Pathogenesis Of Cancer Research Articles

New anti-ovarian cancer quinolone derivatives acting by modulating microRNA processing machinery.

MicroRNAs (miRNAs) play a crucial role in ovarian cancer (OC) pathogenesis and miRNA processing can be the object of pharmacological intervention. By exploiting our in-house quinolone library, we combined a cell-based screening with medicinal chemistry efforts, ultimately leading to derivative 33 with anti-OC activity against distinct cell lines (GI50 values 13.52-31.04 μM) and CC50 Wi-38 = 142.9 μM. Compound 33 retained anticancer activity against additional cancer cells and demonstrated a synergistic effect with cisplatin against cisplatin-resistant A2780 cells. Compound 33 bound TRBP by SPR (K D = 4.09 μM) and thermal shift assays and its activity was TRBP-dependent, leading to modulation of siRNA and miRNA maturation. Derivative 33 exhibited augmented potency against OC cells and a stronger binding affinity for TRBP compared to enoxacin, the sole quinolone identified as a modulator of miRNA maturation. Consequently, 33 represents a promising template for developing novel anti-OC agents with a distinctive mechanism of action.

Analytical validation of the LungLB test: a 4-color fluorescence in-situ hybridization assay for the evaluation of indeterminate pulmonary nodules

BackgroundEvaluation of indeterminate pulmonary nodules (IPNs) often creates a diagnostic conundrum which may delay the early detection of lung cancer. Rare circulating genetically abnormal cells (CGAC) have previously demonstrated utility as a biomarker for discriminating benign from malignant small IPNs in the LungLB assay. CGAC are identified using a unique 4-color fluorescence in-situ hybridization (FISH) assay and are thought to reflect early cell-based events in lung cancer pathogenesis and the anti-tumor immune response. LungLB is a prognostic tool that combines the CGAC biomarker and clinical features to aid in IPN evaluation by improving the stratification of patient risk of malignancy.MethodsHerein we describe the analytical performance of the LungLB blood test. Analytical validation was performed according to Clinical and Laboratory Standards Institute (CLSI) guidelines with adaptations for rare cell-based assays. Multiple operators, reagent lots, and assay runs were tested to examine accuracy, precision, reproducibility, and interfering factors.ResultsThe FISH probes used in the LungLB assay demonstrate 100% sensitivity and specificity for their intended chromosomal loci (3q29, 3p22.1, 10q22.3 and 10cen). LungLB demonstrates analytical sensitivity of 10 CGAC per 10,000 lymphocytes analyzed, 100% analytical specificity, and high linearity (R2 = 0.9971). Within run measurements across 100 samples demonstrated 96% reproducibility. Interfering factors normally found in blood (lipemia, biotin) and exposure to adverse temperatures (-20ºC or 37ºC) did not interfere with results. Sample stability was validated to 96 hours.ConclusionThe analytical performance of LungLB in this validation study successfully demonstrates it is robust and suitable for everyday clinical use.

SSCI: Self-Supervised Deep Learning Improves Network Structure for Cancer Driver Gene Identification.

The pathogenesis of cancer is complex, involving abnormalities in some genes in organisms. Accurately identifying cancer genes is crucial for the early detection of cancer and personalized treatment, among other applications. Recent studies have used graph deep learning methods to identify cancer driver genes based on biological networks. However, incompleteness and the noise of the networks will weaken the performance of models. To address this, we propose a cancer driver gene identification method based on self-supervision for graph convolutional networks, which can efficiently enhance the structure of the network and further improve predictive accuracy. The reliability of SSCI is verified by the area under the receiver operating characteristic curves (AUROC), the area under the precision-recall curves (AUPRC), and the F1 score, with respective values of 0.966, 0.964, and 0.913. The results show that our method can identify cancer driver genes with strong discriminative power and biological interpretability.

