Tumor-promoting inflammation significantly impacts cancer progression, and targeting inflammatory cytokines has emerged as a promising therapeutic approach in clinical trials. Interleukin (IL)-1α, a member of the IL-1 cytokine family, plays a crucial role in both inflammation and carcinogenesis. How IL-1α is secreted in the tumor microenvironment has been poorly understood, and we previously showed that calpain 1 cleaves pro-IL-1α for mature IL-1α secretion, which exacerbates hepatocellular carcinoma by recruiting myeloid-derived suppressor cells. In this study, we report that calpain 2 also modulates IL-1α secretion. Notably, a deficiency in calpain 2 resulted in enhanced hepatocellular carcinoma development within an IL-1α-enriched tumor microenvironment. Further investigations revealed that calpain 2 deficiency increased calpain 1 expression, implying a compensatory mechanism between the two calpains. Mechanistically, calpain 2 deficiency led to increased expression of FoxO3, which is a forkhead transcription factor that promotes calpain 1 expression. Collectively, these results suggest that calpain 2 modulates calpain 1 expression, and therefore IL-1α secretion through the induction of FoxO3, offering novel potential therapeutic targets for cancer treatment.

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.

Cancer, influenced by genetics and the environment, involves anoikis, a cell death mechanism upon extracellular matrix detachment crucial for metastasis. Understanding this relationship is key for therapy. We analyze cancer and anoikis trends using bibliometrics.

A search was conducted from Web of Science Core, PubMed, Scopus and non-English databases such as the CNKI (inception- 21 December 2024). Data analysis employed Microsoft Excel, VOSviewer, CiteSpace, R software, and the online platform (https://bibliometric.com/).

2510 publications were retrieved, with a significant increase in the last decade. China led, the University of Texas system was productive, and the Oncogene Journal was popular. Breast, and colorectal cancers were frequently studied. Among them, representative tumor-related mechanisms were identified, commonalities such as (EMT, ECM, autophagy) and respective specific mechanisms were summarized.

This bibliometric analysis highlights rapid advances in anoikis research in cancer, emphasizing EMT and FAK pathways' translational potential, guiding targeted therapies, and improving cancer treatment outcomes.

Cancer is a long-term illness that involves an imbalance in cellular and immune functions. It can be caused by a range of factors, including exposure to environmental carcinogens, poor diet, infections, and genetic alterations. Maintaining a healthy gut microbiome is crucial for overall health, and short-chain fatty acids (SCFAs) produced by gut microbiota play a vital role in this process. Recent research has established that alterations in the gut microbiome led to decreased production of SCFA's in lumen of the colon, which associated with changes in the intestinal epithelial barrier function, and immunity, are closely linked to colorectal cancer (CRC) development and its progression. SCFAs influence cancer progression by modifying epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNA functions thereby affecting tumor initiation and metastasis. This suggests that restoring SCFA levels in colon through microbiota modulation could serve as an innovative strategy for CRC prevention and treatment. This review highlights the critical relationship between gut microbiota and CRC, emphasizing the potential of targeting SCFAs to enhance gut health and reduce CRC risk.

This study describes the development of a pyruvate kinase (PyK)-biosensor for the evaluation of PyK activity, as a diagnostic tool for early cancer screening and detection of kinase inhibitors used in cancer treatment, with the evaluation of the inhibition mechanism. The biosensor was constructed by co-immobilizing the enzymes PyK and pyruvate oxidase (PyOx) on Au film electrodes by crosslinking with glutaraldehyde (GA) and evaluated electrochemically by cyclic voltammetry (CV) and fixed potential amperometry (CA). First, the experimental conditions were optimized in terms of applied potential, enzyme ratio PyK:PyOx and enzyme substrate concentration: phosphoenolpyruvate (PEP) and adenosine diphosphate (ADP). The biosensor sensitivity towards PEP detection was 2.11 ± 0.08 μA mM-1 cm-2, with very high reproducibility and repeatability, which made it suitable for inhibition studies of PyK inhibitor. The inhibition mechanism of shikonin was determined in relation to both PEP and ADP, with the calculation of IC50 values and binding constants (Ki). Detection of shikonin was possible at very low concentrations in the linear range of 0.1-4.0 pM. The electrochemical results were validated by UV-Vis spectrophotometry. The developed biosensor is a valuable tool for drug screening by enabling enzyme catalytic function examination with applicability to identify inhibitors, estimate their affinity, inhibition mechanism linked to their molecular mechanisms of action and evaluate selectivity, of great interest in both pharmaceutical and medical domains.

Tumor cellular senescence, characterized by reversible cell cycle arrest following anti-cancer therapies, presents a complex paradigm in oncology. Given that senescent tumor cells may promote angiogenesis, tumorigenesis, and metastasis, selective killing senescent cells (SCs)-a strategy termed senotherapy-has emerged as a promising approach to improve cancer treatment. However, the clinical implementation of senotherapy faces significant hurdles, including lack of precise methods for SCs identification and the potential for adverse effects associated with highly cytotoxic senolytic agents. In this account, we elucidate recent advancement in developing novel approaches for the detection and selective elimination of SCs, encompassing prodrugs, nanoparticles, and other cutting-edge drug delivery systems such as PROTAC technology and CAR T cell therapy. Furthermore, we explore the paradoxical nature of SCs, which can induce growth arrest in adjacent neoplastic cells and recruit immunomodulatory cells that contribute to tumor suppression. Therefore, we utilize SCs membrane as vehicles to elicit antitumor immunity and potentially augment existing anti-cancer therapies. Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of SCs detection, elimination or utilization.

