Combined COX-2/PPARγ Expression as Independent Negative Prognosticator for Vulvar Cancer Patients.
Ontology highlight
ABSTRACT:
SUBMITTER: Ansorge N
PROVIDER: S-EPMC8001561 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Vulvar cancer incidence numbers have been steadily rising over the past decades. In particular, the number of young patients with vulvar cancer has recently increased. Therefore, the need to identify new prognostic factors and, in addition, therapeutic options for vulvar carcinoma is more apparent. The aim of this study was to analyze the influx of COX-2 positive tumor-infiltrating lymphocytes and monocytes and their influence on prognosis. Using subtyping by immunofluorescence, the majority of COX-2 expressing immune cells were identified as FOXP3-positive regulatory T cells. In addition, peri- and intra-tumoral macrophages in the same tumor tissue were detected simultaneously as M2-polarized macrophages. COX-2 positive immune cells were independent negative prognostic markers in long-term overall survival of patients with vulvar cancer. These results show an influence of immune cell infiltration for vulvar carcinoma patients. Immune cell infiltration and immune checkpoint expression may, therefore, become interesting targets for further research on new vulvar cancer treatment strategies.
| S-EPMC9099805 | biostudies-literature
Project description:Retinoid X receptor α (RXRα) is a nuclear receptor (NR) which functions as the primary heterodimeric partner of other NRs including the peroxisome proliferator-activated receptor γ (PPARγ). We previously reported that, in breast cancers (BC), the subcellular localization of these two receptors was strongly associated with patient prognosis. In the present work, we investigated the prognosis value of the combined cytoplasmic expression of RXRα and PPARγ using a retrospective cohort of 250 BC samples. Patients with tumors expressing both NRs in tumor cell cytoplasm exhibited a significant shorter overall (OS) and disease-free survival (DFS). This was also observed for patients with stage 1 tumors. Cox univariate analysis indicated that patients with tumors coexpressing RXRα and PPARγ in the cytoplasm of tumor cells have a decreased 5 y OS rate. Cytoplasmic co-expression of the two NRs significantly correlated with HER2 positivity and with NCAD and CD133, two markers of tumor aggressiveness. Finally, in Cox multivariate analysis, the co-expression of RXRα and PPARγ in the cytoplasm appeared as an independent OS prognosticator. Altogether, this study demonstrates that the cytoplasmic co-expression of RXRα and PPARγ could be of relevance for clinicians by identifying high-risk BC patients, especially amongst those with early and node-negative disease.
| S-EPMC8997589 | biostudies-literature
Project description:So far, studies about targeted therapies and predictive biomarkers for vulva carcinomas are rare. The leucine zipper downregulated in cancer 1 gene (LDOC1) has been identified in various carcinomas as a tumor-relevant protein influencing patients' survival and prognosis. Due to the lack of information about LDOC1 and its exact functionality, this study focuses on the expression of LDOC1 in vulvar carcinoma cells and its surrounding immune cells as well as its correlation to clinicopathological characteristics and prognosis. Additionally, a possible regulation of LDOC1 in vulvar cancer cell lines via the NF-κB signaling pathway was analyzed. Vulvar carcinoma sections of 157 patients were immunohistochemically stained and examined regarding LDOC1 expression by using the immunoreactive score (IRS). To characterize LDOC1-positively stained immune cell subpopulations, immunofluorescence double staining was performed. The effect of the NF-κB inhibitor C-DIM 12 (3,3'-[(4-chlorophenyl)methylene]bis[1 H-indole]) on vulvar cancer cell lines A431 and SW 954 was measured according to MTT and BrdU assays. Baseline expression levels of LDOC1 in the vulvar cancer cell lines A431 and SW 954 was analyzed by real-time PCR. LDOC1 was expressed by about 90% of the cancer cells in the cytoplasm and about half of the cells in the nucleus. Cytoplasmatic expression of LDOC1 was associated with decreased ten-year overall survival of the patient, whereas nuclear staining showed a negative association with disease-free survival. Infiltrating immune cells were mainly macrophages followed by regulatory T cells. Incubation with C-DIM 12 decreased the cell viability and proliferation of vulvar cancer cell line A431, but not of cell line SW 954. LDOC1 expression on mRNA level was twice as high in the cell line A431 compared to the cell line SW 954. Overexpression of LDOC1 was associated with unfavorable overall and disease-free survival. Tumor growth could be inhibited by C-DIM 12 in vitro if the expressed LDOC1 level was high enough.
