Translational Oncology最新文献

Ferroptosis is a novel type of programmed cell death caused by excessive iron-dependent lipid peroxidation. According to various studies, there may be a link between ferroptosis and lipid metabolism. However, few studies have been reported on the lipid metabolism of ferroptosis in acute myeloid leukemia (AML). Here, we analyzed the relationship between lipid metabolism and ferroptosis in AML cells to explore new clinical treatment strategies. This study found that 12 fatty acids were significantly changed in acute myeloid leukemia cell ferroptosis, including dihomo-γ-linolenic acid (DGLA), arachidonic acid (AA), docosahexaenoic acid (DHA), etc. Exogenous DGLA substantially increases the sensitivity to ferroptosis and induces ferroptosis alone in AML cells. In addition, acyl-CoA synthetase long-chain family member 4 (ACSL4) knockout significantly inhibited DGLA-induced AML cells ferroptosis, and ACSL4 regulates DGLA-associated lipid synthesis to affect the sensitivity of AML cells to ferroptosis. Collectively, our studies indicate that a DGLA-enriched diet significantly restricted the growth of leukemia cells as well as induced ferroptosis in vivo.

Objective: Cisplatin is the main chemotherapy drug for advanced ovarian cancer, but drug resistance often occurs. The aim of this study is to explore the molecular mechanism by which Guizhi Fuling capsule inhibits cisplatin resistance in ovarian cancer.

Methods: First, differences in cisplatin resistance, PA2G4 gene expression, migration, and invasion in A2780 cells and A2780/DDP cells were analyzed by qRT-PCR, scratch assay, transwell, immunofluorescence, and western blotting. Then, LC-MS/MS analysis of GFC chemical composition. qRT-PCR, scratch tests, transwell, pseudopodium formation, immunofluorescence, and western blotting were used to explore the mechanism by which GFC inhibited A2780/DDP cell migration and invasion. Finally, the anti-tumor efficacy of GFC was verified by in vivo experiments.

Results: A2780/DDP cells had a greater ability to migrate and invade compared to their parents. Cell viability experiments showed that the migration and invasion ability of A278/DDP cells were significantly inhibited with the increase of GFC concentration. qRT-PCR results showed that compared with the blank control group, cisplatin group and GFC group, the transcription level of PA2G4 gene in the combination treatment group was significantly reduced. We also found that GFC combined with cisplatin inhibited the PI3K/AKT/GSK-3β signaling pathway by targeting PA2G4 gene expression, inhibited the epithelial-mesenchymal transition signaling pathway, decreased cell adhesion and inhibited the formation of cell pseudopodias.

Conclusion: GFC combined with cisplatin can target PA2G4 gene to regulate PI3K/AKT/GSK-3β Signaling pathway, inhibiting the invasion and migration of cisplatin resistant A2780/DDP cells in ovarian cancer.

Early-onset pancreatic cancer (EOPC) is usually defined as patients with pancreatic cancer before the age of 50 years, which is relatively rare. However, the research on EOPC is somewhat obscure, and the specific clinical and molecular characteristics of this condition are debated. In this review, we discussed the differences between EOPC and late-onset pancreatic cancer (LOPC) or average-onset pancreatic cancer (AOPC) with a focus on clinical and molecular characteristics, survival outcomes and treatment to promote the diagnosis and treatment of EOPC.

Background: Taxane-based chemotherapy is the primary treatment for triple-negative breast cancer (TNBC), yet clinical outcomes remain unsatisfactory due to the persistence of chemoresistance. Identifying key factors that contribute to chemoresistance and understanding the associated molecular mechanisms is therefore essential.

Method: The GEO databases were utilized to pinpoint factors related to chemoresistance, which were subsequently validated using clinical tissue samples. The role of UGCG in the malignant progression and chemoresistance of TNBC was assessed through various functional assays. Western blotting, qRT-PCR, and immunohistochemistry were employed to investigate the signaling pathways associated with UGCG in TNBC.

Results: UGCG expression was notably elevated in chemoresistant breast cancer tissues and cells, as identified in GEO databases and confirmed through immunohistochemistry. Additionally, findings from our cohorts indicated that higher levels of UGCG expression correlated with a lower rate of pathological complete response (pCR), suggesting it could serve as an independent predictor of chemotherapy effectiveness. Gain- and loss-of-function experiments demonstrated that UGCG enhanced the proliferation, metastasis, and stemness of breast cancer cells. Furthermore, treatment with paclitaxel or docetaxel resulted in increased UGCG expression, which in turn reduced chemotherapy-induced cell apoptosis and improved drug resistance and metastatic capabilities. Mechanistically, UGCG was found to amplify the activation of NF-κB and Wnt/β-catenin pathways, and the use of inhibitors targeting these pathways diminished the UGCG-induced malignant effects.

