Medical Oncology最新文献

Early-stage prostate cancer is typically manageable with standard therapies, yet the eventual development of castration-resistant prostate cancer (CRPC) remains a significant barrier to effective clinical management. Specifically, the response to immunotherapy in CRPC remains limited, primarily due to a lack of predictive biomarkers and specific therapeutic targets. This study systematically integrates single-cell transcriptomic data across various disease stages, coupled with multi-dimensional validation, to reveal that glutamate ionotropic receptor NMDA type 3A (GRIN3A) expression is persistently elevated throughout tumor evolution and correlates significantly with advanced pathological stages and poor prognosis. Notably, during the transition to CRPC, tumor subpopulations with high GRIN3A expression exhibit pronounced immunoregulatory properties. Experimental validation demonstrated that GRIN3A levels inversely correlate with T-cell infiltration and promote an immunosuppressive microenvironment, partially mediated by TGF-β signaling activation. Furthermore, GRIN3A expression predicts the efficacy of immune checkpoint blockade (ICB) therapy and sensitivity to multiple chemotherapeutic agents. Collectively, these results suggest that GRIN3A has the potential to serve as a biomarker for tumor heterogeneity and immunotherapy resistance, providing a rationale for further exploration of strategies to overcome immune evasion in advanced PCa.

Hepatocellular carcinoma (HCC) is one of the most prevalent solid cancers with the highest mortality rate, despite various treatment modalities. Sodium pentaborate pentahydrate (NaB) is a boron derivative that has an effect on cell death pathways against cancer. Curcumin (Cur) is the primary bioactive substance in the plant Curcuma longa and has anti-inflammatory, antioxidant and anti-cancer activities, mostly whose bioactivity is enhanced by combining piperine (Pip). Ferroptosis is a form of cell death different from apoptosis, necrosis, and autophagy due to reactive oxygen species (ROS) and disturbance in iron homeostasis. In our current study, we evaluated the effects of a NaB, Cur, and Pip combination on ferroptosis in HCC cell lines HepG2 and Hep3B. Our findings demonstrated that this combination treatment significantly decreased glutathione peroxidase (GSH-Px) activity and also increased ROS levels and intracellular ferrous iron in HCC cells. Additionally, qRT-PCR and Western blot analyses revealed upregulation of ferroptosis-related genes and protein expressions, indicating a synergistic induction of ferroptotic pathways by NaB, Cur, and Pip. These results suggest that this combination may represent a promising strategy for inducing ferroptosis in HCC, providing a basis for preliminary research into its potential as a therapeutic approach.

In recent studies, circ_0060055, a newly identified circRNA with implications in oncology, was examined for its expression levels in pancreatic cancer cells versus normal pancreatic tissue, utilizing RT-qPCR. This circRNA was evaluated for its effects on cellular functions, including invasion, migration, proliferation, tube formation, vascular leakiness and apoptosis through a series of functional assays, both inhibitory and promotional. Moreover, investigations extended to in vivo studies. Findings suggest a strong association between circ_0060055 and enhanced cellular proliferation, migration, and invasion capabilities, alongside a notable reduction in apoptosis. Alterations in the expression levels of proteins that regulate apoptosis have been observed, characterized by elevated levels of the anti-apoptotic protein Bcl-2 and diminished levels of the pro-apoptotic protein Bax. Additionally, through dual luciferase reporter assays and further qRT-PCR analyses, miR-1298-5p was identified as a direct interactor with circ_0060055, which in turn modulates miR-1298-5p levels, thereby acting as a molecular sponge. The findings highlight the critical influence of circ_0060055 on the progression of pancreatic cancer by regulating essential apoptotic proteins, suggesting it could serve as a potential therapeutic target for pancreatic cancer.

CAR-T cell therapy is leading the way in the field of cancer cell immunotherapies due to its high success rates. However, the manufacturing of CAR-T cells remains complex and expensive. T-cell enrichment from patient apheresis starting material is a key step in the manufacture but cellular impurities interfere with the ex vivo transduction of T-cells and their proliferation. Current enrichment methods including magnetic bead selection suffer from various limitations. We report here a bead-less T-cell enrichment process through a two-stage procedure based on inertial microfluidics. Using apheresis like starting material samples from healthy donors, the dual-stage process showed an efficient 87% (SD ± 6%) enrichment and 80% (SD ± 30%) recovery of T-cells. Validation of the process with ovarian cancer samples resulted in a T-cell purity 70% (SD ± 10%) from a starting purity of 48% (SD ± 6%) at a 64% (SD ± 4%) T-cell recovery. The two-stage inertial microfluidic process was also shown to have no detectable effect on the proliferation of the cells.

