Translational cancer research最新文献

Background: Glutamine, an essential nutrient for healthy cells, supports immunity and cytoprotection during anticancer treatments. However, intense glutaminolysis may promote proliferation and chemoresistance in ovarian carcinomas by activating the PI3K/AKT/mTORC1 pathway and overexpressing c-Myc. This study aimed to characterize glutamine metabolism in ovarian carcinomas and assess its impact on tumor aggressiveness and chemosensitivity, to inform nutritional supplementation or therapeutic targeting.

Methods: Glutamine and glucose consumption, chemosensitivity to cisplatin and paclitaxel, and doubling time were analyzed in three ovarian carcinoma cell lines (ES-2, TOV-21G: clear cell; OVCAR-3: serous papillary) and primary ascites cells under varying glutamine concentrations (0.5, 1, 2, 4 mM). Expression of glutaminase, glutamate dehydrogenase 1 (GDH1), and c-Myc, as well as PI3K/AKT/mTORC1 activation, were assessed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot.

Results: TOV-21G exhibited significantly higher glutamine consumption (13.3±1.3 vs. 6.5±0.3 and 7±0.5 U/mg protein, P<0.001), increased expression of glutaminase, GDH1, and c-Myc, marked PI3K/AKT/mTORC1 activation (P=0.045), and a shorter doubling time (11.5±1.5 h, P=0.04) compared to ES-2 and OVCAR-3. OVCAR-3 showed significantly greater resistance to cisplatin and paclitaxel (P=0.03). Varying glutamine concentrations did not affect chemosensitivity.

Conclusions: Intense glutaminolysis is associated with increased tumor aggressiveness, suggesting a prognostic role for ¹⁸F-(2S,4R)-4-fluoroglutamine (¹⁸F-fluoroglutamine) positron emission tomography (PET) imaging. Glutamine supplementation, without impacting chemoresistance, may mitigate iatrogenic effects, while targeting glutaminolysis offers a therapeutic perspective.

Background and objective: MET alterations have been identified as both primary oncogenic drivers and drivers of acquired resistance in non-small cell lung cancer (NSCLC). There are several mechanisms by which the MET axis can become altered, and an evolving understanding of these pathways provides insight into unique therapeutic targets. Despite considerable research and numerous strategies under investigation, challenges remain, and approved therapies are limited. The purpose of this review is to provide an updated summary of the current evidence, key challenges, and future directions for the diagnosis, classification, and management of advanced and metastatic NSCLC harboring MET alterations.

Methods: A broad literature review was conducted using key terms related to MET-alterations and targeted therapy in advanced and metastatic NSCLC. While no definitive inclusion or exclusion criteria were applied, articles were selected based on their relevance and rigor, with an emphasis on primary and secondary literature published within the last 10 years.

Key content and findings: We review here the pathophysiology and epidemiology of MET alterations that have been identified in NSCLC, including MET exon 14 skipping mutation (METex14), MET amplification (MET AMP), MET overexpression (MET OE), and MET fusion (MET FUS). We review data supporting established treatment strategies as well as areas of active investigation, with a focus on MET tyrosine kinase inhibitors (TKIs), anti-MET and anti-hepatocyte growth factor (HGF) antibodies, bispecific antibodies (B-Abs), antibody-drug conjugates (ADCs), and immunotherapy (IO). We identify key challenges to progress in this space, including standardization of biomarker-driven patient selection, identification of novel therapeutic mechanisms, and management of emerging treatment resistance. Finally, we discuss future directions and areas of promising development, including multi-omics diagnostic approaches, ADCs, and B-Abs.

Conclusions: MET-altered NSCLC is a challenging and heterogeneous molecular subset, and our knowledge is rapidly evolving. Work is ongoing to define the spectrum of actionable mutations, to develop standardized and clinically meaningful biomarker-driven identification of these alterations, and to determine the most effective treatment approaches, with the goal of expanding the treatment landscape and improving outcomes for a subset of patients with limited treatment options.