Reducing metastasis ability of gastric cancer cell line by targeting MMP16 using miR-193a-5p and 5-FU

PurposeCo-administration of microRNAs and chemotherapy drugs effectively treats several cancers. The current study sought to investigate the function of matrix metalloproteinase 16 (MMP16) and miR-193a-5p in the pathogenesis of gastric cancer (GC). Materials/methodsSixty-five surgical patients, 15 receiving 5-fluorouracil (5-FU), provided GC and adjacent non-cancerous tissue. Following that, qPCR was used to assess the expression levels of MMP16 and miR-193a-5p in GC cells. The impact of miR-193a-5p and 5-FU administration on MMP16 mRNA expression was evaluated using qRT-PCR and Western blotting. MTT and Scratch tests were also conducted to assess their effects on cell viability and migration. Moreover, a rescue experiment using an MTT assay was performed. Using flow cytometry, the apoptotic rate was calculated. Finally, it was evaluated how MMP16 and miR-193a-5p related to the clinicopathological characteristics of the patients. ResultsThe current study found that while MMP16 expression increased in GC patients (P ​< ​0.0001), miR-193a-5p expression significantly decreased (P ​< ​0.001). MMP16 down-regulation was another effect of miR-193a-5p replacement, particularly when 5-FU was added (P ​< ​0.01). In addition, this study found that miR-193a-5p, by concentrating on MMP16, decreased the migration of GC cells brought on by MMP16. In GC cell lines, miR-193 and 5-FU induce apoptosis, with the 5-FU being more pronounced when combined with mir-193, according to flow cytometry results. A strong correlation was also found between clinicopathological traits associated with MMP16 and miR-193a-5p. ConclusionsThese findings suggest that miR-193a-5p, in conjunction with 5-FU, down-regulates MMP16 in GC, where it suppresses tumor growth.

The Effects of Severe Symptoms of SARS-CoV-2 Infections on the Anti/Proapoptotic Molecules: A 6-Month Cohort Study.

The plausible effects of SARS-CoV-2 infection on the expression of anti/proapoptotic molecules have been suspected. This cohort study examined the expression of p53, Bcl-2, Bid, Bak, and Bax molecules, the genes associated with induction or inhibition of apoptosis, in the SARS-CoV-2-infected patients with severe and mild symptoms in an Iranian population. In this 6-month cohort study, the expression of p53, Bcl-2, Bid, Bak, and Bax molecules was evaluated at onset of diagnosis, 24 h after symptom onset, and 6 months later in the nasopharyngeal cells of SARS-CoV-2-infected hospitalized patients and outpatients in comparison with healthy controls using the real-time PCR technique. At the onset of the study, the relative expression of p53, Bcl-2, Bid, Bak, and Bax significantly increased in the SARS-CoV-2-infected hospitalized patients and decreased after 6 months. The healthy controls showed potential positive correlations among the molecules, but the patients did not show these correlations. Since SARS-CoV-2 needs host cell survival, it appears that the virus induces the expression of Bcl-2 as an antiapoptotic molecule, and the host cells upregulate the proapoptotic molecules to neutralize the effects. Dysregulation of correlation expression of the molecules among the patients proved that SARS-CoV-2 affects the expression of the molecules involved in apoptosis. SARS-CoV-2 could be considered an important factor that regulates the expression of several molecules participating in cancer pathogenesis.

Cross-omics strategies and personalised options for lung cancer immunotherapy.

Lung cancer is one of the most common malignant tumours worldwide and its high mortality rate makes it a leading cause of cancer-related deaths. To address this daunting challenge, we need a comprehensive understanding of the pathogenesis and progression of lung cancer in order to adopt more effective therapeutic strategies. In this regard, integrating multi-omics data of the lung provides a highly promising avenue. Multi-omics approaches such as genomics, transcriptomics, proteomics, and metabolomics have become key tools in the study of lung cancer. The application of these methods not only helps to resolve the immunotherapeutic mechanisms of lung cancer, but also provides a theoretical basis for the development of personalised treatment plans. By integrating multi-omics, we have gained a more comprehensive understanding of the process of lung cancer development and progression, and discovered potential immunotherapy targets. This review summarises the studies on multi-omics and immunology in lung cancer, and explores the application of these studies in early diagnosis, treatment selection and prognostic assessment of lung cancer, with the aim of providing more personalised and effective treatment options for lung cancer patients.

