Anticancer research最新文献

Background/aim: Dose-dense chemotherapy is recommended for patients with breast cancer who have a high recurrence risk. However, whether dose-dense neoadjuvant chemotherapy (ddNAC) improves patient prognoses compared to the normal-dose regimen remains controversial. In this study, we evaluated the predictive value of immune activities on short-term outcomes for patients treated with ddNAC.

Patients and methods: We classified 82 patients with human epidermal growth factor receptor 2-negative breast cancer treated with NAC into a normal dose group (62 patients) and ddNAC group (20 patients) and examined the differences in clinicopathological features. The ddNAC group was further divided according to patient responses to NAC and the predictive factors for pathological complete response (pCR) were evaluated.

Results: There were no differences in the clinicopathological features before NAC between the normal dose and ddNAC groups. Although the pCR rates tended to be higher in the ddNAC group compared than those in the normal dose group (35.0% vs. 25.8%), there was not significant difference (p=0.264). Among all patients treated with ddNAC, the absolute lymphocyte count decreased and the neutrophil-to-lymphocyte ratio increased during dose-dense doxorubicin plus cyclophosphamide treatment. There was no significant correlation between the pCR and any of the clinicopathological parameters tested including systemic peripheral markers and tumor-infiltrating lymphocyte levels.

Conclusion: ddNAC affected the levels of systemic peripheral immune markers. However, monitoring these markers may not be useful for predicting responses to ddNAC.

Background/aim: Non-small-cell lung cancer (NSCLC) comprises approximately 85% of lung cancer. Treatment with docetaxel prolongs the survival of patients with NSCLC. However, the development of resistance to docetaxel has compromised its efficacy. Caffeic acid phenethyl ester (CAPE) has been reported to suppress survival and radiotherapy resistance in lung cancer cells. We determined in this study if combination treatment of docetaxel with CAPE suppresses the proliferation and the survival of NSCLC cells more effectively.

Materials and methods: Proliferation, viability, flow cytometric and comet assays were used to examine the difference in anticancer effects of combined treatment as compared to docetaxel treatment alone. Western blot and gene overexpression were used to unravel the underlying molecular mechanism.

Results: Treatment with docetaxel or CAPE alone dose-dependently suppressed the proliferation and survival of H1299 and A549 cells. Combined treatment of docetaxel with CAPE caused greater inhibition of survival of H1299 and A549 cells. Docetaxel alone and the combined treatment both dose-dependently increased apoptosis of H1299 cells; however, combined treatment induced much more apoptosis than docetaxel alone. Combined treatment suppressed the protein expression of phospho-protein kinase B (AKT, Ser 473), S-phase protein 2 (SKP2), MYC proto-oncogene bHLH transcription factor (c-MYC), epidermal growth factor receptor (EGFR), phospho-EGFR (Tyr 1045, and Tyr 992) but increased levels of cleaved caspase 3 and cytochrome c proteins in H1299 and A549 cells. The inhibition of expression of SKP2, c-MYC, phospho-EGFR (Tyr 992) proteins by combined treatment was significantly greater than that with treatment using either CAPE or docetaxel alone. Overexpression of c-MYC in rescued proliferation of H1299 cells under combination treatment.

Conclusion: Our study revealed that the combination of CAPE with docetaxel is more effective at reducing the proliferation and survival of NSCLC cells, and this is via inhibition of c-MYC. Combined therapy of docetaxel and CAPE may benefit patients with NSCLC.

Background/aim: Aberrant activation of the Wnt/β-catenin signaling pathway contributes to the pathogenesis of acute myelogenous leukemia (AML). Thus, targeting this pathway offers a promising therapeutic strategy against AML. Here, we synthesized a novel dipeptide-type inhibitor of the Wnt/β-catenin signaling pathway, compound #41, and explored its anti-tumor effects on AML cells.

Materials and methods: We evaluated the inhibitory effect of compound #41 on T cell factor (TCF)/β-catenin transcriptional activity using a luciferase (Luc) reporter assay. The anti-tumor effects were assessed on KG1a and MV4;11 human AML cells using RT-qPCR, western blotting, and WST-8, cell cycle, and apoptosis assays. Differentially expressed genes were analyzed by RNA-sequencing (RNA-seq). Additionally, we investigated the in vivo effects of compound #41 using KG1a-Luc/GFP cells in an orthotopic mouse model.

Results: The Luc reporter assay showed that compound #41 decreased the TCF/β-catenin transcriptional activity. Compound #41 blocked the cell cycle progression, inhibited cell proliferation, and induced apoptosis in AML cells. Treatment with compound #41 down-regulated the expression of β-catenin, Survivin, and β-catenin-specific target genes, as demonstrated by RNA-seq. In vivo analysis showed that compound #41 blocked the expansion of KG1a-Luc/GFP cells in the bone marrow and prolonged the overall survival of KG1a-Luc/GFP-transplanted mice.

Conclusion: Compound #41 suppressed the Wnt/β-catenin signaling pathway by reducing CTNNB1 levels and induced apoptosis in AML cells. Furthermore, compound #41 inhibited the proliferation of KG1a-Luc/GFP cells in the bone marrow and extended the overall survival of mice. Thus, compound #41 is an attractive Wnt/β-catenin signaling pathway inhibitor of AML.

