Cancer Biology & Medicine最新文献

Neutrophil extracellular traps (NETs) are web-like structures of DNA and proteins that are released by activated neutrophils. While originally identified as antimicrobial defense mechanisms, NETs are now recognized as key modulators of tumor progression. NETs interact with the tumor microenvironment and metabolic pathways in renal cell carcinoma (RCC), which promotes immune evasion and metastasis. This review explores the interplay between NET formation and metabolic reprogramming in RCC, highlighting the implications for immunotherapy resistance and therapeutic targeting. NET-associated signaling, immunometabolism disruption, and current strategies to inhibit NETs in preclinical and clinical settings are discussed. Targeting NETs may represent a promising adjunct in RCC therapy, particularly when integrated with immune checkpoint blockade.

Objective: Osimertinib (OSI) therapy, a cornerstone in treating non-small cell lung cancer (NSCLC), has been severely limited by rapidly developing acquired resistance. Inhibition of bypass activation using a combination strategy holds promise in overcoming this resistance. Biguanides, with excellent anti-tumor effects, have recently attracted much attention for this potential. The current study investigated whether novel biguanide compounds developed by our team could overcome OSI resistance and the underlying mechanisms were explored.

Methods: A comprehensive screening assay using OSI-resistant cells identified the optimal combination of biguanide compounds with OSI. Proteomics, co-immunoprecipitation mass spectrometry, RNA sequencing, and homologous recombination assays were used to elucidate the molecular mechanisms underlying combination therapy. NSCLC tumor tissues, especially OSI-resistant tissues, obtained from our clinic were used to assess the correlations between key proteins and OSI resistance.

Results: SMK-010, a highly potent biguanide compound, effectively overcame OSI resistance in vitro and in vivo. Mechanistical studies showed that BMI1/FGFR1 pathway activation is responsible for OSI resistance. Specifically, silencing BMI1 promoted NEDD4-mediated FGFR1 ubiquitination and proteasomal degradation, whereas SMK-010 treatment induced FGFR1 lysosomal degradation. This reduction in FGFR1 levels impaired homologous recombination, increased DNA damage, and surmounted OSI resistance. Analysis of clinical samples revealed overexpression of BMI1 and FGFR1 in NSCLC tissues and represented potential biomarkers for OSI resistance.

Conclusions: These findings highlight the crucial role of the BMI1/FGFR1 axis in OSI resistance and provide a rational basis for the future clinical application of the biguanide, SMK-010, in combination with OSI.

The occurrence and progression of liver cancer are closely associated with mitochondrial dysfunction. Mitochondria exhibit characteristics, such as decreased oxidative phosphorylation efficiency, abnormal accumulation of reactive oxygen species in liver cancer and promoting tumor proliferation and drug resistance through the Warburg effect, as the core of energy metabolism and apoptosis regulation. Mutations in mitochondrial DNA (mtDNA) and dysregulation of mitochondrial autophagy (mitophagy) further enhance the invasive and metastatic capabilities of liver cancer. Current targeted therapeutic strategies focus on modulating the activity of respiratory chain complexes, regulating calcium homeostasis, repairing mtDNA, and activating mitochondrial apoptotic pathways. Although these approaches have shown therapeutic effects, challenges persist, such as tumor heterogeneity, insufficient drug specificity, and drug resistance. Future research needs to integrate the concept of precision medicine by focusing on breakthroughs in the molecular mechanisms underlying mitochondrial dysfunction, development of targeted delivery systems, optimization of combination therapy regimens, and screening of biomarkers to provide new pathways for individualized treatment. With advances in technology, targeting mitochondrial dysfunction is expected to become an important breakthrough for improving the prognosis of liver cancer.

Objective: The key molecular events signifying the Helicobacter pylori-induced gastric carcinogenesis process are largely unknown.