Background: In the case of lymph node metastasis, small-tumor breast cancer patients show distinct survival rates. Current studies have not conducted in-depth analyses of small-tumor patients with different immune subtypes and different lymph node metastases. This study aimed to examine the survival outcomes and chemotherapy efficacy of patients with different immune subtypes.

Methods: Retrospective clinical data of small-tumor breast cancer patients were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. A multivariate Cox proportional hazards model was used to analyze prognostic factors. Survival analysis was stratified based on stage T, stage N and immune subtypes.

Results: Patients with T1cN2+ stage had the highest risk of death. However, in T1N1 stage cancers, compared with patients of other subtypes in T1mi/a-bN1 stage, the overall survival (OS) and breast cancer-specific survival (BCSS) of patients with T1mi/a-bN1 hormone receptor negative human epidermal growth factor receptor 2 positive (HR-HER2+) were significantly worse. HR+HER2- subtype patients showed a similar trend. Additionally, postoperative adjuvant chemotherapy (AC) was a favorable prognostic factor for OS in small-tumor breast cancer patients [hazard ratio (HR) =0.78, P<0.001] but had no significant effect on BCSS (HR =1.1, P=0.11). In the pT1mi/a-bN0-1 HR+HER2- subtype and pT1mi/a-bN0 HR-HER2-/HR+HER2+ subtype patients, AC did not significantly improve survival (P>0.05).

Conclusions: In addition to T1cN2+ stage or HR-HER2- subtype, this study identified T1mi/a-bN1 HR-HER2+ subgroup as a high-risk type in small-tumor breast cancer. And small-tumor breast cancer patients do not usually benefit from AC. AC may not be recommended for certain subgroups, such as patients with pT1mi/a-bN0-1 HR+HER2- or pT1mi/a-bN0 HR-HER2-/HR+HER2+ can be exempted from chemotherapy.

Background: Gastric cancer (GC) is the fifth most commonly diagnosed cancer worldwide and ranks as the third leading cause of cancer-related deaths. In the tumor microenvironment (TME), malignant cells undergo hypoxic adaptation via metabolic reprogramming, which promotes cellular proliferation and lactate accumulation. However, the significance of hypoxia- and lactylation-related genes (HALRGs) in GC remains unclear. This study aimed to investigate the impact of hypoxia and lactylation on GC and to construct relevant prognostic models.

Methods: We downloaded single-cell RNA sequencing (scRNA-seq), spatial transcriptome (ST) data, and clinical data. The least absolute shrinkage and selection operator (LASSO) algorithm was used to develop a prognostic model, which was validated in an external cohort. Immune cell infiltration was analyzed using the CIBERSORT algorithm, while the Tumor Immune Dysfunction and Exclusion (TIDE) score and ESTIMATE method were combined to evaluate the prognostic potential of immunotherapy response.

Results: We analyzed 23,447 genes and 104,150 cells from scRNA-seq, classifying the cells into seven distinct types. The spatial distribution characteristics of these cell types were further examined using ST data. Inference of copy number variations (InferCNV) analysis was performed on epithelial cells to differentiate between malignant and normal cells, revealing that normal epithelial cells could be further categorized into five subtypes. We then developed a prognostic model based on HALRGs using The Cancer Genome Atlas (TCGA) data, which was validated in the Gene Expression Omnibus (GEO) dataset. Patients were divided into high- and low-risk groups according to HALRG scores. Interestingly, the high-risk group exhibited higher TIDE scores, suggesting a poorer response to immunotherapy.

Conclusions: This study uncovered the cellular heterogeneity of GC by integrating scRNA-seq and ST data. The results demonstrated that the HALRG risk model may be effective in predicting the clinical prognosis and has the potential to guide personalized treatment in GC.

Background: Duodenal adenocarcinoma (DAC), the most common subtype of small bowel adenocarcinoma, is rare. As a result, the survival benefit of adjuvant chemotherapy (AC) for patients with DAC following surgical resection remains controversial and poorly defined. This study aimed to evaluate the association between AC and survival and to identify patient subgroups that derive the greatest benefit.

