Cellular Oncology最新文献

Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies worldwide, with its pathogenesis involving complex biological processes such as DNA damage, epigenetic modification and oncogene mutation. Over the past two decades, the role of long non-coding RNAs (lncRNAs) in the occurrence, metastasis and progression of HCC has received increasing attention. As an important noncoding RNA molecule, lncRNAs play a key role in regulating gene expression, affecting RNA transcription and mRNA stability. This review elucidates the potential pathogenic processes of HCC and elaborates on the synthesis mechanisms of the above three non-coding RNAs. It comprehensively summarizes various non-coding RNAs that have been identified as playing key regulatory roles in HCC, as well as how these non-coding RNAs affect disease progression by regulating gene expression and protein functions. For example: lncRNAs such as NEAT1, DSCR8, PNUTS, HULC, and HOTAIR can play different roles in the proliferation, migration, and apoptosis of HCC cells in different ways. lncRNAs such as HClnc1, LINC01343, FAM111A-DT, CERS6-AS1, and TLNC1 significantly affect the progression of HCC by regulating key signaling axes or protein functions, and are closely related to the prognosis of patients. In addition, we also discuss the potential of lncRNAs as therapeutic targets for HCC, such as: lncRNA MIR31HG, CASC2c, and lncRNA AC115619. Furthermore, we also explore the application prospects of lncRNAs as potential biomarkers and therapeutic targets, providing new perspectives and directions for future HCC research.

Purpose: Combining paclitaxel with antiangiogenic agents has demonstrated improved efficacy as second-line treatment for advanced gastric cancer. Surufatinib, a multi-kinase inhibitor with antiangiogenic and immunomodulatory properties, has exhibited synergistic effects with chemotherapy in preclinical studies.

Methods: This single-arm phase 2 trial enrolled patients aged 18-75 with HER2-negative unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma who had failed first-line therapy. All received surufatinib 250 mg once daily plus paclitaxel 150mg/m² every 3 weeks for up to 6 cycles, followed by maintenance surufatinib until progression, intolerable toxicity, or withdrawal. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.

Results: Thirty-five patients were enrolled. Among 32 tumor response-evaluable patients, the ORR and DCR were 25.0% (95% confidence interval [CI]: 11.5, 43.4) and 87.5% (95% CI: 71.0, 96.5), respectively. Median PFS was 5.7 (95% CI: 4.7, 6.9) months and median OS was 10.8 (95% CI: 7.0, 17.2) months. In 26 patients with prior immunotherapy exposure, the median OS was 14.4 (95% CI: 8.5, not estimable) months. Overall, treatment-related adverse events of grade ≥ 3 occurred in 19 (54.3%) patients, with neutropenia (40.0%), leukopenia (34.3%), and hypertension (11.4%) being the most commonly observed.

Conclusions: Surufatinib plus paclitaxel showed promising efficacy and manageable safety as second-line treatment for advanced gastric cancer, especially in patients who had failed prior immunotherapy.

Clinical trial number: ChiCTR2200063336, registered in the Chinese Clinical Trial Registry on September 5, 2022.

Purpose: Tumor cells reprogram their fatty acid metabolism to meet the demands for their rapid proliferation. However, the interplay between fatty acid metabolism and the tumor microenvironment (TME) in lung cancer remains poorly defined. This study aims to elucidate how arachidonic acid (AA) metabolism, specifically via the enzyme 5-lipoxygenase (ALOX5), modulates anti-tumor immunity in non-small cell lung cancer (NSCLC).

Methods: Data from public transcriptomic datasets were analyzed to identify differentially expressed and immune regulatory fatty acid metabolism-related genes in NSCLC. Spatial correlation between ALOX5 expression and CD8⁺ T cell infiltration was assessed via immunofluorescence. Functional impacts of ALOX5 on tumor growth, immune recruitment, and immunotherapy response were characterized using knockdown and overexpression models. Clinical relevance was evaluated by profiling plasma fatty acids via mass spectrometry in immunotherapy-treated cohorts.

Results: Bioinformatic analysis nominated ALOX5-mediatedAA metabolic pathway as a key regulator of immune infiltration. Genetic knockdown of ALOX5 accelerated tumor progression, attenuated CD8⁺ T cell recruitment, and reduced leukotriene B4 (LTB4) production alongside downregulation of cytotoxic (granzymes) and chemotactic genes. Conversely, ALOX5 overexpression suppressed tumor growth and synergized with anti-PD-1 therapy. Exogenous AA supplementation similarly potentiated the efficacy of PD-1 blockade in vivo. Clinically, elevated plasma levels of AA and linoleic acid correlated with improved immunotherapy response and survival outcomes.

Conclusion: Tumor-intrinsic ALOX5 is a novel tumor suppressor that orchestrates CD8⁺ T infiltration via the AA-LTB4 axis in NSCLC. Our findings establish ALOX5-mediated AA metabolism as a therapeutically targetable pathway to overcome immunotherapy resistance, positioning dietary AA supplementation as a promising adjunctive strategy.