Methods: Bulk tissue-proteomics profiling were leveraged across multi-stage gastric lesions from Linqu (n = 166) and Beijing sets (n = 99) and single-cell transcriptomic profiling (n = 18) to decipher key molecular signatures of H. pylori-related gastric lesion progression and gastric cancer (GC) development. The association of key proteins association with gastric lesion progression and GC development were prospectively studied building on follow-up of the Linqu set and UK Biobank (n = 48,529).

Results: Concordant proteomics signatures associated with H. pylori infection and gastric carcinogenesis (ρ = 0.784, correlation P = 1.80 × 10^-36) were identified. RNA expression of genes encoding 13 up- and 15 down-regulated key proteins displayed trending alterations in the transition from normal gastric epithelium to intestinal metaplasia, then to malignant cells. A 15-tissue protein panel integrating these signatures demonstrated potential for targeting individuals at high risk for progressing to gastric neoplasia (OR = 7.22, 95% CI: 1.31-39.72 for the high-score group). A 4-circulating protein panel may be used as non-invasive markers predicting the risk of GC development (hazard ratio = 3.73, 95% confidence interval: 1.63-8.54, high-risk vs. low-risk populations, area under the curve = 0.75).

Conclusions: Concordant proteomics signatures associated with H. pylori infection and gastric carcinogenesis were unveiled with potential as biomarkers for targeted prevention strategies.

Prostate cancer is a significant global health issue with inflammation emerging as a critical driver of progression. The prostate tumor microenvironment (TME) is comprised of tumor cells, mesenchymal stem cells, immune cells, cancer-associated fibroblasts, adipocytes, and the extracellular matrix. All of these TME components interact via soluble factors, such as growth factors, cytokines, and chemokines. These interactions remodel the TME and drive inflammation and tumor progression. Prolonged inflammation leads to dysregulated activation and infiltration of immune cells in the TME. This process maintains an immunosuppressive environment and facilitates epithelial-to-mesenchymal transition, migration, and invasion. Chronic inflammation causes inflammatory mediators to enter the circulation over time, as evidenced by systemic biomarkers, such as the systemic immune-inflammation index, which links inflammation to disease severity. Interactions between the prostate gland and adipose tissues further exacerbate systemic inflammation. Inflammation in the prostate gland confers resistance to therapy, primes distant metastatic niches, and promotes metastatic spread, resulting in poor clinical outcomes. Therapeutic strategies, such as anti-inflammatory agents and immunotherapies, hold promise in mitigating disease burden. This review explored the immune landscape of systemic inflammation in prostate cancer, discussed the role of the immune landscape in resistance to therapy and metastasis, and offered insights into potential interventions for targeting inflammation to limit prostate cancer burden.

Objective: This study aimed to assess the global, regional, and national burden of early-onset gastric cancer (EOGC) and the attributable risk factors from 1990-2021 with projections extending to 2040.

Methods: The EOGC burden was quantified using incidence, prevalence, mortality, and disability-adjusted life years (DALYs) with calculation of age-standardized rates. The risk factor contributions were analyzed and disparities were evaluated using the slope index of inequality. Future trends for 2021-2040 were estimated using a Bayesian age-period-cohort model.

Results: There were approximately 125,000 new cases of EOGC globally in 2021 with an estimated 336,000 individuals living with EOGC and 78,000 associated deaths, contributing to 3.86 million DALYs. The highest EOGC incidence rates existed among individuals 45-49 years of age. The global age-standardized incidence, prevalence, mortality, and DALY rates demonstrated an overall decline between 1990 and 2021. Smoking and high-salt dietary intake were the leading risk factors for DALYs with regional and gender-based variations. Smoking accounted for > 10% of DALYs in Central Europe and East Asia, while high-salt dietary intake accounted for approximately 8% of DALYs. Despite the overall decline in the EOGC burden, disparities across geographic regions widened. Projections indicated a continued gradual reduction in EOGC burden through 2040.

Conclusions: Although the global burden of EOGC has decreased, significant disparities persist across geographic regions, age groups, and genders. Public health interventions should combine smoking prevention strategies (e.g., youth education and tobacco taxation) with cessation programs with dietary salt reduction initiatives.