancer progression. In addition, our models aim to use non-equidistantly sampled data collected in clinical routine to analyse the whole patient trajectory over the course of the disease. The model formulation features closed-form expressions of the likelihood functions for parameter inference from clinical data. The efficacy of our model approach is demonstrated through a simulation study involving four exemplary models, which utilise both analytic and numerical likelihoods. The results of the simulation studies demonstrate the accuracy and computational efficiency of the analytic likelihood formulations. We found that estimation can retrieve the correct model parameters and reveal the underlying data dynamics, and that this modelling framework is flexible in choosing the precise parameterisation. This work can serve as a foundation for the development of combined stochastic models for guiding personalized therapies in oncology.

One of the most common sites of cancer metastasis is to the bone. Bone metastasis is associated with substantial morbidity and mortality, and current therapeutic interventions remain largely palliative. Metastasizing tumor cells need to reprogram their metabolic states to adapt to the nutrient environment of distant organs; however, the role and translational relevance of lipid metabolism in bone metastasis remain unclear. Here, we used an in vivo CRISPR activation screening system coupled with positive selection to identify acyl-coenzyme A (CoA) binding protein (ACBP) as a bone metastasis driver. In nonmetastatic and weakly metastatic cancer cells, overexpression of wild-type ACBP, but not the acyl-CoA-binding deficient mutant, stimulated fatty acid oxidation (FAO) and bone metastasis. Conversely, knockout of ACBP in highly bone metastatic cancer cells abrogated metastatic bone colonization. Mechanistically, ACBP-mediated FAO increased ATP and NADPH production, reduced reactive oxygen species, and inhibited lipid peroxidation and ferroptosis. We found that ACBP expression correlated with metabolic signaling, bone metastatic ability, and poor clinical outcomes. In mouse models, pharmacological blockade of FAO or treatment with a ferroptosis inducer inhibited bone metastasis. Together, our findings reveal the role of lipid metabolism in tumor cells adapting and thriving in the bone and identify ACBP as a key regulator of this process. Agents that target FAO or induce ferroptosis represent a promising therapeutic approach for treating bone metastases.

Cellular metabolism has a key role in the pathogenesis of human disease. Mitochondria are the organelles that generate most of the energy needed for a cell to function and drive cellular metabolism. Understanding the link between metabolic and mitochondrial function can be challenging due to the variation in methods used to measure mitochondrial function and heterogeneity in mitochondria, cells, tissues, and end organs. Mitochondrial dysfunction can be determined at both the cellular and tissue levels using several methods, such as assessment of cellular bioenergetics, levels of mitochondrial DNA (mtDNA), mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mito-ROS), and levels of mitochondrial enzymes. Recent advances involving novel radiotracers in combination with PET imaging have allowed for the determination of mitochondrial function in vivo with high specificity. Understanding the barriers in existing methodologies used to study mitochondrial function may help further establish the assessment of mitochondrial function as a biologically and clinically relevant biomarker for human disease severity and prognosis. Herein, we critically review the existing literature regarding the strengths and limitations of methods that determine mitochondrial function, and we subsequently discuss how emerging research methods have begun to overcome some of these hurdles. We conclude that a combination of techniques, including respirometry and mitochondrial membrane potential assessment, is necessary to understand the complexity and biological and clinical relevance of mitochondrial function in human disease.

Drug delivery to solid tumors is challenged by multiple physiological barriers arising from the tumor microenvironment, including dense extracellular matrix, cellular heterogeneity, hypoxic gradients, and elevated interstitial fluid pressure. These features hinder the uniform distribution and accumulation of therapeutics, reducing treatment efficacy. Despite their widespread use, conventional two-dimensional monolayer cultures fail to reproduce these complexities, contributing to the poor translational predictability of many preclinical candidates. Three-dimensional multicellular tumor spheroids have emerged as more representative in vitro models that capture essential features of tumor architecture, stromal interactions, and microenvironmental resistance mechanisms. Spheroids exhibit spatially organized regions of proliferation, quiescence, and hypoxia, and can incorporate non-tumor cells to mimic tumor-stroma crosstalk. Advances in spheroid analysis now enable detailed evaluation of drug penetration, cellular migration, cytotoxic response, and molecular gradients using techniques such as optical and confocal imaging, large-particle flow cytometry, biochemical viability assays, and microfluidic integration. By combining physiological relevance with analytical accessibility, spheroid models support mechanistic studies of drug transport and efficacy under tumor-like conditions. Their adoption into routine preclinical workflows has the potential to improve translational accuracy while reducing reliance on animal models.