Non-small cell lung cancer (NSCLC) has shown limited response to immunotherapy, primarily due to an immunosuppressive tumor microenvironment characterized by hypoxia and lipid raft formation, which together inhibit T-cell infiltration and function, impeding effective immune responses. To address these challenges, we developed Abstatin, an albumin-bound fluvastatin formulation that targets lipid raft disruption and mitochondrial respiration inhibition, aiming to reduce hypoxia and destabilize lipid rafts to enhance T-cell activity within the tumor. Using bioinformatics analysis, in vitro assays, and in vivo studies in both murine and humanized PDX models, we demonstrated that Abstatin reprograms the NSCLC microenvironment by concurrently lowering hypoxia levels and lipid raft integrity, thereby restoring T-cell infiltration, enhancing cytotoxic T-cell function, and ultimately improving response to Anti-PD-1 therapy. Results showed that Abstatin significantly amplifies Anti-PD-1 efficacy with minimal toxicity, indicating a favorable safety profile for clinical use. This study highlights Abstatin as a promising immunotherapy adjuvant that addresses critical barriers in NSCLC by modulating metabolic pathways linked to immune resistance. Abstatin's approach, which combines modulation of cellular metabolism with immune sensitization, broadens the potential of immunotherapy and provides a practical, scalable strategy to enhance treatment outcomes in NSCLC and potentially other tumors, offering insights into combinatory cancer therapies.

Ovarian cancer is a critical health issue for women nowadays. Its impact is significant because of its high mortality rate (324,603 worldwide), late-stage diagnosis and poor survival rate. Lack of screening tests, vague symptoms, misdiagnosis, and age factor makes it even more difficult to detect. Neutrophils, a subset of immune cells, undergo tumor-specific changes as ovarian cancer progresses inside ovarian tumour microenvironment. Therefore, monitoring the time-specific activity of neutrophils in circulation has the potential to aid in the diagnosis of ovarian cancer. Most ovarian tumor-specific antigens are unknown, making it difficult to identify neutrophils associated with ovarian tumor. We present ovarian tumor-associated circulating neutrophil cell profiling as a stand-alone cancer diagnostic method using a liquid biopsy. Using a SERS-functionalized nano probe, the metabolic profiles of neutrophils from ovarian tumor interaction are detected. We demonstrate that neutrophils associated with cancer stem cells have a distinct metabolic profile and are useful in the diagnosis of early ovarian cancer. Using 5 μL of peripheral blood and an artificial neural network, the characteristics of neutrophil profiles in patient blood could distinguish cancer cohort from non-cancer (healthy) with a 90 % sensitivity and 100 % specificity. Our results demonstrate the viability of using circulating neutrophils for non-invasive cancer diagnostics.

Medical gases were primarily used for respiratory therapy and anesthesia, which showed promising potential in the cancer therapy. Several physiological and pathological processes were affected by the key gases, such as oxygen, carbon dioxide, nitric oxide, hydrogen sulfide, and carbon monoxide. Oxygen targets shrinking the tumor via hyperbaric oxygen therapy, and once combined with radiation therapy it enhances its effect. Nitric oxide has both anti- and pro-tumor effects depending on its level; at high doses, it triggers cell death while at low doses it supports cancer growth. The same concept is applied to hydrogen sulfide which promotes cancer growth by enhancing mitochondrial bioenergetics and supporting angiogenesis at low concentrations, while at high concentrations it induces cancer cell death while sparing normal cells. Furthermore, carbon dioxide helps induce apoptosis and improve oxygenation for cancer treatments by increasing the release of oxygen from hemoglobin. Moreover, high-dose carbon monoxide gas therapy has demonstrated significant tumor reductions in vivo and is supported by nanomedicine and specialized medicines to boost its delivery to tumor cells and the availability of hydrogen peroxide. Despite the promising potentials of these gases, several challenges remain. Gas concentrations should be regulated to balance pro-tumor and anti-tumor effects for gases such as nitric oxide and hydrogen sulfide. Furthermore, effective delivery systems, such as nanoparticles, should be developed for targeted therapy.

Cancer affects millions of people, and early detection and efficient treatment are two strong levers to hurdle this disease. Recent studies on exosomes, a subset of extracellular vesicles, have deliberately shown the potential to function as a biomarker or treatment tool, thereby attracting the attention of researchers who work on developing biosensors. Due to the ability of computational methods to predict of the behavior of biomolecules, the combination of experimental and computational methods would enhance the analytical performance of the biosensor, including sensitivity, accuracy, and specificity, even detecting such vesicles from bodily fluids. In this regard, the role of computational methods such as molecular docking, molecular dynamics simulation, and density functional theory is overviewed in the development of biosensors. This review highlights the investigations and studies that have been reported using these methods to design exosome-based biosensors. This review concludes with the role of the quantum mechanics/molecular mechanics method in the investigation of chemical processes of biomolecular systems and the deficiencies in using this approach to develop exosome-based biosensors. In addition, the artificial intelligence theory is explained briefly to show its importance in the study of these biosensors.