Hepatocellular carcinoma (HCC) develops under sustained oxidative and inflammatory stress, where thioredoxin-binding protein 2 (TBP2/TXNIP) and apoptosis signal-regulating kinase 1 (ASK1/MAP3K5) act as central redox sensors. Under basal conditions, TBP2 inhibits reduced thioredoxin, enabling ASK1 activation and c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) signaling to promote apoptosis, senescence, and immune surveillance. In HCC, transcriptional repression, epigenetic silencing, and post-transcriptional regulation downregulate TBP2 and ASK1, fostering tumor cell survival, metabolic adaptation, and immune evasion. Both proteins intersect with the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which induce pyroptosis and provides antitumor immunity. This review synthesizes current mechanistic insights into TBP2/ASK1 regulation, their integration with redox and inflammasome signaling, and modulation by natural compounds such as curcumin, piperine and other natural compounds. We also examine therapeutic approaches including gene therapy, epigenetic reactivation, and redox-modulating agents. Translational challenges include context-dependent effects, biomarker limitations, and delivery specificity. Refining strategies to achieve precise, transient TBP2/ASK1 activation may unlock their tumor-suppressive potential while minimizing inflammatory risk, offering a novel avenue for HCC treatment.

Breast cancer progression is driven by aberrant signaling pathways that include proliferation, apoptosis, and cytoskeletal remodeling. While tamoxifen remains central to breast cancer therapy, its clinical utility is restricted by developing resistance and toxicity, prompting the need for safer alternatives. To this end, glycyrrhizin, a triterpenoid saponin derived from Glycyrrhiza glabra, has shown activity against different cancers, yet its exact role in breast carcinogenesis remains elusive. In the present study, the effects of glycyrrhizin and tamoxifen were evaluated in a 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary carcinoma model. Both treatments significantly delayed tumor onset, reduced incidence, and decreased overall tumor burden. Histopathology revealed that DMBA exposure produced predominantly high-grade adenocarcinomas, whereas preventive glycyrrhizin and tamoxifen markedly reduced tumor grade to well-differentiated lesions. Curative protocols using glycyrrhizin and tamoxifen eliminated high-grade features. Gene expression studies indicated downregulation of oncogenic drivers (c-Myc, stathmin, cyclin D1, RAN, α-tubulin) and suppression of the anti-apoptotic protein Bcl-2. Both agents increased p53 mRNA expression, modulated interferon-γ expression, and decreased HSP84 expression. Importantly, glycyrrhizin uniquely enhanced PTEN mRNA expression versus tamoxifen, suggesting a potential influence on PI3K/AKT-related signaling. Protein expression analysis of cyclin D1 and α-tubulin demonstrated reduced levels, consistent with disrupted cell-cycle progression along with compromised cytoskeletal integrity. Collectively, these findings indicate that glycyrrhizin exerts anticancer activity associated with modulation of multiple cancer-related genes and histopathological regression, with a distinctive impact on PTEN mRNA expression and cytoskeletal regulators. These data support glycyrrhizin as a promising natural compound for breast cancer and warrant further protein-level mechanistic and translational evaluation.

Oral squamous cell carcinoma (OSCC) is a prevalent malignancy with poor prognosis due to therapeutic resistance and tumor heterogeneity. N⁶-methyladenosine (m⁶A) modification, mediated by methyltransferase-like 3 (METTL3), drives OSCC progression via the HNRNPA2B1/FOXQ1 axis. STM2457, a selective METTL3 inhibitor, and Astragalus polysaccharide (APS), a traditional Chinese medicine with antitumor properties, hold promise for enhancing OSCC treatment, but their combined efficacy remains unexplored. In CAL27 OSCC cells, optimal concentrations of STM2457 (15 µM) and APS (100 µg/mL) were determined using EdU assays. Effects on m⁶A levels, METTL3, HNRNPA2B1, and FOXQ1 expression, and mRNA stability were assessed via RT-qPCR, Western blot, and RIP-qPCR. Cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) were evaluated using EdU, wound healing, and Transwell assays. In vivo efficacy was tested in nude mouse xenografts treated with STM2457 (50 mg/kg/day) and APS (80 mg/kg/day), with tumor growth and FOXQ1 expression analyzed. Combined STM2457 and APS treatment significantly reduced m⁶A levels, METTL3, HNRNPA2B1, and FOXQ1 expression, and mRNA stability compared to single-drug treatments, approaching or surpassing METTL3 silencing effects. The combination markedly suppressed cell proliferation, migration, invasion, and EMT, with increased E-cadherin and decreased N-cadherin levels. Regarding the role of APS in regulating m⁶A, we acknowledge that the current evidence is speculative and requires further mechanistic validation. In vivo, combination therapy significantly reduced tumor growth and FOXQ1 expression, outperforming single-drug treatments. STM2457 and APS enhance the inhibitory effects on OSCC progression by targeting the METTL3/HNRNPA2B1/FOXQ1 axis, offering a potential therapeutic strategy that integrates precision oncology with traditional herbal medicine. Further mechanistic and clinical studies are warranted to validate these findings.