Clinical trail number: Not applicable.

Background: Despite advances in ovarian cancer treatment, the tendency for cancer cells to metastasise to the peritoneum still results in poor prognosis. Studies have demonstrated that the integrin family plays a role in this metastasis; however, the underlying mechanism remains unclear. Triptolide (TP) has been confirmed to have a strong cytotoxic effect against ovarian cancer. However, its clinical application is limited by its severe systemic toxicity and low water solubility.

Methods: This study investigated the integrins involved in peritoneal metastasis and their associated mechanisms. Furthermore, Si/TP@Exos were constructed to counteract the metastatic potential of ovarian cancer cells.

Results: In vitro experiments showed that the construction of the ITGA4B2/AEP ternary complex contributed to the peritoneal metastasis of ovarian cancer by activating the IL-17 and NF-kappa B signalling pathways. Thus, whether the combined application of siRNA targeting ITGA4B2 and TP could further overcome peritoneal metastasis in ovarian cancer was investigated. In vitro results indicated that Si/TP@Exos were efficiently taken up by ovarian cancer cells, thus significantly enhancing the apoptosis of tumor cells. Similarly, Si/TP@Exos were effectively enriched in the tumor areas and exerted anti-tumor activity obviously in vivo.

Conclusions: Together, these findings present a novel strategy to overcome the peritoneal metastasis tendency of ovarian cancer and offer a potential therapeutic solution for clinical treatment of ovarian cancer. The combination of traditional Chinese medicine nano drug delivery platforms provides a new perspective for cancer treatment.

Purpose: Cancer-associated fibroblasts (CAFs) are major constituents of the tumor microenvironment (TME) and have been associated with chemotherapeutic failure via different mechanisms. However, the CAFs inhibit chemotherapy mechanism in lung adenocarcinoma (LUAD) remains undetermined.

Methods: Fibroblasts were isolated from tumor and normal lung tissues from patients with poorly differentiated LUAD (pCAFs), moderately differentiated LUAD (mCAFs), and normal fibroblasts (NFs). Then, the influence of these fibroblasts on carboplatin's cytotoxic effects on LUAD cell lines A549 and NCI-H1299 was assessed by measuring their IC₅₀ values. Furthermore, CXCL12 secretion and its role in chemotherapeutics were also evaluated.

Results: The data revealed that pCAFs significantly inhibited apoptosis in LUAD cells and increased carboplatin IC₅₀ values. Furthermore, pCAFs secreted higher CXCL12 content than mCAFs and NFs. Moreover, in pCAFs, CXCL12 silencing enhanced carboplatin's cytotoxic effects, while NFs overexpressing CXCL12 inhibited carboplatin's efficacy. Mechanistically, pCAFs promote the secretion of CXCL12 by activating the NF-κB pathway, and CXCL12 binds to CXCR4 on LUAD cells, thereby promoting carboplatin resistance. Moreover, in the xenograft models, pCAFs were found to reduce carboplatin's cytotoxicity by CXCL12 secretion. Moreover, the analysis of the LUAD patient's tumor and peripheral blood sample indicated a correlation between lower differentiation and higher CXCL12 expression levels.

Conclusion: This study revealed that LUAD-derived CAFs activate the NF-κB axis to secrete CXCL12, thereby weakening the carboplatin's killing effect on LUAD. Furthermore, poorly differentiated LUAD secreted more CXCL12. These findings indicate a novel strategy to enhance carboplatin's chemotherapeutic potential against LUAD.

Purpose: Natural killer (NK) cells mediate anti-tumor immunity through integrated signaling of inhibitory and activating receptors. The efficacy of NK cell adoptive transfer therapy varies among patients due to heterogeneous receptor-ligand expression. This study aimed to develop a predictive model based on receptor-ligand interactions to determine NK cells' therapeutic effects.

Methods: Through analyses of receptor-ligand expression profiles of NK and tumor cells and assessment of NK cell cytotoxicity, we developed a machine learning-based random forest model using 11 key receptor-ligand pairs selected through database mining and experimental screening. Flow cytometry was used to obtain receptor-ligand profiles, and combined predictors were calculated for each pair. The model was validated using independent datasets and evaluated for generalizability across different tumor types.

Results: The model showed significant predictive performance, achieving an accuracy of 84.2% and an area under the curve (AUC) of 0.908 in ovarian cancer cohorts. This predictive capability was validated in both in vitro experiments and clinical samples, revealing complex non-linear interactions between receptor-ligand expression and NK cell killing efficacy. Cancer-specific ligand expression patterns were identified. While showing optimal performance in studied cancer types, it exhibited moderate applicability to other cancers and demonstrated potential compatibility with transcriptomic data for prediction.

Conclusions: This model provides tools and foundations for the precise treatment of tumors using NK immune cells and may be applied in clinical practice.