| S-EPMC7730493 | biostudies-literature
Project description:Inhibition of the programmed cell death protein-1/ligand-1 (PD-1/PD-L1) axis has opened a new era in the treatment of solid cancers. However, there is no data on the expression and relevance of PD-L1 in Western gallbladder cancer (GBC). We assessed PD-L1 immunohistochemically in 131 GBC patients as Tumor Proportion Score (TPS), Immune Cell Score (IC) and Combined Positivity Score (CPS). Tumor cells expressed PD-L1 in a subset of 14.7% GBC patients at a TPS cut-off of 1%. Higher PD-L1 levels above 10% and 25% TPS were reached in 4.7% and 3.1% of GBC cases, respectively. At a 10% cut-off, TPS was associated with distinct histomorphological subtypes and correlated with poor tumor differentiation. Survival analysis revealed a TPS above 10% to be a highly significant and independent negative prognosticator in GBC. PD-L1 expression was associated with increased CD4+, CD8+ and PD-1+ immune cell densities. In 14.8% of the cases, scattered immune cells expressed T-cell immunoreceptor with Ig and ITIM domains (TIGIT), which was correlated to tumoral expression of its ligand CD155. We here show that a high PD-L1 expression confers a negative prognostic value in Western-world GBC and highlight the TIGIT/CD155 immune checkpoint as a potential new target for GBC immunotherapy.
| S-EPMC8038183 | biostudies-literature
Project description:Simple Summary Within this study we investigated the expression of EP4 in vulvar cancer, its correlation with clinic-pathological parameters, its association with overall survival, and the effect oft EP4 antagonism on vulvar cancer cells, aiming to find a prognostic and potentially targetable marker in vulvar cancer. Cox regression revealed EP4 as an independent negative prognostic factor for overall survival when other factors were taken into account. We could show in vitro that EP4 antagonism attenuates both viability and proliferation of vulvar cancer cells. Further investigation of the EP4 signaling pathway and its role in the micro tumor environment in vulvar cancer could lead to a deeper understanding of the molecular mechanisms of cancer genesis. Abstract New prognostic factors and targeted therapies are urgently needed to improve therapeutic outcomes in vulvar cancer patients and to reduce therapy related morbidity. Previous studies demonstrated the important role of prostaglandin receptors in inflammation and carcinogenesis in a variety of tumor entities. In this study, we aimed to investigate the expression of EP4 in vulvar cancer tissue and its association with clinicopathological data and its prognostic relevance on survival. Immunohistochemistry was performed on tumor specimens of 157 patients with vulvar cancer treated in the Department of Obstetrics and Gynecology, Ludwig-Maximilian-University of Munich, Germany, between 1990 and 2008. The expression of EP4 was analyzed using the well-established semiquantitative immunoreactivity score (IRS) and EP4 expression levels were correlated with clinicopathological data and patients’ survival. To specify the tumor-associated immune cells, immunofluorescence double staining was performed on tissue samples. In vitro experiments including 5-Bromo-2′-Deoxyuridine (BrdU) proliferation assay and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromid (MTT) viability assay were conducted in order to examine the effect of EP4 antagonist L-161,982 on vulvar carcinoma cells. EP4 expression was a common finding in in the analyzed vulvar cancer tissue. EP4 expression correlated significantly with tumor size and FIGO classification and differed significantly between keratinizing vulvar carcinoma and nonkeratinizing carcinoma. Survival analysis showed a significant correlation of high EP4 expression with poorer overall survival (p = 0.001) and a trending correlation between high EP4 expression and shorter disease-free survival (p = 0.069). Cox regression revealed EP4 as an independent prognostic factor for overall survival when other factors were taken into account. We could show in vitro that EP4 antagonism attenuates both viability and proliferation of vulvar cancer cells. In order to evaluate EP4 as a prognostic marker and possible target for endocrinological therapy, more research is needed on the influence of EP4 in the tumor environment and its impact in vulvar carcinoma.