Conclusion: Our findings underscore the significant role of UGCG in the chemoresistance and progression of breast cancer, suggesting it as a predictive biomarker and potential therapeutic target to combat chemoresistance in this disease.

Liver cancer, encompassing hepatocellular carcinoma (HCC) and hepatoblastoma, the latter of which primarily occurs in early childhood, is the most common malignant tumor arising from liver and is responsible for a significant number of cancer-related deaths worldwide. Targeted drugs have been used for anti-liver cancer treatment in the advanced stage, while their efficacy is greatly compromised by development of drug resistance. Drug resistance is a complicated process regulated by intrinsic and extrinsic signals and has been associated with poorer prognosis in cancer patients. In the current study, online available dataset analysis uncovered that angiopoietin-like protein 3 (ANGPTL3) manifested lower expression in sorafenib-resistant liver cancer cell lines. Additionally, ANGPTL3 was downregulated in HCC tissues, with its expression positively correlated with good prognosis. Functionally, ectopic expression of ANGPTL3 re-sensitized sorafenib-resistant cells, enhancing the sorafenib-induced reduction in cell viability and migration by suppressing zinc finger protein SNAI1 (SNAI1) expression and the protein stability of carnitine O-palmitoyltransferase 1, liver isoform (CPT1A). Clinical correlation analysis revealed that ANGPTL3 was negatively associated with SNAI1 expression. In conclusion, we identify a novel association between ANGPTL3, SNAI1 and CPT1A on sorafenib therapeutic response. Targeting ANGPTL3/SNAI1/CPT1A axis may serve as a therapeutic approach to improve prognosis of liver cancer patients with sorafenib resistance.

Background: Endocervical adenocarcinoma (ECA) comprises a heterogeneous group of diseases whose incidence has increased significantly in recent decades. ECA can be histologically classified into human papillomavirus-associated (HPVA) and non-HPVA (NHPVA) types. Given the variability in pathological features and clinical behavior between the subtypes, evaluating their respective immune microenvironments is essential. They can be categorized into distinct tumor microenvironment immune types (TMIT).

Methods: A total of 540 surgically resected ECA samples were classified into HPVA and NHPVA subgroups. Tumor-infiltrating immune markers were assessed using immunohistochemistry. We categorized ECA into four TMIT based on PD-L1 and CD8+ tumor-infiltrating lymphocytes (TILs) expression, and analyzed their prognostic significance.

Results: PD-L1 positivity was observed in 319 out of 464 (68.8%) HPVA and 55 out of 76 (72.4%) NHPVA. Across the entire cohort, high CD8+ TILs expression was significantly associated with improved disease-free survival (DFS, p=0.018) and overall survival (OS, p=0.031). A total of 177 samples (32.8%) were classified as TMIT I (high PD-L1 and high CD8+ TILs), exhibiting markedly denser immune cell infiltration compared to the other TMIT groups. In NHPVA subgroup, TMIT was significantly associated with both DFS (p=0.005) and OS (p=0.003). Multivariate analysis identified TMIT as an independent prognostic factor for DFS in the NHPVA group, with TMIT I indicating a more favorable prognosis (p=0.042).

Conclusions: TMIT I group within the NHPVA population is most likely to benefit from PD-L1/PD-1 blockade immunotherapies. The immune classification of ECA demonstrates significant prognostic value, suggesting its potential utility in guiding clinical stratification and therapeutic decision-making.

Wilms tumor 1 (WT1) is a multifaceted protein with dual functions, acting both as a tumor suppressor and as a transcriptional activator of oncogenes. WT1 is highly expressed in various types of solid tumors and leukemia, and its elevated expression is associated with a poor prognosis for patients. High WT1 expression also indicates a greater risk of refractory disease or relapse. Consequently, targeting WT1 is an effective strategy for disease prevention and relapse mitigation. Substantial information is available on the pathogenesis of WT1 in various diseases, and several WT1-targeted therapies, including chemical drugs, natural products, and targeted vaccines, are available. We provide a comprehensive review of the mechanisms by which WT1 influences malignancies and summarize the resulting therapeutic approaches thoroughly. This article provides information on the roles of WT1 in the pathogenesis of different cancers and provides insights into drugs and immunotherapies targeting WT1. The goal of this work is to provide a systematic understanding of the current research landscape and of future directions for WT1-related studies.

