Cancer Cell International最新文献

Background: Neutrophils, serving as crucial innate immune cells, exert anti-tumor effects through cytotoxic mediators, antibody-dependent responses, and coordination of immune networks. They also release exosomes that carry bioactive molecules such as microRNAs (miRNAs). Our previous work identified neutrophil-derived exosomes (N-Exo) as contributors to their anti-tumor activity, but the underlying mechanisms remain unclear.

Methods: Functional experiments integrating high-throughput sequencing and validation assays were performed to screen and identify key anti-tumor miRNAs in N-Exo. An in vivo subcutaneous xenograft mouse tumor model assessed the therapeutic effects of N-Exo-delivered miR-101-3p on tumor growth. Bioinformatics analysis combined with experimental validation, including dual-luciferase reporter assays, co-immunoprecipitation (Co-IP), and chromatin immunoprecipitation (ChIP), elucidated the mechanism by which the key miRNA suppresses tumorigenesis through targeting specific genes and signaling pathways. Recombinant interleukin-36 gamma (rmIL-36γ) was used to stimulate neutrophils, and functional assays were performed to evaluate its effect.

Results: Hsa-miR-101-3p was enriched in N-Exo. N-Exo-delivered miR-101-3p directly targets MCL1 to suppress its expression and indirectly inhibits MCL1 transcription via regulation of the EZH2/c-Myc axis, collectively promoting apoptosis in gastric cancer (GC) cells. Furthermore, rmIL-36γ priming upregulated miR-101-3p expression in neutrophils and enhanced their anti-tumor effects.

Conclusion: We demonstrate that N-Exo exerts tumor-suppressive effects by delivering miR-101-3p, which dually targets and suppresses MCL1 expression. Moreover, rmIL-36γ treatment enhances both miR-101-3p abundance and anti-tumor efficacy in neutrophils. These findings highlight the N-Exo/miR-101-3p/MCL1 axis as a therapeutic target and support cytokine priming as a strategy to enhance neutrophil-based cancer therapy.

Background: Biomechanical features show notable heterogeneity in tumor risk stratification, yet their role in prostate cancer (PCa) progression remains unclear. This study aimed to elucidate the role and underlying mechanism of biomechanical features in PCa progression.

Methods: We integrated transcriptomic data from 1693 PCa patients across ten public cohorts and single-cell RNA sequencing (scRNA-seq) data from 19 PCa samples to define biomechanical subtypes. RT-qPCR was used to assess the impact of mechanical stimulation on malignant phenotypes. Biomechanical regulatory genes (BMRGs) were identified using consensus clustering and Weighted Gene Co-expression Network Analysis (WGCNA). A prognostic index (MRPX) was developed using machine learning. Immune infiltration and drug sensitivity analyses were conducted to assess the clinical utility of MRPX in guiding precision therapy. A co-culture model was employed to assess the impact of COL5A1-positive fibroblasts on the metastatic potential of PCa cells.

Results: Loss of biomechanical features was associated with smooth muscle disruption and PCa progression. In vitro mechanical stimulation suppressed EMT-related gene expression in PC-3 cells. WGCNA identified 137 hub BMRGs, from which MRPX was constructed. MRPX demonstrated strong generalizability in predicting PCa progression and effectively stratified patient responses to both immunotherapy and chemotherapy. Elevated MRPX was associated with smooth muscle disruption, which linked MRPX to extracapsular extension (ECE) and enhanced metastatic potential. Mechanistically, COL5A1 was closely linked to PCa progression, and CellChat analysis indicated that COL5A1⁺ fibroblasts contribute to shaping an aggressive tumor microenvironment. Co-culture experiments confirmed a marked upregulation of COL5A1 in cancer-associated fibroblasts (CAFs). Furthermore, silencing of COL5A1 significantly attenuated the ability of CAFs to promote the metastatic potential of PC-3 cells.

Conclusions: This study establishes MRPX as a robust biomarker for prognostic stratification and therapeutic guidance in PCa, offering new insights into biomechanical regulation of tumor progression and providing a potential avenue for precision oncology.

Background: Glycosylation, as one of the most prevalent forms of post-translational modification, plays a pivotal role in tumor progression through structural alterations of serum N-glycans in hepatocellular carcinoma (HCC). In this study, we systematically investigated these N-glycan profiles as potential prognostic biomarkers for predicting patient survival outcomes.

Methods: This study enrolled a cohort of 150 hepatitis B virus (HBV)-related HCC patients (BCLC stages A-D) who received treatment and follow-up monitoring at Southwest Medical University Hospital from 2022 to 2023. Additionally, 105 chronic hepatitis B (CHB) patients, 50 healthy individuals matched for age and gender were recruited as controls. Serum N-glycan profiles were characterized using capillary gel electrophoresis laser-induced fluorescence detection (CGE-LIF).

Results: The relative intensities (RIs) of Peak 9 (NA3Fb) was specifically elevated in HBV-related HCC patients. This peak emerged as an independent predictor of survival (p = 0.004), strongly correlated with advanced tumor stage (p < 0.01), and it was associated with HBsAg loss following anti-PD-1 therapy. MGAT4A, the gene implicated in regulating Peak 9, is likely significantly involved in critical pathways driving HCC progression.

Conclusions: Serum N-glycan profiling represents a promising noninvasive tool for monitoring prognosis and outcomes in HCC patients. Peak 9 (NA3Fb) was identified as a prognostic biomarker significantly associated with clinical outcomes in HBV-related HCC.

Polyploid giant cancer cells (PGCCs) are a distinct subpopulation of tumor cells characterized by enlarged morphology, increased nuclear content, and stem cell-like plasticity. Once considered senescent or non-functional, PGCCs are now recognized as critical drivers of tumor progression, metastasis, therapeutic resistance, and relapse. Their formation can be triggered by various stresses, including chemotherapy, radiotherapy, targeted therapies, as well as by other conditions such as endoplasmic reticulum (ER) stress or hypoxia. Mechanistically, PGCCs arise through processes such as endoreplication, mitotic slippage, cell fusion, and failed cytokinesis, which enable cells to escape mitotic catastrophe and transition into a polyploid state. Under therapeutic stress, PGCCs can persist by adopting a dormant or quiescent phenotype and later resume proliferation through neosis, characterized by asymmetric cytokinesis, generating daughter cells with enhanced migratory, invasive, and tumor-initiating capabilities. These progenies, along with the PGCCs themselves, frequently exhibit cancer stem cell (CSC)-like traits and undergo epithelial-mesenchymal transition (EMT), contributing to tumor heterogeneity and plasticity. Key signaling pathways implicated in PGCC biology include IL-6/IL-6R signaling, unfolded protein response (UPR), impaired p53 pathway, Aurora kinase B (AURKB) inhibition, and activation of the PLK4/CDC25C axis. PGCCs have also been shown to promote angiogenesis, induce therapy resistance, and evade immune surveillance. Clinically, elevated PGCC levels correlate with poor prognosis and resistance across multiple cancer types, including breast, colorectal, lung, ovarian, and so on. Given their unique properties and clinical relevance, PGCCs represent a promising frontier in cancer biology with the potential to overcome therapeutic resistance and prevent tumor recurrence through targeted interventions. This review seeks to elucidate the role of PGCCs across multiple cancer types and highlights their emerging potential as novel targets for future cancer therapies.