Targeting protein for Xklp2 (TPX2) is critical for mitosis and spindle assembly because of its control of Aurora kinase A (AURKA). However, the regulation of TPX2 activity and its subsequent effects on mitosis and cancer progression remain unclear. Here, we show that TPX2 is lactylated at K249 in hepatocellular carcinoma (HCC) tumour tissues and that this process is regulated by the lactylase CBP and the delactylase HDAC1. Lactate reduction via either shRNAs targeting lactate dehydrogenase A or the lactate dehydrogenase A inhibitor GSK2837808A decreases the level of TPX2 lactylation. Importantly, TPX2 lactylation is required for the cell cycle regulation and tumour growth. Mechanistically, TPX2 lactylation disrupts protein phosphatase 1 (PP1) binding to AURKA, enhances AURKA T288 phosphorylation, and facilitates the cell cycle progression. Overall, our study reveals a previously unappreciated role of TPX2 lactylation in regulating cell cycle progression and HCC tumorigenesis, exposing an important correlation between metabolic reprogramming and cell cycle regulation in HCC.

Lipid metabolism has been increasingly recognized to play an influencing role in tumor initiation, progression, metastasis, and therapeutic drug resistance. Targeting lipid metabolic reprogramming represents a promising therapeutic strategy. Despite their structural complexity and poor targeting efficacy, lipid-metabolizing drugs, either used alone or in combination with chemotherapeutic agents, have been employed in clinical practice. The advent of nanotechnology offers new approaches to enhancing therapeutic effects, includingthe targeted delivery and integration of lipid metabolic reprogramming with chemotherapy, photodynamic therapy (PDT), and immunotherapy. The integrated nanoformulation, nanomedicine, could significantly advance the field of lipid metabolism therapy. In this review, we will briefly introduce the concept of cancer lipid metabolism reprogramming, then elaborate the latest advances in engineered nanomedicine for targeting lipid metabolism during cancer treatment, and finally provide our insights into future perspectives of nanomedicine for interference with lipid metabolism in the tumor microenvironment.

Tristetraprolin (TTP) can inhibit the abnormal proliferation of malignant tumors but there are no studies involving TTP and esophageal squamous cell carcinoma (ESCC). We aimed to determine the effect of TTP on ESCC cell proliferation and to elucidate the underlying mechanism.

The human ESCC cell line, KYSE-510, and the human ESCC cell line, KYSE-150, stably infected with tetracycline-inducible expression (Tet-on-TTP and Tet-on-EV, respectively) were screened with puromycin. After Tet-on-TTP KYSE-150 cells were treated with different concentrations of doxycycline [Dox] (0, 0.5, and 1 ug/mL), the levels of TTP mRNA and protein expression were detected by real-time fluorescent quantitative PCR and western blotting, respectively. The effects of TTP on proliferation and migration were estimated by CCK-8 and Transwell assays, respectively. Cell apoptosis and cell cycle were measured by flow cytometry. Cellular apoptosis-related gene protein expression was determined by western blotting.

TTP overexpression significantly inhibited KYSE-510 and KYSE-150 proliferation. TTP overexpression also significantly inhibited KYSE-150 migration. In addition, TTP expression upregulation promoted the KYSE-150 apoptosis and induced cell cycle arrest in the G2 phase, downregulated Bcl-2 expression, and upregulated Bax expression.

TTP inhibited ESCC cell proliferation, promoted ESCC cell apoptosis, and arrested cell cycle progression in the G2 phase.

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.

The chemotherapeutic drug doxorubicin (DOX) has been widely used for treating solid tumors attributed to its antiproliferative effectiveness; however, its clinical use is limited due to side effects, including cardiotoxicity, myelosuppression, and drug resistance. Combining DOX with buthionine sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, showed promising results in overcoming these adverse effects, potentially reducing the required DOX dose while maintaining efficacy. The aim of the present study was to examine the effects of different concentrations of BSO and DOX, both individually and in combination, utilizing B16/F10 (murine melanoma), SNB-19 (human glioblastoma), S180 (murine sarcoma), and SVEC4-10 (murine endothelial) cell lines. Cell viability, migration, and clonogenicity were assessed using the following assays MTT, scratch, and colony formation. Antioxidant levels of GSH, as well as activities catalase (CAT), and superoxide dismutase (SOD) were measured. BSO alone exhibited minimal cytotoxic effects, while DOX alone reduced cell viability significantly. The combination of BSO+DOX decreased IC50 values for most cell lines, demonstrating a synergistic effect, especially in B16/F10, S180, and SVEC4-10 cells. BSO+DOX combination significantly inhibited cell migration and clonogenicity compared to DOX alone. While GSH levels were decreased with BSO+DOX treatment activities of CAT and SOD increased following DOX administration but remained unchanged by BSO. These results suggest that BSO may be considered a valuable tool to improve DOX therapeutic efficacy, particularly in cases of chemotherapy-resistant tumors, as BSO enhances DOX activity while potentially reducing systemic chemotherapeutic drug toxicity.