Vaccine-based therapeutic interventions in lung cancer management: A recent perspective.

The incidence of lung cancer continues to grow globally, contributing to an ever-increasing load on healthcare systems. Emerging evidence has indicated lowered efficacy of conventional treatment strategies, such as chemotherapy, surgical interventions and radiotherapy, prompting the need for exploring alternative interventions. A growing focus on immunotherapy and the development of personalized medicine has paved the way for vaccine-based delivery in lung cancer. With various prominent targets such as CD8+T cells and PD-L1, immune-targeted, anti-cancer vaccines have been evaluated in both, pre-clinical and clinical settings, to improve therapeutic outcomes. However, there are a number of challenges that must be addressed, including the scalability of such delivery systems, heterogeneity of lung cancers, and long-term safety as well as efficacy. In addition to this, natural compounds, in combination with immunotherapy, have gained considerable research interest in recent times. This makes it necessary to explore their role in synergism with immune-targeted agents. The authors of this review aim to offer an overview of recent advances in our understanding of lung cancer pathogenesis, detection and management strategies, and the emergence of immunotherapy with a special focus on vaccine delivery. This finding is supported with evidence from testing in non-human and human models, showcasing promising results. Prospects for phytotherapy have also been discussed, in order to combat some pitfalls and limitations. Finally, the future perspectives of vaccine usage in lung cancer management have also been discussed, to offer a holistic perspective to readers, and to prompt further research in the domain.

Role of low-density cholesterol and Interleukin-17 interaction in breast cancer pathogenesis and treatment.

Breast cancer (BC) has become the most prevalent cancer worldwide, and further research is being conducted to deepen our understanding of its pathogenesis and treatment. Lipid metabolism disorder is a significant alteration in cancer cells, and the investigation into the role of Interleukin-17 (IL-17) in malignant tumors has emerged as a research focus in recent years. Thus, exploring changes in lipid metabolism and inflammatory factors in BC cells is crucial in identifying potential therapeutic targets. This article summarizes the progress made in the research on the main low-density cholesterol (LDL) transporter and IL-17 in lipid metabolism, and their potential involvement in the development of BC. The article aims to establish a theoretical foundation for the development of BC-related therapies.

Exploring the Role of Escherichia coli K-12 in Reducing MIR17HG Expression as a Poor Prognostic Biomarker in Colorectal Cancer

Background: Long noncoding RNAs (lncRNAs) play significant roles in various cellular processes, and alterations in their expression levels can contribute to the pathogenesis of colorectal cancer (CRC). Objectives: This study aims to identify lncRNAs highly associated with poor prognosis in CRC and determine those that exhibit significant expression changes under the influence of Escherichia coli K-12. Methods: Potentially susceptible lncRNAs to expression modulation in the presence of E. coli K-12 were identified by analyzing GSE50040 datasets. Data from the cancer genome Atlas (TCGA) were utilized to assess E. coli K-12-affected lncRNAs with the most significant impact on CRC pathogenesis. The association between the candidate lncRNA and patient prognosis was investigated using clinical data. The co-expression network was employed to identify pathways related to the identified lncRNA via the MsigDB database. To validate the in silico findings, CRC and adjacent normal samples were examined using the RT-qPCR method. Results: Cox regression analysis demonstrated that MIR17HG is a strong biomarker associated with poor prognosis in CRC patients. Increased expression of MIR17HG in cancer samples was correlated with key pathways involving cell proliferation, anti-apoptosis, and metastasis. RT-qPCR results showed that the expression level of MIR17HG in CRC samples was significantly higher than in normal samples. Further analysis revealed that MIR17HG expression is susceptible to suppression by E. coli K-12. Conclusions: High expression of MIR17HG in cancer samples is associated with an increased probability of mortality in CRC patients. Our study highlights the potential of E. coli K-12 to reduce CRC malignancy by downregulating MIR17HG expression.

