Oncology Research最新文献

Background: The regulatory mechanisms governing vasculogenic mimicry (VM) in oral squamous cell carcinoma (OSCC) remain largely undefined. This study aimed to identify critical factors and elucidate the epigenetic mechanisms underlying VM in OSCC.

Methods: Bioinformatics analysis was performed utilizing single-cell RNA-seq, bulk RNA-seq, and histone H3 lysine 27 acetylation (H3K27ac) Chromatin Immunoprecipitation (ChIP)-seq data obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. ChIP-qPCR was used to validate the binding of ETS transcription factor ELK4 (ELK4) to the dihydrofolate reductase (DHFR) enhancer. In vitro VM formation and invasion of OSCC cells were assessed using Matrigel-based tube formation and Transwell assays, respectively.

Results: Elevated expression of VM-related genes predicts unfavorable prognosis in OSCC patients. High-dimensional weighted gene co-expression network analysis (hdWGCNA) identified epithelial subcluster C4 as most strongly associated with VM and metastasis. Three co-expression modules within this subcluster exhibited significant positive correlations with both phenotypic traits. Among the 30 eigengenes from the three modules, DHFR emerged as a key regulator of VM and metastasis. Knockdown or inhibition of DHFR significantly suppressed VM formation and invasion in OSCC cells. Mechanistically, ELK4 activated DHFR transcription through direct binding to its enhancer. DHFR overexpression rescued VM and invasion impairment induced by ELK4 knockdown.

Conclusion: DHFR was a pivotal enhancer-regulated gene driving VM and metastasis in OSCC. ELK4 directly binds to DHFR enhancer regions to activate its transcription, thereby promoting these malignant phenotypes. These findings identified the ELK4/DHFR axis as a promising therapeutic target for anti-angiogenic intervention in OSCC.

Objectives: Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and Philadelphia-like B-cell acute lymphoblastic leukemia (Ph+/Ph-like ALL) constitute the majority of relapsed/refractory B-ALL (R/R B-ALL) cases, highlighting an urgent need to discover new therapeutic targets. This study aims to elucidate the mechanisms underlying poor prognosis in Ph+/Ph-like ALL through transcriptome sequencing and functional cytological assays, with the goal of informing new clinical treatment strategies.

Results: Transcriptomic analysis of Ph+/Ph-like ALL patients revealed that low expression of P2X Purinoceptor 1 (P2RX1) was associated with unfavorable outcomes. Specifically, patients with poor prognosis and low P2RX1 expression exhibited downregulation of genes involved in energy and calcium metabolism pathways, along with upregulation of genes governing key cellular processes such as cell proliferation (e.g., MYC), cell cycle progression (e.g., CCND2), and apoptosis inhibition (e.g., DASP6). Cellular experiments demonstrated that SUP-B15 cells overexpressing P2RX1 displayed elevated intracellular levels of ATP, calcium, and glucose, together with enhanced glycolytic capacity, compared to empty vector controls. Treatment of SUP-B15 cells with dexamethasone (Dex), Imatinib, or their combination significantly suppressed proliferation and promoted apoptosis, which was accompanied by increases in intracellular ATP, calcium, and glucose. Moreover, exogenous ATP administration (a P2RX1 agonist) enhanced apoptosis and inhibited proliferation in control cells. Conversely, treatment with NF449 (a P2RX1 inhibitor) increased proliferation in both P2RX1-overexpressing and control SUP-B15 cells.

Conclusion: Our findings indicate that P2RX1 may exert this function through modulating energy metabolism and calcium homeostasis, resulting in elevated intracellular calcium levels. Sustained elevation of calcium promotes apoptosis, whereas exogenous ATP activates P2RX1, enhances calcium influx, and attenuates the suppression of apoptosis associated with P2RX1 underexpression, ultimately correlating with improved treatment response.