Background: Chimeric antigen receptor (CAR) T cells have long been regarded as living drugs, those activation, diffusion, and expansion influence the clinical efficacy. Dynamic monitoring of CAR-T cells in vivo is crucial for understanding their biodistribution and optimizing therapeutic outcomes. However, due to the challenges in sampling tissue-resident CAR-T cells from patients, limited data have been reported on their spatial and temporal distribution.

Methods: This study enrolled 43 patients with haematological malignancies receiving CAR-T cell therapy. CAR copy numbers in the peripheral blood (PB) and serous cavity effusion (SCE) were sequentially quantified and analysed.

Results: High expansion of CAR-T cells in PB was associated with subsequent expansion in SCE. The median T_max in SCE occurred later than in PB. Patients with immune effector cell-associated neurotoxicity syndrome (ICANS) exhibited higher CAR copy numbers in cerebrospinal fluid (CSF) compared to those without ICANS. Peripheral infection was associated with increased CAR copy numbers in CSF, which may be caused by cell diffusion or/and expansion. Tumour invasion favored local accumulation and expansion of CAR-T cells in pleural effusion or ascites (PE/A), and patients with tumour invasion had a higher incidence of local cytokine release syndrome (L-CRS).

Conclusion: We characterized the spatial and temporal distribution of CAR-T cells and identified associations between CAR copy numbers and local inflammation, tumour invasion, and adverse events. These findings enhance our understanding of CAR-T cells diffusion, trafficking, and expansion, providing novel insights for clinical management and therapeutic optimization.

Purpose: Helicobacter pylori (Hp) markedly elevates the risk of gastric cancer (GC) through the induction of chronic inflammation, which facilitates the accumulation of cancer-associated fibroblasts (CAFs) within the immune microenvironment of GC. CAFs contribute to the progression of GC and adversely affect subsequent therapeutic outcomes for patients. However, there is a paucity of research concerning the impact of Hp on CAFs or the identification of potential targets for therapeutic intervention.

Methods: We analyzed public microRNA and transcriptome sequencing data to identify key microRNAs and signaling pathways in Hp + GC. We also used single-cell sequencing to explore cellular localization and interaction mechanisms. Molecular biology experiments, in vitro cell co-culture, and in vivo cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models validated our findings and assessed the pathway's impact on GC proliferation and therapeutic potential.

Results: We identified the "TLR/miR-148a-5p/CALD1/collagen VI" signaling pathway in Hp-stimulated cancer-associated fibroblasts (CAFs) as a critical signaling pathway influencing the proliferation of Hp + GC. These CAFs contributed to GC cell proliferation by releasing substantial amounts of collagen VI, which interacted with tumoral SDC4 receptors. Administration of miR-148a-5p agomir in vivo effectively inhibited the proliferative effects and concurrently enhanced the efficacy of chemotherapy in Hp + GC mice models.

Conclusion: Hp-stimulated CAFs played a significant role in promoting tumor proliferation in Hp + GC. Targeting its "TLR/miR-148a-5p/CALD1/collagen VI" pathway was a promising method to ease the collagen-rich microenvironment and inhibit the proliferation of GC cells. Furthermore, miR-148a-5p agomir might serve as a safer and more efficacious chemotherapeutic sensitizer for patients with Hp + GC.

Background: Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) is a very rare and aggressiveness malignancy with poor outcome. Previous studies suggested that programmed cell death protein-1 ligand 1 (PDL1) was characterized with high mRNA and low protein in Xp11.2 tRCC, however, the potential mechanism is still blurry.

Methods: Immunohistochemistry was conducted to verify Cyclin D1 and PDL1 expression in Xp11.2 tRCC. ChIP and dual-luciferase reporter gene assay were applied to evaluate transcriptional-regulation of TFE3 fusion proteins on CCND1/Cyclin D1 and NR1D1, we used RNA-seq to detect the regulation role of NR1D1 on CCND1/Cyclin D1, half-life experiment and autophagy flux were employed to demonstrate Cyclin D1-CDK4 speeded PDL1 degradation.

Results: Here, we demonstrated that CCND1/Cyclin D1 was not only a direct target gene for positive regulation of TFE3 fusion proteins, but also up-regulated by nuclear receptor subfamily 1 group D member 1 (NR1D1) which was positively transcriptional regulation of TFE3 fusion proteins. Besides, TFE3 fusion proteins reduced the degradation of Cyclin D1 by activating the AKT/mTOR pathway. As a result, the high-expression of CCND1/Cyclin D1 mediated degradation of PDL1 protein through ubiquitin-proteasome system and autophagy pathway.

Conclusion: This research found that CCND1/Cyclin D1 was upregulated in Xp11.2 tRCC through three mechanisms, high-expression CCND1/Cyclin D1 inducing PDL1 degradation. Overall, the study provided a theoretical basis for sequentially using CDK4 inhibitors and anti-PDL1 for Xp11.2 tRCC treatment.

Clinical trial number: Not applicable.