A comprehensive in silico analysis and experimental validation of miRNAs capable of discriminating between lung adenocarcinoma and squamous cell carcinoma.

Accurate differentiation between lung adenocarcinoma (AC) and lung squamous cell carcinoma (SCC) is crucial owing to their distinct therapeutic approaches. MicroRNAs (miRNAs) exhibit variable expression across subtypes, making them promising biomarkers for discrimination. This study aimed to identify miRNAs with robust discriminatory potential between AC and SCC and elucidate their clinical significance. MiRNA expression profiles for AC and SCC patients were obtained from The Cancer Genome Atlas (TCGA) database. Differential expression analysis and supervised machine learning methods (Support Vector Machine, Decision trees and Naïve Bayes) were employed. Clinical significance was assessed through receiver operating characteristic (ROC) curve analysis, survival analysis, and correlation with clinicopathological features. Validation was conducted using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Furthermore, signaling pathway and gene ontology enrichment analyses were conducted to unveil biological functions. Five miRNAs (miR-205-3p, miR-205-5p, miR-944, miR-375 and miR-326) emerged as potential discriminative markers. The combination of miR-944 and miR-326 yielded an impressive area under the curve of 0.985. RT-qPCR validation confirmed their biomarker potential. miR-326 and miR-375 were identified as prognostic factors in AC, while miR-326 and miR-944 correlated significantly with survival outcomes in SCC. Additionally, exploration of signaling pathways implicated their involvement in key pathways including PI3K-Akt, MAPK, FoxO, and Ras. This study enhances our understanding of miRNAs as discriminative markers between AC and SCC, shedding light on their role as prognostic indicators and their association with clinicopathological characteristics. Moreover, it highlights their potential involvement in signaling pathways crucial in non-small cell lung cancer pathogenesis.

Abstract B011: FOXA1 as a pioneer factor in ERα-DNA interactions and its therapeutic potential in ER+ breast cancer: Insights from ChIP-seq and GWAS in Hispanic populations

Abstract Forkhead box A1 (FOXA1) acts as a pioneer factor for Estrogen Receptor alpha (ERα), playing a crucial role in determining where ERα binds to DNA and regulates gene expression in breast cancer cells. A pioneer factor is a class of transcription factors (TF) that is responsible for opening the chromatin to allow other TFs to attach and activate transcription of that gene. FOXA1 acts as a facilitator for ERα-DNA interactions. It binds to specific DNA regions, opening the chromatin for ERα to bind. It “pre-marks” these sites in the genome even in the absence of estrogen. In fact, FOXA1 is frequently overexpressed in ER+ breast cancers, suggesting it has a crucial role in driving tumor growth. As such, FOXA1 is an attractive therapeutic target that already serves as a great biomarker for many types of breast cancers. Inhibiting FOXA1 can potentially block ER activity and inhibit growth of ER+ breast cancer, especially in those resistant to anti-estrogen therapies, such as tamoxifen. In this project, we identified sites that FOXA1 opens and correlated them with SNP mutations commonly found in the Hispanic population. The presence of these SNPs portends a worse outcome in Hispanic patients. To assess which open chromatin regions are crucial for breast cancer pathogenesis, a ChIP-seq analysis was done on vehicle-treated and estrogen-treated samples to determine FOXA1 binding sites. After identifying gained, lost, and differentially expressed peaks set, these were compared to genome-wide association studies (GWAS) of Hispanic patients to develop an understanding of how much overlap is common between sites of mutations and open sections of chromatin due to FOXA1. Through our analysis, we uncovered a subset of FOXA1 binding sites that overlap with sites of inherited mutation in Hispanic patients. This informs on the subset of genes that are linked to breast cancer and potential therapeutic targets. Citation Format: Hemakshat Sharma, Alyssa Maria Arreola, Frances L. Heredia, Hector L. Franco, Julie Dutil. FOXA1 as a pioneer factor in ERα-DNA interactions and its therapeutic potential in ER+ breast cancer: Insights from ChIP-seq and GWAS in Hispanic populations [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B011.