Ferroptosis is an iron-dependent, excessive lipid peroxidation-driven form of regulated cell death. The core mechanisms of ferroptosis include lipid peroxidation cascade, System X_c ^--glutathioneglutathione peroxidase 4 axis, iron and lipid metabolism chaos, the NAD(P)Hferroptosis suppressor protein 1-ubiquinone axis, and GTP cyclohydrolase 1 tetrahydrobiopterin-dihydrofolate reductase axis. Cuproptosis is triggered by copper ions and involves ferredoxin 1-mediated aggregation of lipoylated proteins, differing fundamentally from ferroptosis. Both ferroptosis and cuproptosis exhibit dual roles (promote or inhibit) in cancers. And the sensitivity of different cancer types to ferroptosis varies, which may depend on special metabolic signatures (e.g., E-cadherin loss causes epithelial-mesenchymal transition, making tumors gain resistance to ferroptosis) and expression of antioxidant defense regulators (e.g., high expression of Acyl-CoA synthetase long-chain family member 4 and lncFASA make tumors easily sensitive). At present, traditional Chinese herbal medicine, combination therapy, and nano-delivery technology correlated with ferroptosis are being hotly studied by researchers in order to realize clinical translation of ferroptosis. In this review, we have summarized the core mechanisms of ferroptosis, ferroptosis differences from cuproptosis, its impact on cancers, and its translational implications in cancer therapy, helping readers quickly get the new information and horizons on them.

Objectives: High-grade serous ovarian cancer (HGSOC), the most common subtype of epithelial ovarian cancer (EOC), exhibits a mesenchymal phenotype characterized by fibrotic stroma and poor prognosis. Human epididymis protein 4 (HE4), a key diagnostic biomarker for ovarian cancer, is involved in fibrotic processes in several non-malignant diseases. Given the clinical significance of stromal fibrosis in HGSOC and the potential link between HE4 and fibrosis, this study aimed to investigate the role of HE4 in the formation of stromal fibrosis in HGSOC.

Methods: A total of 126 patients with gynecological conditions were included and divided into normal, benign, and EOC groups. Tissue stiffness was quantitatively measured and analyzed for its correlation with clinicopathological features. We further investigated the correlation between tumor stiffness and the expression levels of HE4 and fibroblast activation markers (α-smooth muscle actin (α-SMA) and fibroblast activation protein (FAP)) in tumor tissues from 22 HGSOC patients. In vitro, primary fibroblasts were treated with recombinant HE4 (rHE4) or conditioned media from HE4-knockdown ovarian cancer cells to assess fibroblasts activation and matrix contractility (Collagen gel contraction assays). In vivo, a subcutaneous xenograft model using HE4-knockdown cells was established to evaluate the effects of HE4 suppression on tumor growth and extensive extracellular matrix (ECM) remodeling.

Results: Ovarian cancer tissues showed significantly increased stiffness compared to benign/normal groups, showing positive correlation with serum HE4 levels. High-stiffness HGSOC tumors exhibited upregulated expression of HE4, α-SMA, FAP, and collagen I. rHE4 stimulated fibroblast activation and enhanced matrix contractility, whereas HE4 knockdown in cancer cells abrogated these pro-fibrotic effects. In vivo, HE4-silenced xenografts displayed restricted tumor growth accompanied by reduced stromal expression of α-SMA, FAP, and collagen I.

Conclusion: Our findings suggest that HE4 may facilitate ECM remodeling in HGSOC through promoting fibroblast activation and increasing collagen deposition.

Objectives: Breast cancer (BC) is the leading cause of cancer-related mortality in women, largely due to metastasis. This study aims to explore the role of purine nucleoside phosphorylase (PNP), a key enzyme in purine metabolism, in the aggressiveness and metastatic behavior of BC.

Methods: A comprehensive analysis was performed using in silico transcriptomic data (n = 2509 patients), immunohistochemical profiling of BC tissues (n = 103), and validation through western blotting in multiple BC cell lines. Gene expression and survival analyses were conducted using Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis 2 (GEPIA2), and the cBioPortal for cancer genomics (cBioPortal) platforms. Correlations between PNP and key epithelial-mesenchymal transition (EMT) markers, molecular subtypes, tumor grades, and stages were examined.

Results: PNP was significantly overexpressed in human epidermal growth factor receptor 2 (HER-2)-positive and triple-negative BCs compared to luminal subtypes. High PNP levels were strongly associated with advanced BC stages, high-grade tumors, EMT phenotypes, and poor overall survival. Notably, HER-2 inhibition suppressed PNP expression, while PNP gene silencing induced HER-2 upregulation, revealing a reciprocal regulatory loop. Dual inhibition of PNP and HER-2 resulted in a significant reduction in cell viability compared to HER-2 inhibition alone.