| S-EPMC8003514 | biostudies-literature
Project description:BackgroundSeveral lines of evidence indicate that Sirt1, a class III histone deacetylase (HDAC) is implicated in the initiation and progression of malignancies and thus gained attraction as druggable target. Since data on the role of Sirt1 in pancreatic ductal adenocarcinoma (PDAC) are sparse, we investigated the expression profile and prognostic significance of Sirt1 in vivo as well as cellular effects of Sirt1 inhibition in vitro.MethodsSirt1 expression was analyzed by immunohistochemistry in a large cohort of PDACs and correlated with clinicopathological and survival data. Furthermore, we investigated the impact of overexpression and small molecule inhibition on Sirt1 in pancreatic cancer cell culture models including combinatorial treatment with chemotherapy and EGFR-inhibition. Cellular events were measured quantitatively in real time and corroborated by conventional readouts including FACS analysis and MTT assays.ResultsWe detected nuclear Sirt1 expression in 36 (27.9%) of 129 PDACs. SIRT1 expression was significantly higher in poorly differentiated carcinomas. Strong SIRT1 expression was a significant predictor of poor survival both in univariate (p?=?0.002) and multivariate (HR 1.65, p?=?0.045) analysis. Accordingly, overexpression of Sirt1 led to increased cell viability, while small molecule inhibition led to a growth arrest in pancreatic cancer cells and impaired cell survival. This effect was even more pronounced in combinatorial regimens with gefitinib, but not in combination with gemcitabine.ConclusionsSirt1 is an independent prognosticator in PDACs and plays an important role in pancreatic cancer cell growth, which can be levered out by small molecule inhibition. Our data warrant further studies on SIRT1 as a novel chemotherapeutic target in PDAC.
| S-EPMC3850795 | biostudies-literature
Project description:CXC chemokine receptor 1 (CXCR1) signaling has been shown as an essential molecular nexus regarding cancer cell proliferation, tumor inflammation, and angiogenesis in clear cell renal cell carcinoma (ccRCC). The aim of this study was to investigate the prognostic significance of CXCR1 in patients with non-metastatic ccRCC. Data from 446 consecutive non-metastatic ccRCC patients, operated between 2003 and 2008 at a single institution, were evaluated retrospectively. The cohort was split into a training set (n = 223) and a validation set (n = 223). CXCR1 expression was assessed by immunohistochemistry staining and its association with clinicopathologic features and prognosis were evaluated. High CXCR1 epithelial expression presented prognostic value, and indicated poor overall survival (OS) (P = 0.010 and P = 0.015, respectively) and recurrence-free survival (P = 0.011 and P = 0.019, respectively) in the training and validation sets. The incorporation of CXCR1 into the T stage and SSIGN score would help to refine individual risk stratification. Multivariate analysis identified increased epithelial CXCR1 was statistically significantly associated with a poor outcome for OS (HR [95% CI] 1.808 [1.184-2.761]; P = 0.006) and RFS (HR [95% CI] 1.570 [1.076-2.290]; P = 0.019) in all non-metastatic ccRCC patients. Predictive nomograms were generated with identified independent prognosticators to assess patient overall survival and recurrence-free survival at 3, 5 and 10 y. Furthermore, high CXCR1 expression were correlated with elevated infiltrated neutrophils and enriched MMP family gene expression. To conclude, high CXCR1 level within epithelial area represented a potential independent negative prognostic factor regarding OS and RFS in non-metastatic ccRCC patients after nephrectomy.