Evidence of the Link between Stroma Remodeling and Prostate Cancer Prognosis.

Prostate cancer (PCa), the most commonly diagnosed cancer in men worldwide, is particularly challenging for oncologists when a precise prognosis needs to be established. Indeed, the entire clinical management in PCa has important drawbacks, generating an intense debate concerning the possibility to individuate molecular biomarkers able to avoid overtreatment in patients with pathological indolent cancers. To date, the paradigmatic change in the view of cancer pathogenesis prompts to look for prognostic biomarkers not only in cancer epithelial cells but also in the tumor microenvironment. PCa ecology has been defined with increasing details in the last few years, and a number of promising key markers associated with the reactive stroma are now available. Here, we provide an updated description of the most biologically significant and cited prognosis-oriented microenvironment biomarkers derived from the main reactive processes during PCa pathogenesis: tissue adaptations, inflammatory response and metabolic reprogramming. Proposed biomarkers include factors involved in stromal cell differentiation, cancer-normal cell crosstalk, angiogenesis, extracellular matrix remodeling and energy metabolism.

Single‐cell transcriptomic atlas reveals immune and metabolism perturbation of depression in the pathogenesis of breast cancer

Single‐cell transcriptomic atlas reveals immune and metabolism perturbation of depression in the pathogenesis of breast cancer

G6pdN126D Variant Increases the Risk of Developing VEGFR (Vascular Endothelial Growth Factor Receptor) Blocker-Induced Pulmonary Vascular Disease.

G6PD (glucose-6-phosphate-dehydrogenase) is a key enzyme in the glycolytic pathway and has been implicated in the pathogenesis of cancer and pulmonary hypertension-associated vascular remodeling. Here, we investigated the role of an X-linked G6pd mutation (N126D polymorphism), which is known to increase the risk of cardiovascular disease in individuals from sub-Saharan Africa and many others with African ancestry, in the pathogenesis of pulmonary hypertension induced by a vascular endothelial cell growth factor receptor blocker used for treating cancer. CRISPR-Cas9 genome editing was used to generate the G6pd variant (N126D; G6pdN126D) in rats. A single dose of the vascular endothelial cell growth factor receptor blocker sugen-5416 (SU; 20 mg/kg in DMSO), which is currently in a Phase 2/3 clinical trial for cancer treatment, was subcutaneously injected into G6pdN126D rats and their wild-type littermates. After 8 weeks of normoxic conditions, right ventricular pressure and hypertrophy, pulmonary artery remodeling, the metabolic profile, and cytokine expression were assessed. Right ventricular pressure and pulmonary arterial wall thickness were increased in G6PDN126D+SU/normoxic rats. Simultaneously, levels of oxidized glutathione, inositol triphosphate, and intracellular Ca2+ were increased in the lungs of G6PDN126D+SU/normoxic rats, whereas nitric oxide was decreased. Also increased in G6PDN126D+SU/normoxic rats were pulmonary levels of plasminogen activator inhibitor-1, thrombin-antithrombin complex, and expression of proinflammatory cytokines CCL3 (chemokine [C-C motif] ligand), CCL5, and CCL7. Our results suggest G6PDN126D increases inositol triphosphate-Ca2+ signaling, inflammation, thrombosis, and hypertrophic pulmonary artery remodeling in SU-treated rats. This suggests an increased risk of vascular endothelial cell growth factor receptor blocker-induced pulmonary hypertension in those carrying this G6PD variant.