Human papillomavirus (HPV)-associated high-grade vulvar intraepithelial lesion (HSIL) is a precursor of vulvar squamous cell carcinoma (VSCC). Because of the 8% cancer risk, many vulvar HSIL patients undergo aggressive and mutilating treatments. Characterizing HSIL by their progression risk can help individualize treatment strategies. Accordingly, copy number alterations (CNAs) and DNA methylation have been identified as biomarkers for cancer risk stratification of HSIL. Here, we assessed their potential correlation, and relation to HPV16 (sub)lineages and progression to vulvar cancer. Eighty-two vulvar formalin-fixed paraffin-embedded (FFPE) samples, including controls, HSIL, HSIL adjacent to VSCC and VSCC, with previously determined DNA methylation profiles, were analysed for CNAs using mFAST-SeqS. Genome-wide z-scores were calculated to determine overall aneuploidy (aneuploidy scores), and compared to the methylation levels and status of marker panel ZNF582/SST/miR124-2. For 52 HPV16-positive cases, HPV (sub)lineages were determined by Sanger sequencing. HPV16 lineage A was predominant (86.4%), followed equally by lineages B, C, and D. Frequent chromosomal alterations included chr1pq, chr3q, chr9q gains, and chr2q, chr4q losses. Median aneuploidy scores increased across disease categories, from 0 in controls, to 3 in HSIL, 16 in HSIL adjacent to VSCC and 29 in VSCC. A positive relationship between aneuploidy scores and DNA methylation levels was found (ρ = 0.61, Spearman's rank correlation test). Aneuploidy scores were significantly higher in methylation-positive samples (p < .001). In conclusion, we showed that DNA methylation and CNAs both rise with increasing severity of disease, indicating their prognostic value for cancer risk stratification of HSIL, while no relation to HPV16 (sub)lineages was found.

Platelets, traditionally regarded as passive mediators of hemostasis, are now recognized as pivotal regulators in the tumor microenvironment, establishing metabolic feedback loops with tumor and immune cells. Tumor-derived signals trigger platelet activation, which induces rapid metabolic reprogramming, particularly glycolysis, to support activation-dependent functions such as granule secretion, morphological changes, and aggregation. Beyond self-regulation, platelets influence the metabolic processes of adjacent cells. Through direct mitochondrial transfer, platelets reprogram tumor and immune cells, promoting oxidative phosphorylation. Additionally, platelet-derived cytokines, granules, and extracellular vesicles drive metabolic alterations in immune cells, fostering suppressive phenotypes that facilitate tumor progression. This review examines three critical aspects: (1) the distinctive metabolic features of platelets, particularly under tumor-induced activation; (2) the metabolic crosstalk between activated platelets and other cellular components; and (3) the therapeutic potential of targeting platelet metabolism to disrupt tumor-promoting networks. By elucidating platelet metabolism, this review highlights its essential role in tumor biology and its therapeutic implications.

The distinctive desmoplastic tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is crucial in determining the stemness of tumor cells. And the conventional two-dimensional (2D) culture does not adequately mimic the TME. Therefore, a three-dimensional (3D) PDAC desmoplastic model was constructed using GelMA and HAMA, which provides benefits in terms of simulating both the main components (COL and HA) and the crosslinking of the extracellular matrix. We found that the 3D PDAC desmoplastic model upregulated the expression of the markers for stemness (NANOG and OCT4) and glycolysis (HK2 and GLUT2), and elevated the level of glycolysis, including increased glucose consumption and lactic acid production. Additionally, YAP1 played a crucial role in promoting glycolysis, which boosted stemness. Furthermore, RNA sequencing (RNA-seq) was employed to explore the underlying mechanisms associated with stemness within the 3D desmoplastic model. Subsequent KEGG pathway analysis indicated the activation of the PI3K-AKT signaling pathway, providing insights into the molecular processes at play. Using bioinformatics, qRT-PCR and western blot, we proposed that ITGAV-PI3K-AKT-YAP1 axis may account for the glycolysis mediated the stemness. Collectively, the 3D desmoplastic model may serve as a new platform for understanding the underlying mechanism by which the TME induces stemness.

As living standards elevate, cancers are appearing in growing numbers among younger individuals globally and these risks escalate with advancing years. One of the reasons is that instability in the cancer genome reduces the effectiveness of conventional drug treatments and chemotherapy, compared with more targeted therapies. Previous research has discovered non-coding RNAs' crucial role in shaping genetic networks involved in cancer cell growth and invasion through their influence on messenger RNA production or protein binding. Additionally, the interaction between non-coding RNAs and oxidative stress, a crucial process in cancer advancement, cannot be overlooked. Essentially, oxidative stress results from the negative effects of radicals within the body and ties directly to cancer gene expression and signaling. Therefore, this review focuses on the mechanism between non-coding RNAs and oxidative stress in cancer progression, which is conducive to finding new cancer treatment strategies.

Transcription factor E74 like ETS transcription factor 4 (ELF4), a member of the ETS family, is highly expressed in normal human hematopoietic tissue, ovary, placenta, colon, and certain pathological cell lines. During normal physiological processes, ELF4 regulates differentiation in osteogenic, adipocyte, and neuronal types. It also exerts a critical impact on the development of the immune system. However, its function is dysregulated through posttranslational modifications, gene fusions, and complex signaling crosstalk under pathological conditions. Furthermore, serving as a double-edged sword in cancer, ELF4 exhibits both tumor-suppressing and tumor-promoting effects. Specifically, ELF4 plays a critical role in cancer metastasis, proliferation, and modulation of the tumor microenvironment. This review provides an in-depth overview of the molecular structure and post-translational modifications of ELF4. It also summarizes the hallmarks of ELF4 in physiology and diseases, with a particular focus on its significance in oncology. Notably, this review underscores the potential of ELF4 as a prognostic biomarker, highlighting its clinical relevance. Finally, it discusses unresolved questions and future research directions of ELF4. An in-depth understanding of ELF4 biology could facilitate its clinical translation and offer promising targeted therapeutic strategies.