Tumor invasion that marks the transition from localized growth to aggressive spread is critical in cancer biology. It involves the breakdown of surrounding tissues through matrix degradation enzymes, such as urokinase plasminogen activator and matrix metalloproteinases, to promote cancer cells migration. Understanding invasion pathways is crucial for developing effective therapies and improving patient outcomes. There is a significant progress in cancer treatments; however, the treatments such as radiotherapy and chemotherapy are ineffective many times in the sense that some cancer cells survive, leading to tumor recurrence. It has been observed that dead cells play a key role in cancer recurrence. The dead cells, particularly due to treatments like radiation or chemotherapy, release signals and cellular components, including nucleotides like inosine, cytokines, and growth factors. These factors influence the tumor microenvironment and promote the survival and proliferation of nearby cancer cells. In this article, a novel mathematical model is proposed to investigate the effects of inosine on tumor recurrence and invasion. The simulated results are in very good agreement with the experimental and numerical results of the literature. The model simulated the inosine generation after some time of radiotherapy treatment withdrawal, and it achieves a log-normal profile. In line of experimental observations, it is obtained that the cancer cells proliferate with usual proliferation but once inosine gets generated from the dead cells, the proliferation intensity of cancer cells is enhanced significantly.

Several classifications have been proposed to define rare cancers; however, the pathophysiological understanding of tumors evolves rapidly. We propose a New Classification of Rare Cancer (NCRC) using the updated International Classification of Diseases for Oncology 3.2 coding system and World Health Organization Classification of Tumors 5th edition. We applied patient data recorded in the National Cancer Registry of Japan to the new classification, setting a cut-off of a crude incidence rate of 6 cases/100 000/year to define rare cancers, and developed a list of rare cancers in Japan from 2016 to 2019. The NCRC system identified various rare cancers, comprising 20.0% of all cancer diagnoses in this period. To examine this classification system's performance, we compared rare/non-rare labeling of cancers by the Surveillance of Rare Cancers in Europe (RARECARENet) project and NCRC system. Compared with cases using the RARECARENet classification in Europe, 69 351 cases/year (6.8%) switched status with our classification, with 45 293 and 232 109 cases (4 years) switching from rare and non-rare, respectively. Major differences included diffuse large B-cell lymphomas, some thyroid cancers, oral cavity and lip cancers, and squamous cell carcinoma of the uterine cervix. As the NCRC includes newly classified tumor entities, it warrants validation using other diverse cohorts.

One of the key challenges in defeating advanced tumors is the ability of cancer cells to evade the selective pressure imposed by chemotherapy, targeted therapies, immunotherapy and cellular therapies. Both genetic and epigenetic alterations contribute to the development of resistance, allowing cancer cells to survive initially effective treatments. In this narration, we explore how genetic and epigenetic regulatory mechanisms influence the state of tumor cells and their responsiveness to different therapeutic strategies. We further propose that an altered balance between cell growth and cell death is a fundamental driver of drug resistance. Cell death programs exist in various forms, shaped by cell type, triggering factors, and microenvironmental conditions. These processes are governed by temporal and spatial constraints and appear to be more heterogeneous than previously understood. To capture the intricate interplay between death-inducing signals and survival mechanisms, we introduce the concept of Death-ision. This framework highlights the dynamic nature of cell death regulation, determining whether specific cancer cell clones evade or succumb to therapy. Building on this understanding offers promising strategies to counteract resistant clones and enhance therapeutic efficacy. For instance, combining DNMT inhibitors with immune checkpoint blockade may counteract YAP1-driven resistance or the use of transcriptional CDK inhibitors could prevent or overcome chemotherapy resistance. Death-ision aims to provide a deeper understanding of the diversity and evolution of cell death programs, not only at diagnosis but also throughout disease progression and treatment adaptation.