Methods: A retrospective analysis was conducted using data from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2021). Patients with DAC who underwent surgical resection were included and divided into AC and no-AC groups. Overall survival (OS) and cancer-specific survival (CSS) were compared. Propensity score matching (PSM) was employed as a sensitivity analysis to minimize confounding. Subgroup interaction analyses were performed to identify differential treatment effects.

Results: Of 3,296 patients, 704 (21.4%) received AC. In the analysis of the entire cohort, AC was independently associated with improved OS [hazard ratio (HR) =0.63, 95% confidence interval (CI): 0.53-0.74, P<0.001] and CSS (HR =0.67, 95% CI: 0.55-0.82, P<0.001). This benefit was robustly confirmed in the PSM-matched cohort of 878 patients. Subgroup analyses revealed significant interactions, indicating that the survival benefit was most pronounced in patients aged ≥65 years and those with lymph node metastasis (N1/N2) or advanced T-stage (T3/T4).

Conclusions: This large, population-based study provides robust evidence that AC is associated with significantly improved survival after surgery for DAC, particularly in older patients and those with lymph node-positive or locally advanced disease. These findings support the use of AC to enhance survival outcomes in specific DAC patient groups.

Brain metastases (BrM) are a frequent and devastating complication of non-small cell lung cancer (NSCLC), affecting up to 40% of patients during their disease course. Historically, treatment relied primarily on surgery and radiation, as systemic therapies were thought to have limited activity in the central nervous system (CNS). However, over the past two decades, the development of more targeted therapies has transformed the treatment landscape. Many of these newer agents have improved CNS penetration, which may offer patients the possibility of deferring or reducing the need for local therapies and their associated toxicities. Despite these advances, many challenges remain. There is still a lack of consistent inclusion of BrM patients in clinical trials, and when they are included, there are inconsistencies in measuring radiographic responses as well as in standardized CNS-specific endpoints, making it difficult to compare outcomes across therapies. As treatment options expand, the integration of systemic therapies with surgery and radiation requires nuanced, multidisciplinary decision-making tailored to individual patients. In this review, we aim to summarize the current treatment landscape of pertinent therapies for BrM in NSCLC patients while highlighting the need for broadening inclusion of these patients and creating well-designed prospective studies that intentionally include patients with active and untreated BrM alongside rigorously assess intracranial outcomes. Such efforts will be critical to developing treatment plans in order to ultimately improve survival and quality of life for NSCLC patients with BrM.

Background and objective: MicroRNAs (miRNAs or miRs) are critical epigenetic regulators in gastric carcinogenesis; however, to date, comprehensive analyses of their stage-specific dysregulation and clinical utility are limited. This review synthesized evidence on miRNA dysregulation throughout the gastritis-metaplasia-cancer cascade to assess the diagnostic and therapeutic potential of miRNAs. Research challenges are also discussed.

Methods: A narrative overview was conducted based on systematic searches of the PubMed and Web of Science databases (from 1993-2025.03), focusing on high-impact studies on miRNA expression, and their functional mechanisms and clinical utility in gastric precancerous and cancerous lesions.

Key content and findings: Stage-specific miRNA dysregulation contributes to gastric disease progression. In chronic gastritis (CG), miR-155 and let-7b regulate inflammation, while miR-92a-1-5p and miR-296-5p participate in intestinal metaplasia (IM) by modulating CDX2/FOXD1 and ERK signaling. In gastric cancer (GC), miR-21 and miR-375 regulate proliferation and apoptosis. Clinically, circulating miRNA panels (e.g., miR-4257, miR-6785-5p, and miR-187-5p) enhance early detection, while miR-125a-5p boosts the trastuzumab response via ERBB2 targeting. Despite progress, challenges remain in the mechanistic and clinical validation of miRNAs. Integrating multi-omics and machine learning may optimize miRNA-based diagnostics and therapeutics for precision medicine.

Conclusions: This review highlights miRNAs as pivotal regulators in gastric carcinogenesis and promising precision medicine tools. The study findings will promote the standardization of profiling methods and accelerate translational research, both of which are essential to the advancement of GC diagnostic and therapeutic strategies.