The Diagnostic Histopathological Techniques of Prostate Cancer

The histology of the prostate is critical for understanding both normal prostate function and the pathogenesis of prostate cancer. The prostate gland comprises a complex architecture that includes a functional secretory epithelium, a basal epithelium, and a supporting stroma with a variety of cell types. Prostate adenocarcinoma is the most common form of prostate cancer, characterized by acinar-type architecture. The consistent ranking of prostate cancer as a leading cause of cancer diagnosis and mortality reflects an urgent need for ongoing research into its etiology, risk factors, and effective treatment modalities. This review article cast a light on the diagnostic histopathological techniques of prostate cancer.

The role of Fusobacterium nucleatum in the pathogenesis of colon cancer.

Previously, many studies have reported changes in the gut microbiota of patients with colorectal cancer (CRC). While CRC is a well-described disease, the relationship between its development and features of the intestinal microbiome is still being understood. Evidence linking Fusobacterium nucleatum enrichment in colorectal tumor tissue has prompted the elucidation of various molecular mechanisms and tumor-promoting attributes. In this review we highlight various aspects of our understanding of the relationship between the development of CRC and the alteration of intestinal microbiome, focusing specifically on the role of F. nucleatum. As the amount of F. nucleatum DNA in CRC tissue is associated with shorter survival, it may potentially serve as a prognostic biomarker, and most importantly may open the door for a role in CRC treatment.

Navigating heme pathways: the breach of heme oxygenase and hemin in breast cancer.

Breast cancer remains a significant global health challenge, with diverse subtypes and complex molecular mechanisms underlying its development and progression. This review comprehensively examines recent advances in breast cancer research, with a focus on classification, molecular pathways, and the role of heme oxygenases (HO), heme metabolism implications, and therapeutic innovations. The classification of breast cancer subtypes based on molecular profiling has significantly improved diagnosis and treatment strategies, allowing for tailored approaches to patient care. Molecular studies have elucidated key signaling pathways and biomarkers implicated in breast cancer pathogenesis, shedding light on potential targets for therapeutic intervention. Notably, emerging evidence suggests a critical role for heme oxygenases, particularly HO-1, in breast cancer progression and therapeutic resistance, highlighting the importance of understanding heme metabolism in cancer biology. Furthermore, this review highlights recent advances in breast cancer therapy, including targeted therapies, immunotherapy, and novel drug delivery systems. Understanding the complex interplay between breast cancer subtypes, molecular pathways, and innovative therapeutic approaches is essential for improving patient outcomes and developing more effective treatment strategies in the fight against breast cancer.

Identification of Tumor Suppressive miR-144-5p Targets: FAM111B Expression Accelerates the Malignant Phenotypes of Lung Adenocarcinoma.

Accumulating evidence suggests that the passenger strands microRNAs (miRNAs) derived from pre-miRNAs are closely involved in cancer pathogenesis. Analysis of our miRNA expression signature of lung adenocarcinoma (LUAD) and The Cancer Genome Atlas (TCGA) data revealed that miR-144-5p (the passenger strand derived from pre-miR-144) was significantly downregulated in LUAD tissues. The aim of this study was to identify therapeutic target molecules controlled by miR-144-5p in LUAD cells. Ectopic expression assays demonstrated that miR-144-5p attenuated LUAD cell aggressiveness, e.g., inhibited cell proliferation, migration and invasion abilities, and induced cell cycle arrest and apoptotic cells. A total of 18 genes were identified as putative cancer-promoting genes controlled by miR-144-5p in LUAD cells based on our in silico analysis. We focused on a family with sequence similarity 111 member B (FAM111B) and investigated its cancer-promoting functions in LUAD cells. Luciferase reporter assay showed that expression of FAM111B was directly regulated by miR-144-5p in LUAD cells. FAM111B knockdown assays showed that LUAD cells significantly suppressed malignant phenotypes, e.g., inhibited cell proliferation, migration and invasion abilities, and induced cell cycle arrest and apoptotic cells. Furthermore, we investigated the FAM111B-mediated molecular networks in LUAD cells. Identifying target genes regulated by passenger strands of miRNAs may aid in the discovery of diagnostic markers and therapeutic targets for LUAD.