Cell dedifferentiation is considered an important hallmark of cancer. The atavistic reversal to a unicellular-like (UC) state is a less widely accepted concept, so far not included in the conventional hallmarks. The activated expression of ontogenetically earlier and evolutionary earlier genes in cancers supports both theories because ontogenesis partially recapitulates phylogenesis during cell differentiation (the cellular biogenetic law). We directly contested both types of gene signatures in stem vs. differentiated and cancer vs. normal cells, using meta-analysis of human single-cell transcriptomes (totally, 38 pairwise comparisons involving over 18,600 cells). Because compared cells can differ in proliferation rate, the correction for cell cycle activity was applied. Taken together as multiple variables in stem vs. differentiated cells analyses, the ontogenetic signature excluded the UC signature from predictive variables, usually even forcing it to change the sign of prediction (from plus to minus). In contrast, in cancer vs. normal cells, the UC signature excluded the ontogenetic signature. Thus, the direct contest decided in favor of the atavistic theory and placed a UC-like state as a central hallmark of cancer, which has a plausible evolutionarily formed mechanism (UC attractor) and can generate other hallmarks. These data suggest a paradigm shift in the understanding of oncogenesis and propose an integrative framework for cancer research. In a practical sense, the upregulation of UC signature over ontogenetic signature indicates potential tumorigenicity, which can be used in early diagnostics and regenerative medicine. For therapy, these results suggest the UC center of cellular networks as a universal target.

Polysaccharides from algae provide a range of biology and health benefits. Lately, there has been a significant interest in how algal polysaccharides affect the immune microenvironment around tumors.

To elucidate the subtle interactions between algal polysaccharides and the tumor immune microenvironment to further understand the medicinal potential of algal polysaccharides.

To give a summary of the sources, bioactivities and characteristics of the tumor immune microenvironment of algal polysaccharides, and to analyze alteration of the immunological milieu surrounding tumors by algal polysaccharides and their potential as immunomodulators of chemotherapeutic agents.

Search popular academic search engines using selected keywords for articles ending before September 2024 using selected keywords Google Scholar, PubMed, ScienceDirect, Scopus, Web of Science, Springer, and official websites.

Algal polysaccharides can fight tumors by changing how immune cells work and affecting inflammation in different ways. Moreover, algal polysaccharides have shown promise in mitigating the adverse effects associated with conventional cancer treatments, such as chemotherapy. Algal polysaccharides, through their immunomodulatory effects, can alleviate some of these side effects, leading to an enhanced overall treatment outcome.

As research continues to uncover the underlying mechanisms of their antitumor effects, algal polysaccharides are poised to become a vital component in the development of novel cancer treatments, providing new hope for patients and advancing the field of oncology.

Sialylation of terminal glycoconjugates is involved in many important physiological and pathological processes such as tumor metastasis, drug resistance, organismal immunity, and viral infections. Sialyltransferases are enzymes responsible for sialylation modification in organisms, and potent sialyltransferase inhibitors can not only serve as probes for glycobiology studies, but also hold great promise to become agents for tumor therapy and viral infection control in the clinic. This review summarizes the latest progress in the development and application of various sialyltransferase inhibitors. The current challenges and development trends are also discussed.

The issue of Cervical cancer has received considerable critical attention. It was the leading cause of death in female cancer patients. Ginsenoside Rg5 has been implicated in the growth of human cancer cells, but the lack of research to determine the influence mechanism has been a significant challenge for many years. In this study, ginsenoside Rg5 was used to treat HeLa cells, and RT-qPCR, Western Blotting and RNA-seq were used to analyze the differentially expressed genes in HeLa cells to study the preliminary mechanism of ginsenoside Rg5 on cervical cancer. The results of RT-qPCR and Western Blotting were in agreement with RNA-seq analysis, which showed a down-regulation of proteins in the cell cycle pathway. These results all indicate that the expression of Minichromosome Maintenance Complex Component 6 (MCM6), Cyclin A2 (CCNA2), Cyclin-dependent kinase 6 (CDK6) and Cell division cycle 6 (CDC6) in HeLa cells treated with ginsenoside Rg5 is significantly reduced, with MCM6 exhibiting the most significant inhibitory effect, making it a potential target for the treatment of cervical cancer.

Centrosome abnormalities are a distinguishing feature of cancer and play a role in the aging process. Cancer cells may evade the immune system by activating immune checkpoints, altering their surrounding microenvironment, abnormalities in antigen presentation and recognition, and metabolic reprogramming to inhibit T-cell activity, allowing cancer cells to survive and spread within the host. When the centrosomes are abnormally shaped or numbered, mitotic errors can occur, cellular senescence occurs, cell death occurs, genomic instability occurs, and aneuploidy forms, resulting in diseases such as cancer. The present study is exploring the strategy of research progress in which centrosome abnormalities contribute to the aging process in various different ways as well as fuel immune escape from cancer cells, providing a new direction for cancer immunotherapy.