Despite widespread deregulation of CDK4/6 activity in non-small cell lung cancer (NSCLC), clinical trials with CDK4/6 inhibitor (CDK4/6i) as a monotherapy have shown poor antitumor activity. Preclinical studies indicate that CDK4/6i may collaborate by influencing DNA damage repair pathways during radiotherapy. Since PARP1 expression was also significantly upregulated in NSCLC, we analyzed the efficacy of combining PARP1 and CDK4/6 inhibition in NSCLC models. We found that CDK4/6is synergize with PARP1 inhibitors (PARPis) to inhibit the clonogenic growth of RB-proficient NSCLC models. This synergy correlates with increased accumulation of DNA damage, interrupted cell-cycle checkpoints, and enhanced apoptotic cell death. Mechanistically, we showed that CDK4/6is promote PARP1 protein degradation, which lead to decreased availability of DNA repair factors involved in homologous recombination and suppression of DNA repair competency. Furthermore, we showed that PARP trapping is engaged in this synergy. We then confirmed that combining PARPi and CDK4/6i blocked the growth of NSCLC xenografts in vivo and patient-derived explant models ex vivo. Our data reveal a previously uncharacterized impact of CDK4/6i on PARP1 levels in RB-proficient NSCLC models and the engagement of PARP trapping in the synergy between CDK4/6i and PARPi. Our findings suggest combining CDK4/6i with PARPi could be a viable therapeutic strategy for patients with RB-proficient NSCLC.

Importance: Gastric cancer is often diagnosed at an advanced stage and at order age, identification of high-risk population is needed for detection of early-stage gastric cancer.

Objective: To examine whether clonal hematopoiesis of indeterminate potential (CHIP) is a risk factor of gastric cancer.

Design: This cohort study used data from the UK Biobank collected from baseline (2006-2010) to the end of follow-up in March 2024.

Setting: Data on age, sex, race, alcohol consumption, smoking status and type 2 diabetes were collected at baseline interview. Previous and diagnosed cancer or diseases were collected from self-reported and in-hospital records.

Participants: Participants with no previous cancer or hematologic disorders were selected. Participants with gastric cancer cases were aged 60.7 (S.D. 6.62), 71.8 % male; controls were aged 56.1 (S.D. 8.11), 47.4 % male.

Exposures: Whole-exome sequencing was performed on blood samples collected at baseline. A CHIP status was identified based on the mutations on 43 CHIP-related genes.

Main outcomes and measures: Odds ratio (OR) of CHIP with gastric cancer risk was estimated using multivariable logistic regression models. Participants were grouped based on age and CHIP status to examine if there are differences in the cumulative incidence of gastric cancer.

Results: Among 402,253 participants, 1,070 incident gastric cancer cases were identified (mean age, 60.7 ± 6.62 years). The prevalence of CHIP at baseline was associated with an increased risk of gastric cancer (cases: 6.54 % vs. controls 5.14 %; OR without adjustment, 1.29; 95 % CI, 1.004 to 1.63). The stratified OR (95 % CI) of individuals aged ≥ 57 was 1.33 (1.02 to 1.72) for overall CHIP, whereas the OR for younger individuals was 0.79 (0.37 to 1.44). CHIP involving DNMT3A (OR, 1.81; 95 % CI, 1.05 to 2.88; P = 0.0193) and ASXL1 (OR, 2.43; 95 % CI, 0.95 to 4.99; P = 0.032) was associated with an increased risk of gastric cancer. These positive associations remained significantly in sensitivity analyses adjusted by known risk factors. Compared to younger individuals and non-CHIP carriers, older participants with CHIP exhibited a significantly higher cumulative incidence of gastric cancer (P < 0.0001).

Conclusions and relevance: CHIP is associated with gastric cancer in the elderly and contributes to the positive association between DNM3A and ASXL1 mutations and risk of gastric cancer.

Background: Circulating tumor DNA (ctDNA) revolutionized the molecular diagnostics of lung cancer by enabling non-invasive, sensitive identification of actionable mutations. However, ctDNA analysis may be challenging due to tumor shedding variability, leading to false negative results. This study aims to understand the determinants for ctDNA shedding based on clinical characteristics of lung cancer patients, for a better interpretation of false negative results to be considered when ordering ctDNA analysis for clinical practice.

Methods: Blood samples were collected from patients with stage IV EGFR-mutated (mEGFR) NSCLC before treatment and monitored until disease progression. EGFR was assessed on tissue by standard procedures, while EGFR status on ctDNA was tested using dPCR at baseline and at the first reassessment. NGS was used to evaluate patients mutational status at the progression of the disease.

Results: A total of 40 mEGFR tissue samples were collected. Plasma samples were analyzed for mEGFR before starting the first line, 65 % of patients had detectable mEGFR in ctDNA ("shedders"). Higher ECOG PS (p = 0.04), bilateral localization of primary tumor (p = 0.04), and the presence of intrathoracic/extrathoracic disease (p = 0.05), were associated to mEGFR shedding. Shedders had shorter PFS compared to non-shedders (p = 0.03). Patients with detectable mEGFR in ctDNA at the first radiological assessment exhibited worse PFS compared to patients with ctDNA clearance (p = 0.05).

Conclusion: Our preliminary data demonstrate that specific clinical characteristics predict mEGFR shedding in ctDNA of NSCLC, suggesting a potential clinical applicability for understanding potential false negative results and appropriate reporting in clinical practice.