The Effect of Perioperative Cimetidine on the Outcomes of Stage 2 Melanoma

Objectives The use of immunotherapies in the treatment of melanoma has significantly improved the survival of patients with advanced disease. Historically, histamine has been implicated in the pathogenesis of several cancers. Cimetidine does play a role in modulating the immune system and was advocated as an immunotherapeutic agent since the 1970s. Cimetidine has been showing promise in conjunction with standard care in many cancers in vitro and in vivo. However, its effects in melanoma have not been explored yet. Our study was designed to determine if cimetidine taken in the perioperative period improves the disease-free survival (DFS) or overall survival in patients with the American Joint Committee on Cancer, seventh edition (AJCC 7) stage 2 melanoma. Materials and Methods We have reviewed all the patients with stage 2 melanoma in our center in a retrospective cohort to assess the difference in survival between patients who received H2 blockers in the perioperative period and those who did not. Statistical Analysis and Results Thirty-two patients were included in the analysis. Nine of 32 patients received H2 blockers in the perioperative period. All the patients were males except for one female in the control group (4.3%). The age in the analyzed population ranged between 51 and 92 years; the median age was 70 years (mean: 71; standard deviation: 10). The median overall survival of the patients who received H2 blockers was 112.7 months and it was 77.2 months for those who did not receive H2 blockers. There was no difference in DFS between the two groups (p = 0.5395), and there was no difference in the overall survival (p = 0.4770). The cumulative dose was strongly correlated with the overall survival in the patients who received H2 blockers (r = 0.8341, p = 0.0196). Conclusion Despite having a small treatment group, we were able to detect a strong correlation between the cumulative dose of H2 blockers received and the overall survival.

Resveratrol inhibits pancreatic cancer proliferation and metastasis by depleting senescent tumor-associated fibroblasts.

Pancreatic cancer, a formidable gastrointestinal neoplasm, is characterized by its insidious onset, rapid progression, and resistance to treatment, which often lead to a grim prognosis. While the complex pathogenesis of pancreatic cancer is well recognized, recent attention has focused on the oncogenic roles of senescent tumor-associated fibroblasts. However, their precise role in pancreatic cancer remains unknown. Resveratrol is a natural polyphenol known for its multifaceted biological actions, including antioxidative and neuroprotective properties, as well as its potential to inhibit tumor proliferation and migration. Our current investigation builds on prior research and reveals the remarkable ability of resveratrol to inhibit pancreatic cancer proliferation and metastasis. To explore the potential of resveratrol in inhibiting pancreatic cancer by targeting senescent tumor-associated fibroblasts. Immunofluorescence staining of pancreatic cancer tissues revealed prominent coexpression of α-SMA and p16. HP-1 expression was determined using immunohistochemistry. Cells were treated with the senescence-inducing factors known as 3CKs. Long-term growth assays confirmed that 3CKs significantly decreased the CAF growth rate. Western blotting was conducted to assess the expression levels of p16 and p21. Immunofluorescence was performed to assess LaminB1 expression. Quantitative real-time polymerase chain reaction was used to measure the levels of several senescence-associated secretory phenotype factors, including IL-4, IL-6, IL-8, IL-13, MMP-2, MMP-9, CXCL1, and CXCL12. A scratch assay was used to assess the migratory capacity of the cells, whereas Transwell assays were used to evaluate their invasive potential. Specifically, we identified the presence of senescent tumor-associated fibroblasts within pancreatic cancer tissues, linking their abundance to cancer progression. Intriguingly, Resveratrol effectively eradicated these fibroblasts and hindered their senescence, which consequently impeded pancreatic cancer progression. This groundbreaking discovery reinforces Resveratrol's stature as a potential antitumor agent and positions senescent tumor-associated fibroblasts as pivotal contenders in future therapeutic strategies against pancreatic cancer.