This study aimed to check the biological functions and uncover the mechanism of armadillo repeat protein C10 (ARMC10) in glioblastoma (GBM). The expression and potential mechanisms of ARMC10 in GBM were analyzed by bioinformatics analysis. In GBM cells, function-loss experiments were used to evaluate the influences of ARMC10 on cell proliferation, cell invasion, lipid levels, and cell migration by colony formation assay, 5-ethynyl-2'-deoxyuridine staining, cell counting kit-8 assay, transwell assay, BODIPY staining, and wound healing assay. Mouse xenograft models were constructed to validate the influences of ARMC10 in vivo. ARMC10 levels in GBM were upregulated, and patients with low ARMC10 levels displayed a better prognosis. ARMC10 knockdown resulted in a decrease of GBM cell invasion, migration, and proliferation. GSEA showed that ARMC10 was positively associated with the Notch pathway and fatty acid metabolism. ARMC10 knockdown reduced the levels of triglyceride, cholesterol, and lipid, and inhibited the expression of proteins related to fatty acid metabolism and Notch pathway. Moreover, notch receptor 1 (Notch1) overexpression reversed the inhibition of cell proliferation, fatty acid metabolism, and invasion induced by ARMC10 knockdown. In vivo, ARMC10 knockdown suppressed tumor growth. RMC10 knockdown suppressed GBM malignant progression, which had a bearing on Notch pathway.

Metabolic shifts in cancer cells were found to participate in tumorigenesis, especially driving chemotherapeutic resistance. Ferroptosis is a newly discovered form of cell death induced by excessive accumulations of iron and lipid peroxidation. Susceptibility to ferroptosis can be intrinsically regulated by various cellular metabolic pathways. Therefore, inducing ferroptosis might be a promising anticancer therapeutic strategy. DEAD-box helicase 3 X-linked (DDX3X), a critical modulator of RNA metabolism, was identified as an oncogene in breast cancer and also participates in cancer metabolism and chemotherapeutic resistance. However, the molecular regulation of the association between DDX3X and ferroptosis is largely unknown. Herein, we investigated the correlation between resistance to ferroptosis and DDX3X expression in breast cancer cells. We found that elevation of DDX3X was associated with increased resistance to a ferroptosis inducer in breast cancer cells, and manipulating DDX3X expression regulated the sensitivity to the ferroptosis inducer. Importantly, DDX3X upregulated expression of the anti-ferroptotic enzyme glutathione peroxidase 4 (GPX4) gene to confer ferroptosis resistance in breast cancer cells. Moreover, DDX3X was transcriptionally upregulated by the yes-associated protein (YAP). Knockdown of YAP downregulated DDX3X mRNA expression and facilitated lipid peroxidation, but that were restored in the presence of DDX3X. Clinically, coexpression of DDX3X and YAP was found in a variety of malignancy, and their elevation conferred poor survival prognosis in patients with breast cancer. Together, our findings reveal the crucial role of DDX3X in sensitivity to ferroptosis and underscore its potential as a diagnostic marker and therapeutic target. DDX3X renders resistance to ferroptosis and plays a role in mitigating lipid peroxidation, paving the way for therapeutic vulnerability via targeting cancer metabolism.

Hypochlorous acid (HClO/ClO-) is a common ROS that exhibits elevated activity levels in cancer cells. In this study, an ClO--triggered TADF probe, PTZ-MNI, was designed based on a naphthalimide core. PTZ-MNI self-assemble in aqueous environments, exhibiting significantly enhanced fluorescence that demonstrated typical aggregation-induced delayed fluorescence (AIDF) characteristics. The probe not only showed high sensitivity to ClO- but also exhibited remarkable selectivity over other reactive oxygen species and disturbance. PTZ-MNI displayed TADF characteristic, including sensitivity to oxygen in toluene, insensitivity to oxygen in aggregated states that maintain long fluorescence lifetimes, a vertical conformation, and a minimal ΔEST of 0.01 eV. Cell imaging studies showed the probe could trace ClO- by red to green fluorescence in HeLa cell. The colocalization analysis indicated its excellent lysosome-targeting specificity. In addition, PTZ-MNI-O, the compound after oxidation, exhibited effective ROS generation ability and significant PDT effect after irradiation. This work provides guidance for the rational design of responsive TADF luminescent materials used in cell imaging and activatable-PDT.

Bi-magnolignan (BM), a novel compound isolated from Magnolia Officinalis leaves, exhibits significant anti-tumor activity in vitro. However, the underlying mechanism remains elusive. This study examines the anti-tumor properties of BM and its mechanism of action, specifically through its interaction with BRD4, a key regulator in oncogene transcription and genome stability. Molecular docking and biolayer interferometry assay (BLI) collectively demonstrate that BM exhibits strong binding affinity to the bromodomain (BD) region of BRD4. Cellular thermal shift assay (CETSA) results confirm that BM binding increases the thermostability of BRD4, providing further evidence of the interaction between BM and BRD4. RNA-seq analysis and western blotting reveal that BM abolishes the G2/M DNA damage checkpoint and disrupts homologous recombination (HR) repair mechanisms. To explore the downstream effects of BRD4, we performed gene set enrichment analysis (GSEA) using RNA-seq data. The results indicate that BM significantly inhibits BRD4 function, leading to the downregulation of various BRD4 target genes at the transcriptional level, including MYC. Importantly, overexpression of BRD4 rescues cells from BM-induced apoptosis, DNA damage, disrupted G2/M checkpoint, and HR deficiency (HRD), highlighting the specificity of BM for BRD4. Furthermore, in vivo experiments demonstrate that BM effectively suppresses tumor growth. Collectively, these findings underscore the potential of BM as a novel and potent BRD4 inhibitor, suggesting promising prospects for the development of targeted anti-tumor therapies that specifically inhibit BRD4.