Background/aim: This study aimed to investigate the effect and underlying mechanism of inhibiting glutamine synthetase (GS) on the vascular permeability of gliomas.

Materials and methods: C6 glioma rat models were randomly divided into control and L-methionine sulfoximine (MSO) treatment groups. MSO was intraperitoneally injected once every other day for a total of three injections in the MSO group. We assessed the effect of MSO on tumor vascular permeability by tail vein injection of Evans blue dye. GS activity, glutamate (Glu) concentration, glutamine (Gln) concentration, and arginine concentration in tumor tissues were measured using the corresponding kits. qPCR experiments were then conducted to examine the effect of glutamate concentration on N-methyl-D-aspartate (NMDA) receptor expression. Finally, the nitric oxide synthase (NOS) assay kit and the nitric oxide (NO) assay kit were employed to detect NOS activity and NO concentration changes, respectively.

Results: Increased glioma tumor vascular permeability was observed after intraperitoneal injection of MSO; MSO acted as an inhibitor of GS, leading to a decrease in GS activity; increased glutamate levels caused activation of NMDA receptors and further activation of NOS; additionally, elevated NO levels were detected in association with an increase in arginine and NOS.

Conclusion: Inhibiting GS results in increased vascular permeability in gliomas, which is associated with elevated NO levels and the vasodilatory effects of NO.

Background/aim: The systemic immune-inflammation index (SII) is a calculated biomarker developed to predict the prognosis of malignant tumors. This study evaluated the influence of the SII in patients with esophageal cancer (EC) who underwent curative resection.

Patients and methods: Patients who underwent radical esophagectomy and lymph node dissection for EC were enrolled. The SII was calculated as follows: neutrophil count (cell/mm³) × platelet count (cell/mm³ ×10³)/lymphocyte count (cell/mm³). The SII, patient characteristics, overall survival (OS), and recurrence-free survival (RFS) were assessed.

Results: A total of 180 patients were included in this study. The cutoff value of the SII was set at 500 according to previous studies. Of the 180 patients, 100 were classified into the SII-high group and 80 into the SII-low group. The 3- and 5-year OS rates were 59.0% and 54.0%, respectively, in the SII-high group and 80.0% and 75.0%, respectively, in the SII-low group, showing significant differences between the groups (p=0.001). A multivariate analysis for the OS demonstrated that the SII was an independent prognostic factor (hazard ratio=2.333, 95% confidence interval=1.411-3.860, p<0.001), with similar results obtained for the RFS. Furthermore, hematological recurrence was significantly higher in the SII-high group than in the SII-low group (36.0% vs. 17.5%, p=0.006).

Conclusion: The preoperative SII was an independent prognostic factor for OS and RFS in patients with EC who underwent curative resection. Thus, the SII can be a useful marker for the treatment and management of EC.

Background/aim: Host microbiota dysbiosis has been recognized as a key factor in lung cancer. However, the specific diversity and composition of microbiota in lung cancer patients remain unknown. This single-center prospective observational study analyzed both saliva and fecal samples from 74 participants [lung cancer (LC) patients: n=53; lung inflammation (LI) patients: n=11; healthy control (HC): n=10].

Patients and methods: We performed 16S ribosomal RNA gene sequencing and analyzed the associations between oral and gut microbiota diversity and composition across the three groups.

Results: Alpha diversity of the oral microbiota was significantly lower in the LC group than in the HC group (Chao 1, p=0.004; Simpson, p=0.018; Shannon, p=0.009). Beta diversity of both oral and gut microbiota showed significant differences among the three groups (PERMANOVA, oral: p=0.005; gut: p=0.002). Compositional differences in the oral microbiota were observed between the HC and LC or LI groups; in particular, Bacilli class, Streptococcaceae family, Streptococcus genus, Firmicutes phylum, and Lactobacillales order were more abundant in the LC group. Additionally, six oral-related microbiota showed significant abundance in the gut of the LC group (p=0.00182).

Conclusion: The oral microbiota in lung cancer patients is significantly different from that in healthy individuals. Specific changes in oral microbiota and oral-related gut microbiota compositions were evident in lung cancer patients. These findings might be useful for identifying novel biomarkers to predict the risk of lung cancer and prevent the disease.

Background/aim: Nestin, an intermediate filament protein expressed in stem/progenitor cells of the developing central nervous system, is involved in the progression and poor prognosis of various malignancies. Difficulties in small-cell lung cancer (SCLC) tissue biopsy reduce the accuracy of immunohistochemistry analyses; therefore, evaluating nestin in blood samples is preferred in clinical practice. This study examined the clinical significance of plasma nestin levels in SCLC.

Patients and methods: A single-center observational study of patients with untreated SCLC was conducted from 2019 to 2021. We determined plasma nestin levels before and after two treatment cycles, and the results were analyzed in relation to clinical outcome.