Conclusion: Collectively, PNP emerges as a promising biomarker of BC aggressiveness and progression. Its reciprocal interaction with HER-2 underscores its potential as a therapeutic target. Dual targeting of PNP and HER-2 may offer a novel strategy for improving outcomes in aggressive BC subtypes.

Hepatocellular carcinoma (HCC) remains one of the most prevalent and lethal malignancies worldwide. Long non-coding RNAs (lncRNAs) have emerged as crucial regulators of gene expression and cancer progression, yet the functional diversity of RP11-derived lncRNAs-originally mapped to bacterial artificial chromosome (BAC) clones from the Roswell Park Cancer Institute-has only recently begun to be appreciated. This mini-review aims to systematically synthesize current findings on RP11-derived lncRNAs in HCC, outlining their genomic origins, molecular mechanisms, and biological significance. We highlight their roles in metabolic reprogramming, microRNA network modulation, and tumor progression, as well as their diagnostic and prognostic value in tissue and serum-based analyses. Finally, we discuss therapeutic opportunities and propose future directions to translate RP11-derived lncRNAs into clinically actionable biomarkers and targets for precision liver cancer therapy.

Metabolic reprogramming involving branched-chain amino acids (BCAAs)-leucine, isoleucine, and valine-is increasingly recognized as pivotal in cancer progression, metastasis, and immune modulation. This review comprehensively explores how cancer cells rewire BCAA metabolism to enhance proliferation, survival, and therapy resistance. Tumors manipulate BCAA uptake and catabolism via high expression of transporters like L-type amino acid transporter 1 (LAT1) and enzymes including branched chain amino acid transaminase 1(BCAT1), branched chain amino acid transaminase 2 (BCAT2), branched-chain alpha-keto acid dehydrogenase (BCKDH), and branched chain alpha-keto acid dehydrogenase kinase (BCKDK). These alterations sustain energy production, biosynthesis, redox homeostasis, and oncogenic signaling (especially mammalian target of rapamycin complex 1 [mTORC1]). Crucially, tumor-driven BCAA depletion also shapes an immunosuppressive microenvironment, impairing anti-tumor immunity by limiting essential nutrients for T cells and natural killer (NK) cells. Innovative therapeutic strategies targeting BCAA pathways-ranging from selective small-molecule inhibitors (e.g., LAT1 and BCAT1/2) to dietary modulation-have shown promising preclinical and early clinical efficacy, highlighting their potential to exploit metabolic vulnerabilities in cancer cells while bolstering immune responses. By integrating multi-omics data and precision targeting approaches, this review underscores the translational significance of BCAA metabolic reprogramming, positioning it as a novel frontier in cancer treatment.

Background: Glioblastoma (GBM) prognosis has seen little improvement over the past two decades. While immunotherapy has revolutionized cancer treatment, its impact on GBM remains limited. To characterize the evolving research landscape and identify future directions in GBM immunotherapy, we conducted a comprehensive bibliometric review.

Methods: All literature related to immunotherapy in GBM from 1999 to 2024 was collected from the Web of Science Core Collection. CtieSpace and VOSviewer were used to conduct bibliometric analysis and visualize the data.

Results: Bibliometric analysis identified 5038 publications authored by 23,335 researchers from 4699 institutions across 96 countries/regions, published in 945 journals. The United States produced the highest number of publications, while Switzerland achieved the highest average citation rate. Duke University led in institutional output and citations. John H Sampson was the most productive author, and Roger Stupp was the most cited. Frontiers in Immunology published the most papers, while Clinical Cancer Research was the most cited journal. Research focus centered on adoptive T cell therapy, particularly chimeric antigen receptor (CAR)-T cells with 572 dedicated publications. Within CAR-T research for GBM, the University of Pennsylvania was the leading institution, Frontiers in Immunology the predominant journal, and Christine E Brown (City of Hope National Medical Center) was the most prolific and cited author.