Carbohydrate kinases serve an oncogenic role in several types of cancer; however, the function of FGGY carbohydrate kinase domain containing (FGGY) in colorectal cancer (CRC) remains unknown. The present study investigated the function and possible molecular mechanisms of FGGY in CRC. The results showed that elevated levels of FGGY mRNA and protein were observed in CRC tissues, and a higher expression of FGGY was associated with advanced N stage and reduced overall survival time in patients with CRC. Silencing FGGY inhibited the viability of CRC cells by inducing cell cycle arrest and promoting apoptosis in vitro, thereby attenuating tumor growth in a xenograft mouse model. FGGY knockdown also enriched the senescence‑associated heterochromatin foci (SAHF) pathway and p53 pathway, as further confirmed by enhancing senescence‑associated β‑galactosidase (SA‑β‑gal) activity, with increased levels of SAHF‑associated proteins HP1γ and trimethylation of H3K9 (H3k9me3) in CRC cells, as well as upregulation of p53 and its downstream protein p21. Furthermore, p53 knockout rescued FGGY knockdown‑mediated reductions in cell viability, SA‑β‑gal activity, and the levels of HP1γ and H3k9me3 in CRC cells. These findings indicated that FGGY could act as a newly identified potential oncogene in CRC, partially through regulating the p53/p21 signaling pathway and altering cell senescence.

This study aimed to determine the feasibility of preoperative multi-sequence magnetic resonance texture analysis (MRTA) for predicting TERT promoter mutation status in IDH-wildtype glioblastoma (IDHwt GB).

The clinical and imaging data of 111 patients with IDHwt GB at our hospital between November 2018 and June 2023 were retrospectively analyzed as the training set, and those of 23 patients with IDHwt GB between July 2023 and November 2023 were interpreted as the validation set. We used molecular sequencing results to classify the training set into TERT promoter mutation and wildtype groups. Textural features of the whole-tumor volume were extracted, including T2-weighted imaging (T2WI), T2-fluid-attenuated inversion recovery, apparent diffusion coefficient (ADC) map, and contrast-enhanced T1-weighted imaging (CE-T1). All textural features were obtained using open-source pyradiomics. After feature selection, logistic regression was used to build prediction models, and a nomogram was generated. Finally, the model was validated using validation cohort.

The CE-T1_Model (AUC 0.704) had a better predictive ability than the T2_Model (AUC 0.684) and ADC_Model (AUC 0.624). The MRI_Combined_Model (CE-T1, T2, and ADC texture features) (AUC 0.780) had a better predictive ability than the Clinical_Model (AUC 0.758). The Combined_Model (CE-T1, T2, ADC texture features, and clinical features) had the best predictive performance (AUC 0.871), with a sensitivity, specificity, and accuracy of 82.60 %, 83.30 %, and 80.18 %, respectively. The AUC, sensitivity, specificity, and accuracy in the validation cohort were 0.775, 86.70 %, 75.00 %, and 69.57 %, respectively.

Whole-tumor multi-sequence MRTA can be used as non-invasive quantitative parameters to assist in the preoperative clinical prediction of TERT promoter mutation status in IDHwt GB.

Breast cancer (BC) is the most common malignant tumor and the leading cause of cancer-related deaths among women worldwide. Great progress has been recently achieved in controlling breast cancer; however, mortality from breast cancer remains a substantial challenge, and new treatment mechanisms are being actively sought. Programmed cell death (PCD) is associated with the progression and treatment of many types of human cancers. PCD can be divided into multiple pathways including autophagy, apoptosis, mitotic catastrophe, necroptosis, ferroptosis, pyroptosis, and anoikis. Ubiquitination is a post-translational modification process in which ubiquitin, a 76-amino acid protein, is coupled to the lysine residues of other proteins. Ubiquitination is involved in many physiological events and promotes cancer development and progression. This review elaborates the role of ubiquitin-specific protease (USP) in programmed cell death, which is common in breast cancer cells, and lays the foundation for tumor diagnosis and targeted therapy.

Tumor inflammation, as one of the hallmarks of cancer, has been the target for anti-cancer treatments. Celecoxib is a selective inhibitor of the enzyme cycloxygenase-2 (COX-2) and inhibits the production of PGE2, which is an important mediator of tumor inflammation produced by cancer cells and cells of the tumor microenvironment. In this study, we aimed at inhibiting COX-2 using celecoxib, expressed in cancer-associated fibroblast (CAF)-like cells isolated from breast cancer and evaluated the alterations in their cytokine profile and gene expression. CAF-like cells were isolated by explant culture from 13 breast cancer tissues. Simultaneously, peripheral blood mononuclear cells (PBMCs) were isolated from patients' blood. CAF-like cells were treated with 10 µM of celecoxib and expression of genes COX-2, smooth muscle actin-alpha (α-SMA), and production of prostaglandin E2 (PGE2), Interleukin 10 (IL10), and transforming growth factor beta1 (TGF-β1) was evaluated. Next, PBMCs were co-cultured with celecoxib-treated CAF-like cells and the expression of genes T-bet, Foxp3, GATA-3; production of cytokines IFN-ɣ, IL-10, IL-4, TGF-β1, and the mediator PGE2 were assessed by real-time-PCR and ELISA, respectively. Isolated CAF-like cells showed expression of fibroblast activation protein (FAP). Treatment with celecoxib was able to efficiently reduce the production of PGE2 and the expression of α-SMA in isolated CAF-like cells. Furthermore, PBMCs in co-culture with these cells showed enhanced Th1 phenotype including T-bet and IFNγ expression and decreased the phenotypical markers of regulatory T cells such as FoxP3 and IL-10 and TGF-β1 production. Our study shows the important role of COX-2 in CAFs by promoting immune suppression. Our results suggested that high expression of COX-2 in CAFs may serve as a new therapeutic, targeting CAFs in enhancing immune responses in breast cancer treatment.