Results: Twenty-five SCLC patients were enrolled. When patients were divided into high-plasma nestin (h-pNES) and low-plasma nestin (l-pNES) groups based on pre-treatment plasma nestin levels, among nine extensive-stage SCLC (ES-SCLC) patients treated with immune checkpoint inhibitor (ICI) combination chemotherapy, h-pNES patients had shorter progression-free survival and overall survival than l-pNES patients (p=0.0150 and p=0.0353, respectively). CD8/FoxP3- and CD8/CD3-positive T-cell ratios in biopsy specimens from h-pNES patients were lower than those of l-pNES patients (p=0.0458 and p=0.0218, respectively).

Conclusion: This pilot study indicated that h-pNES patients exhibited a poorer response to ICI combination chemotherapy than l-pNES patients. Plasma nestin levels are easy to measure in ES-SCLC, in which sufficient tissue is difficult to obtain, and may potentially serve as a predictor of response to ICI combination chemotherapy. A large cohort is needed to investigate the clinical role of plasma nestin.

Background/aim: Pancreatic cancer is the fourth leading cause of cancer-related death in both men and women worldwide. The 5-year relative survival rate for pancreatic ductal adenocarcinoma (PDAC) is 10%, which is the lowest among all cancers. This study aimed to find more effective targets to improve the diagnosis, prognostic prediction, and treatment of PDAC.

Materials and methods: Three datasets were selected from the GEO database. Correlation analysis was used to screen the datasets and samples. Differentially expressed genes were identified using GEO2R. Metascape was used to perform pathway and process enrichment analysis. Survival analysis using the GEPIA2 and Kaplan-Meier plotter databases was conducted to filter hub genes. Principal component analysis and LASSO regression analyses were used to further filter the key genes. Gene expression in PDAC and normal tissues and in different pathological stages was analyzed using the GEPIA2 database. Thereafter, gene expression was detected in three PDAC and HPDE cell lines using real-time polymerase chain reaction.

Results: LPAR5, CYP2C18, SERPINH1, ACSL5, and HCAR3 exhibited higher transcription levels in PDAC tissues compared to matched normal tissues, whereas the PNLIP expression was lower. LPAR5, CYP2C18, SERPINH1 and ACSL5 were markedly upregulated in stage IV PDAC. LPAR5, CYP2C18, SERPINH1 and ACSL5 were upregulated in PDAC cell lines. Further verification suggested that the expression levels of these four genes were closely related to histological type, pathologic stage, therapeutic effects and prognosis of pancreatic cancer.

Conclusion: LPAR5, CYP2C18, SERPINH1 and ACSL5 may serve as potential diagnostic, prognostic, and therapeutic targets for PDAC.

Background/aim: The presence of tumor-infiltrating lymphocytes (TILs) has been demonstrated as a prognostic factor in colorectal cancer after surgical resection of malignancy, but knowledge on their role in pancreatic cancer is lacking. The Immunoscore (IS) assesses TILs at the core of the tumor (CT) and invasive margin (IM) and is being evaluated as a new concept in tumor immunity. The aim of this study was to evaluate the relationship between IS and prognosis in PDAC.

Patients and methods: The IS was analyzed by immunohistochemistry using surgical tissue blocks from 131 patients with pancreatic ductal adenocarcinoma (PDAC) who underwent surgery to investigate the relationship between immune cell infiltration into the tumor and prognosis in PDAC.

Results: A high IS in both CT and IM of the tumor was significantly associated with prolonged overall survival (OS) (p<0.01) and relapse-free survival (RFS) (p<0.01). In multivariate logistic regression models adjusted for clinical pathology data, IS predicted survival and recurrence (p<0.01 and p<0.01, respectively). Moreover, in patients who received preoperative chemotherapy, a high IS was statistically significantly associated with longer OS and RFS (p<0.01 and p<0.01, respectively).

Conclusion: The immunohistochemically assessed IS might be a useful prognostic marker for patients with PDAC who underwent primary tumor resection.

Background/aim: Given the high frequency and mortality rate of lung cancer, diverse molecular studies have been undertaken to understand cancer pathophysiology and develop novel treatment strategies. The PDIA4 gene, which is involved in protein assembly and endoplasmic reticulum homeostasis, is overexpressed in various lung cancer subtypes. However, its exact function in lung adenocarcinoma (LUAD) remains elusive. The study aimed to investigate the role of PDIA4 in LUAD and explore its role as double-agent gene.

Materials and methods: PDIA4 expression was knocked out in A549 and LA-4 lung adenoma cells using the Crispr/Cas9 technology. Cell growth, migration, and apoptosis were analyzed in control and PDIA4-deficient cells.

Results: PDIA4 deficiency resulted in increased cell growth, enhanced migration capacity, and greater resistance to apoptosis in both A549 and LA-4 lung cancer cells. Mechanistically, up-regulation of oxidative stress followed by NF-[Formula: see text]B activation may contribute to tumor-promoting effects observed upon PDIA4 silencing.

Conclusion: PDIA4 appears to function as a tumor suppressor in lung adenocarcinoma, suggesting that PDIA4 may act as a double-agent gene, with roles both on tumor suppression and promotion depending on the context.