Conclusions: There has been a growing interest in GBM immunotherapy over past decades. The United States is the dominant contributor. CAR-T therapy represents the primary research focus. Emerging strategies like chimeric antigen receptor-modified natural killer (CAR-NK) cells, chimeric antigen receptor-engineered macrophages (CAR-M), and cytomegalovirus-specific T cell receptor (CMV-TCR) T cells are gaining prominence, aiming to address limitations in antigen recognition inherent to CAR-T therapy for GBM.

Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have transformed the management of hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer, yet evidence for elderly or poor-performance patients remains limited. This study examined real-world outcomes of palbociclib plus endocrine therapy in Asian patients, with additional subgroup analyses by age and performance status.

Methods: We retrospectively analyzed 46 consecutive Asian patients with recurrent or de novo HR+/HER2- breast cancer treated with first-line palbociclib plus ET between April 2021 and March 2025. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), disease control rate (DCR), and safety. Subgroup analyses were performed by age (<70 vs. ≥70 years) and performance status (PS; 0-1 vs. 2-3).

Results: The median PFS was 26.6 months (range, 1.4-69.5). Stratified by age, median PFS was 26.9 months in patients <70 years and 26.2 months in those ≥70 years (p = 0.760). By PS, PFS was 26.9 months for PS 0-1 and 17.8 months for PS 2-3 (p = 0.099). ORR was 60.9% and DCR 93.5%; notably, all PS 2-3 patients achieved disease control. Hematologic toxicities were common, with neutropenia (80.4%) and leukopenia (86.7%) predominating, but grade ≥ 3 anemia was rare (2.2%). Elderly patients experienced anemia more frequently, while overall toxicity remained manageable. Dose reductions occurred in 47.8% without loss of efficacy.

Conclusions: In routine Japanese practice, palbociclib plus ET provided prolonged PFS and high disease control consistent with pivotal trials and international real-world evidence. Importantly, elderly patients tolerated treatment well, and selected PS 2-3 patients also derived clinical benefit. These findings indicate that neither age nor PS alone should preclude the use of palbociclib in carefully monitored real-world patients.

Background: Breakpoint Cluster Region-Abelson (BCR::ABL1) fusion protein is essential in the pathogenesis of chronic myeloid leukemia (CML); however, the chronic-to-blast phase transformation remains elusive. We identified novel kinesin light chain 2 (KLC2) mutations in CML-myeloid blast phase patients. We aimed to examine the functional role of KLC2 mutations in leukemogenesis.

Methods: To evaluate the biological role of KLC2 mutants (MT) in CML cells, we expressed KLC2-MT in different human CML cell lines harboring BCR::ABL1 and performed immunoblot, immunofluorescence, cell proliferation, differentiation, and apoptosis; Tyrosine kinase inhibitor (TKI)-drug activities; and clonogenic assays for in vitro functional analyses. We co-expressed KLC2-MT and BCR::ABL1 in mouse bone marrow cells (BMCs) to evaluate their clonogenic and self-renewal abilities ex vivo. Furthermore, we examined tumorigenic activity and drug efficacy in the K562 xenograft model.

Results: KLC2-MT overexpression in BCR::ABL1-positive K562 and KU812 CML cells promoted cell proliferation and clonogenic potential, decreased imatinib sensitivity, and reduced apoptosis. Serial colony replating assays revealed that KLC2-MT and BCR::ABL1 co-expression enhanced the self-renewal ability of mouse BMCs with immature morphology. In the K562 xenograft model, KLC2-MT enhanced tumorigenic potential and diminished imatinib efficacy. Further studies reported that KLC2-MT augmented signal transducer and activator of transcription 3 (STAT3) activation and nuclear accumulation in imatinib-treated CML cells. KLC2-WT and KLC2-MT interacted with mothers against decapentaplegic homolog 2 (SMAD2); however, the latter impaired transforming growth factor-beta (TGF-β)-mediated SMAD2/3 activation while enhancing STAT3 phosphorylation.

Conclusions: This study demonstrates the biological and functional importance of KLC2 mutation in CML cells, potentially enabling the development of better treatment strategies for CML patients carrying KLC2 mutations and providing enhanced understanding of the disease progression.