| S-EPMC5674945 | biostudies-literature
Project description:BackgroundThe advanced lung cancer inflammation index (ALI), which comprehensively evaluates the patient body composition and inflammation/nutritional status, is reportedly associated with the patient outcome in lung cancer. However, the clinical significance in colorectal cancer (CRC) patients after curative resection remains unclear.MethodsA total of 813 CRC patients after curative resection between April 2005 and June 2019 in a single institution were retrospectively enrolled. The association of the preoperative ALI (calculated as follows: body mass index × albumin value/neutrophil-to-lymphocyte ratio) with clinicopathological factors, postoperative complications, and survival was analyzed.ResultsA low ALI was significantly associated with male gender, older age, a higher depth of tumor invasion, progressed TNM stage, and preoperative carcinoembryonic antigen (CEA) positivity. Both postoperative complications and severe complications occurred more frequently in the ALI-low group than in the ALI-high group (P < .001 and P < .001, respectively), especially postoperative complications in stage III patients (P < .001) and severe complications in stages II and III patients (P = .024 and P = .004, respectively). In addition, a low ALI was an independent predictor of a poor overall survival (hazard ratio: 2.30, 95% confidence interval: 1.52-3.50, P < .001) and relapse-free survival (hazard ratio: 1.73, 95% confidence interval: 1.22-2.44, P = .002), especially in older patients, and in patients without lymph node metastasis or severe postoperative complications.ConclusionThis study suggests that preoperative ALI may serve as a novel independent predictive index for severe postoperative complications and recurrence in CRC patients after curative resection.
| S-EPMC8786697 | biostudies-literature
Project description:PurposeLCN1 (lipocalin-1), a gene that encodes tear lipocalin (or von Ebner's gland protein), is mainly expressed in secretory glands and tissues, such as the lachrymal and lingual gland, and nasal, mammary, and tracheobronchial mucosae. Analysis of the Cancer Genome Atlas (TCGA) Breast Carcinoma (BRCA) level 3 data revealed a relationship between LCN1 expression and survival in breast cancer patients.MethodsThe χ2 test and Fisher exact test were applied to analyze the clinical data and RNA sequencing expression data, and the association between LCN1 expression and clinicopathologic features was determined. The receiver-operating characteristic (ROC) curve of LCN1 was drawn to assess its ability as a diagnostic marker, and the optimal cutoff value was obtained from the ROC curve to distinguish groups with high and low LCN1 expression. Cox regression was used to compare both groups, and a log-rank test was applied to calculate p values and compare the -Kaplan-Meier curves. Furthermore, GEO datasets were employed for external data validation.ResultsAnalysis of 1,104 breast cancer patients with a primary tumor revealed that LCN1 was overexpressed in breast cancer. High LCN1 expression was associated with clinicopathologic features and poor survival. Analyzing the area under the ROC curve (AUC) of LCN1, it was found that its diagnostic ability was limited. Multivariate analysis indicated that LCN1 expression is an independent predictor of survival in breast cancer patients. Through validation in GEO datasets, LCN1 expression was higher in tumor than normal tissue of the breast. High LCN1 expression was associated with poor survival in breast cancer patients.ConclusionsHigh LCN1 expression is an independent prognosticator of a poor prognosis in breast cancer.
| S-EPMC7383281 | biostudies-literature
Project description:Classical Non-homologous End Joining (NHEJ) pathway is the mainstay of cellular response to DNA double strand breaks. While aberrant expression of genes involved in this pathway has been linked with genomic instability and drug resistance in several cancers, limited information is available about its clinical significance in colon cancer. We performed a comprehensive analysis of seven essential genes, including XRCC5, XRCC6, PRKDC, LIG4, XRCC4, NHEJ1, and PAXX of this pathway, in colon cancer using multi-omics datasets, and studied their associations with molecular and clinicopathological features, including age, gender, stage, KRAS mutation, BRAF mutation, microsatellite instability status and promoter DNA methylation in TCGA colon cancer dataset. This analysis revealed upregulation of XRCC5, PRKDC, and PAXX in colon cancer compared to normal colon tissues, while LIG4 and NHEJ1 (XLF) displayed downregulation. The expression of these genes was independent of age and KRAS status, while XRCC5, PRKDC, and LIG4 exhibited reduced expression in BRAF mutant tumors. Interestingly, we observed a strong association between XRCC6, XRCC5, PRKDC and LIG4 overexpression and microsatellite instability status of the tumors. In multivariate analysis, high PAXX expression emerged as an independent prognostic marker for poor overall and disease specific survival. We also observed hypomethylation of PAXX promoter in tumors, which exhibited a strong correlation with its overexpression. Furthermore, PAXX overexpression was also associated with several oncogenic pathways as well as a reduction in numbers of tumor-infiltrating lymphocytes.
| S-EPMC7649742 | biostudies-literature