Neuronal excitatory activity promotes glioma progression through glutamate-mediated signaling, yet effective ways to counter this using intrinsic brain mechanisms remain undefined. Repeated low-frequency neuronal stimulation can lead to glutamate buildup and pathway-specific activation of inhibitory presynaptic metabotropic glutamate receptors (mGluRs) within neural circuits. This perspective introduces a hypothesis that this mechanism can disrupt tumor-promoting neuron-glioma interactions. This direction introduces a biologically grounded strategy for a distinctive therapeutic path in precision neuro-oncology.

This study aimed to evaluate the potential effects of agmatine on cell viability, migration, invasion, apoptosis, and the expression of the ABCB1, ABCC1, and ABCG2 genes in the Caco-2 colon cancer cell line. Agmatine efficacy was assessed thruogh proliferation, migration, and invasion assays at various concentrations. The apoptotic index was determined using apoptosis-related markers (Bax, Bcl-2, Csp-3) via apoptosis assays, quantitative real-time PCR (qRT-PCR), and Western blot analysis. Expression levels of the ABCG2, ABCB1, and ABCC1 genes were measured by qRT-PCR in agmatine-treated Caco-2 cells. Oxidative stress markers, including glutathione peroxidase (GPx) and catalase (CAT), were evaluated by qRT-PCR. Cell viability analysis revealed that agmatine exerted its most pronounced effects at 72 h, with significant reductions at concentrations of 6, 7.3, and 9 mM in Caco-2 cells and 6, 6.25, and 9 mM in L929 cells (p < 0.05). At these concentrations, migration and invasion assays showed dose-dependent decreases in cell motility and invasiveness in Caco-2 cells. Apoptosis analysis demonstrated a significant increase in the apoptotic index with rising agmatine concentrations. Significant decreases in GPx and CAT were observed in all three agmatine-treated Caco-2 groups compared to untreated controls (p < 0.01). However, the expression levels of ABCG2, ABCB1, and ABCC1 showed no significant changes following agmatine treatment (p > 0.05). These findings indicate that agmatine exerts antiproliferative, anti-migratory, anti-invasive, and pro-apoptotic effects in Caco-2 colon cancer cells, potentially through the modulation of apoptosis- and oxidative stress-related pathways. The lack of significant impacts on ABC transporter gene expression suggests that agmatine may be a promising candidate molecule for further translational studies in colorectal cancer.

Cervical cancer (CESC) presents a significant clinical challenge, primarily due to an incomplete understanding of the immunometabolic crosstalk within the tumor microenvironment (TME) and the lack of reliable biomarkers for immunotherapy stratification. Thymidylate synthase (TYMS), a pivotal enzyme in nucleotide synthesis, has been implicated in tumor progression, but its role as an immunometabolic regulator in CESC remains unexplored. Through an integrative approach combining single-cell RNA sequencing (scRNA-seq) of 47,589 cells, bulk transcriptomics, functional assays, and in vivo modeling, we delineated the multifaceted functions of TYMS. scRNA-seq analysis revealed a dynamic shift from CD4 + to exhausted CD8 + T-cell dominance during progression, orchestrated by specific ligand-receptor interactions like PTPRC-MRC1. A robust T cell-associated prognostic signature comprising TYMS, MYO6, SPINT1 and ESD was developed, effectively stratifying patients into distinct risk groups with differential tumor stemness, immune infiltration, and response to immunotherapy. Mechanistically, TYMS silencing promoted tumor stemness, migration, and invasion in vitro via targeting miR-197-3p. Crucially, in immunocompetent micemodel, TYMS knockdown accelerated tumor growth and potently suppressed CD8 + T-cell infiltration, demonstrating its role in promoting immune evasion. Conversely, TYMS overexpression suppressed tumorigenesis. Molecular docking identified Deoxyuridine Monophosphate as a high-affinity inhibitor of TYMS. Our findings demonstrate that targeting thymidylate synthase enhances CD8 + T-cell infiltration and inhibits tumor growth in cervical cancer, establishing TYMS as a promising therapeutic target.