Melanoma is a malignant tumor that originates from activated or genetically altered epidermal melanocytes, resulting from the interplay of genetic, somatic, and environmental factors. It is the fastest-growing malignancy among the Caucasian population and has a high mortality rate, second only to lung cancer. Current mainstream treatments have led to unavoidable drug resistance and toxic side effects despite improvements in efficacy and prognosis. Traditional Chinese Medicine is a significant component of complementary and alternative medicine, playing a vital role in cancer treatment. Natural compounds derived from Chinese herbal medicines offer notable advantages owing to their multimolecular, multitarget, and multipathway characteristics. These compounds exert anti-melanoma effects through various mechanisms, including antiproliferation, promotion of apoptosis, inhibition of metastasis, suppression of angiogenesis, modulation of autophagy, and enhancement of the immune response. Furthermore, combining natural compounds with mainstream antagonistic medicine not only enhances treatment efficacy but also significantly reverses multidrug resistance. This article discusses the specific mechanisms by which natural compounds combat melanoma and reviews the recent research advancements in this field. It also addresses the challenges faced in the widespread clinical application of these natural compounds in melanoma treatment and outlines the future directions for their development.

SCEL serves as a precursor protein for the cornified envelope (CE), and its abnormal expression has been identified in various malignancies. Despite this, the functional role and detailed mechanisms of SCEL in oral squamous cell carcinoma (OSCC) remain to be clarified.

mRNA and protein expression of SCEL in OSCC cell lines and patient tissues were examined by qRT-PCR and IHC. In vitro and in vivo experiments assessed SCEL's influence on proliferation, apoptosis, cell cycle, ROS production, migration, and invasion. Western blotting was used to analyze SCEL's effect on various signaling pathways, and a dual-luciferase reporter assay identified the miRNA that targets SCEL.

SCEL is downregulated in OSCC, which correlates with reduced tumor cell differentiation and lymph node metastasis. SCEL inhibits OSCC proliferation, induces cell cycle arrest, apoptosis, and ROS production. SCEL suppresses the TGF-β/Smad pathway, inhibiting migration and invasion. SCEL also triggers MET and downregulates VEGFC, reducing lymph node metastasis probability. miR-5696 inhibitor effectively inhibits OSCC proliferation and invasion by targeting SCEL.

SCEL acts as a tumor suppressor in OSCC, influencing its progression and potential metastasis. Loss of SCEL facilitates OSCC progression by activating TGF-β/Smad signaling. Upregulating SCEL and silencing miR-5696 hold therapeutic promise for OSCC.

Cancer is a leading cause of death worldwide, resulting in substantial economic costs. Because cancer is a complex, heterogeneous group of diseases affecting a variety of cells, its detection may sometimes be difficult. Herein we review a large group of the gastrointestinal cancers (oral, esophageal, stomach, pancreatic, liver, and bowel cancers) and the possibility of using glycans conjugated to protein backbones for less-invasive diagnoses than the commonly used endoscopic approaches. The reality of bacterial N-glycosylation and the effect of epithelial mucosa on gut microbiota are discussed. Current advantages, barriers, and advantages in the prospective use of selected glycomic approaches in clinical practice are also detailed.

The integrated stress response (ISR) is a key regulator of cell survival, promoting apoptosis through the effector protein CHOP in instances of prolonged or severe stress. The ISR's role in the initiation and progression of epithelial malignancies has been investigated; however, the ISR has not been evaluated in ocular adnexal sebaceous carcinoma (SebCA). Though uncommon, mortality rates of up to 40% have been reported, and the mechanisms underlying SebCA tumorigenesis remain unresolved; however, c-MYC upregulation has been documented. Our objective was to determine the role of MYC in modulating the ISR in the Meibomian gland. Human Meibomian gland epithelial cells (HMGECs) were subject to both pharmacologic and genetic manipulations of MYC expression. Cytotoxicity, proliferation, and changes in protein and gene expression were assessed. Conditionally MYC-overexpressing mice were subject to topical 4-hydroxytamoxifen (4-OHT) induction of the eyelids prior to tissue harvest for histology, immunohistochemistry, immunoblotting, and qPCR. MYC-inhibited HMGECs exhibited dose-dependent decreased proliferation, increased CHOP expression, and increased apoptosis. Conversely, MYC-overexpressing HMGECs and Meibomian glands from 4-OHT-induced mice demonstrated suppressed CHOP expression, reduced apoptosis, and upregulated fatty acid synthase expression. These results suggest that MYC inhibition induces the ISR and promotes apoptosis, while MYC induction suppresses CHOP expression. High MYC expression may, therefore, serve as a mechanism for SebCA to elude cell death by promoting lipogenesis.