It is well known that activation of oncogenic K-ras alone is insufficient to drive tumor development and that additional factors are needed for full malignant transformation, but the metabolic pathways and regulatory mechanisms that facilitate K-ras-driven cancer development remain to be characterized. Here we show that SQLE, a key enzyme in cholesterol synthesis, is upregulated in K-ras-driven cancer and its high expression is correlated with poor clinical outcome. K-ras regulates SQLE expression in a biphasic manner through reactive oxygen species and MYC signaling. Surprisingly, the pro-oncogenic role of SQLE is not mediated by promoting cholesterol synthesis, but by metabolic removal of squalene and thus mitigating its suppressive effect on the PGC-1α-mediated mitochondrial biogenesis and metabolism. Genetic silencing of SQLE in pancreatic cancer cells causes an accumulation of cellular squalene, which binds to Sp1 protein and causes a formation of a tight Sp1-TFAP2E promoter DNA complex with a highly negative binding score. This aberrant squalene/Sp1/TFAP2E promoter complex hinders the expression of TFAP2E and its downstream molecule PGC-1α, leading to suppression of mitochondrial metabolism and an almost complete inhibition of tumor formation in vivo. Importantly, administration of pharmacological squalene to mice bearing pancreatic cancer xenografts could significantly inhibit tumor growth. Our study has revealed a previously unrecognized role of SQLE in regulating gene expression and mitochondrial metabolism to facilitate K-ras-driven cancer development, and identified SQLE as a novel therapeutic target for potential treatment of pancreatic cancer.

Genomic instability is an enabling characteristic that allows cancer cells to acquire additional hallmarks of cancer through the accumulation of alterations in driver genes. Furthermore, it creates opportunities to enhance the sensitivity of cancer cells to chemotherapeutic agents targeting DNA, owing to the presence of incomplete DNA damage repair pathways. This study identifies LIN28B as a crucial regulator of colon cancer cells' sensitivity to DNA damage- or repair-related compounds by promoting genomic instability. LIN28B mechanistically reduces glutathione (GSH) synthesis and activity by inhibiting the expression of four GSH metabolic enzymes (GCLC, G6PD, GSTM4, and GSTT2B), thereby reducing the capacity of cells to eliminate reactive oxygen species (ROS). LIN28B enhances the proinflammatory signaling pathway in cancer cells through the upregulation of ARID3A, a transcription factor that transactivates PTGES and PTGES2, resulting in increased production of PGE2, a key inflammatory mediator that can elevate ROS generation. In conclusion, LIN28B altered the equilibrium of ROS production and elimination in colon cancer, resulting in elevated ROS levels and subsequent genomic instability.

The nervous system plays an important role in regulating physiological functions of the stomach, and its abnormal activity often impairs gastric homeostasis. In response to constant exposure to oncogenic stimuli that leads to gastric tumorigenesis, the neural system becomes an essential component of the tumor microenvironment via perineural infiltration, de novo neurogenesis, and axonogenesis, thereby driving cancer initiation and progression. In this review, we highlight emerging discoveries related to neural-cancer crosstalk and discuss how the nervous system is remodeled by tumor cells including neural components and modulators (including neurotransmitters and neuropeptides). Moreover, we provide a systematic analysis of neural control of the cellular hallmarks of cancer. Finally, we propose how the molecular circuits of neural-cancer crosstalk could be exploited as potential targets for novel anti-cancer treatment, providing new insights into a new modality of neural-based cancer therapeutic strategies.

Pyruvate Dehydrogenase Kinase 1 (PDK1) regulates glycolysis and oxidative phosphorylation pathways and is linked to prostate cancer metastasis and poor prognosis. The therapeutic application of 2,2-dichloroacetophenone (DAP), a PDK1 inhibitor, remains underexplored in prostate cancer. In this study we demonstrated that DAP exhibited a superior ability to inhibit prostate cancer cell proliferation, migration and colony formation at a lower concentration (20 μM) compared to a previously established inhibitor, dichloroacetate (DCA), which required concentrations of 30 mM or higher. However, poor aqueous solubility and lower stability of DAP limits its therapeutic application. Nano formulation of DAP with natural lactoferrin enhanced its dispersion and stability by increasing polydispersity index and intensity, and reduced zeta potential values upon conjugation that overcame the solubility limitations of DAP. The lactoferrin-DAP nanoparticles exhibited enhanced therapeutic efficacy by precisely targeting prostate cancer cells that express high lactoferrin receptors and high anti-tumor activity in vitro (at 1 μM) and in mouse prostate tumor xenografts (20 mg/kg). Mechanistically, these nanoparticles induce apoptosis in cancer cells by inducing caspase3/7 activity and disrupting the glycolytic and oxidative phosphorylation pathways. Moreover, lactoferrin-conjugated DAP nanoparticles suppressed the viability of docetaxel-resistant cells exhibiting a higher inhibitory efficacy compared to free DAP and DCA. Targeting PDK1 through lactoferrin-conjugated DAP nanoparticles represents a potent targeted therapeutic strategy for disrupting prostate tumor metabolism and offers promising implications for overcoming drug resistance.