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    DNA Methylation of PI3K/AKT Pathway-Related Genes Predicts Outcome in Patients with Pancreatic Cancer: A Comprehensive Bioinformatics-Based Study
    (MDPI, 2021-01-01) Faleiro, Ines; Roberto, Vania Palma; Demirkol Canli, Secil; Fraunhoffer, Nicolas A.; Iovanna, Juan; Gure, Ali Osmay; Link, Wolfgang; Castelo-Branco, Pedro
    Simple Summary Pancreatic cancer is a highly lethal malignancy. Dysregulation of epigenetic mechanisms leads to abnormal patterns of gene expression contributing to the development and progression of cancer. We explored the ability of DNA methylation of PI3K-related genes to differentiate between malignant and healthy pancreatic tissue using distinct pancreatic cancer cohorts, and found that the methylation levels of the ITGA4, SFN, ITGA2, and PIK3R1 genes are altered in tumour samples since the early stages of malignant transformation and could serve as new diagnostic tools. We also demonstrate that these alterations correlate with overall survival and recurrence-free survival of the patients suggesting that its assessment can serve as independent prognostic indicators of patients' survival with higher sensitivity and specificity than the currently implemented biomarkers. Therefore, the methylation profile of genes involved in this pathway may be an alternative method for predicting cell malignancy and help doctors' decisions on patient care. Pancreatic cancer (PCA) is one of the most lethal malignancies worldwide with a 5-year survival rate of 9\%. Despite the advances in the field, the need for an earlier detection and effective therapies is paramount. PCA high heterogeneity suggests that epigenetic alterations play a key role in tumour development. However, only few epigenetic biomarkers or therapeutic targets have been identified so far. Here we explored the potential of distinct DNA methylation signatures as biomarkers for early detection and prognosis of PCA. PI3K/AKT-related genes differentially expressed in PCA were identified using the Pancreatic Expression Database (n = 153). Methylation data from PCA patients was obtained from The Cancer Genome Atlas (n = 183), crossed with clinical data to evaluate the biomarker potential of the epigenetic signatures identified and validated in independent cohorts. The majority of selected genes presented higher expression and hypomethylation in tumour tissue. The methylation signatures of specific genes in the PI3K/AKT pathway could distinguish normal from malignant tissue at initial disease stages with AUC > 0.8, revealing their potential as PCA diagnostic tools. ITGA4, SFN, ITGA2, and PIK3R1 methylation levels could be independent prognostic indicators of patients' survival. Methylation status of SFN and PIK3R1 were also associated with disease recurrence. Our study reveals that the methylation levels of PIK3/AKT genes involved in PCA could be used to diagnose and predict patients' clinical outcome with high sensitivity and specificity. These results provide new evidence of the potential of epigenetic alterations as biomarkers for disease screening and management and highlight possible therapeutic targets.
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    Patterns and Relevance of Langerhans Islet Invasion in Pancreatic Cancer
    (MDPI, 2021-01-01) Goess, Ruediger; Mutgan, Ayse Ceren; Calisan, Umut; Erdogan, Yusuf Ceyhun; Ren, Lei; Jager, Carsten; Safak, Okan; Stupakov, Pavel; Istvanffy, Rouzanna; Friess, Helmut; Ceyhan, Guralp O.; Demir, Ihsan Ekin
    Simple Summary The pathogenesis of pancreatic cancer-associated diabetes mellitus is poorly understood. We analyzed tumor infiltration into Langerhans islets and characterized it systematically for the first time, identifying four different main patterns of islet invasion. In a cohort of 68 pancreatic ductal adenocarcinoma (PDAC) patients, these islet invasion patterns were not related to occurrence of diabetes mellitus. However, severe islet invasion was associated with worsened overall survival. Background: Pancreatic cancer-associated diabetes mellitus (PC-DM) is present in most patients with pancreatic cancer, but its pathogenesis remains poorly understood. Therefore, we aimed to characterize tumor infiltration in Langerhans islets in pancreatic cancer and determine its clinical relevance. Methods: Langerhans islet invasion was systematically analyzed in 68 patients with pancreatic ductal adenocarcinoma (PDAC) using histopathological examination and 3D in vitro migration assays were performed to assess chemoattraction of pancreatic cancer cells to islet cells. Results: Langerhans islet invasion was present in all patients. We found four different patterns of islet invasion: (Type I) peri-insular invasion with tumor cells directly touching the boundary, but not penetrating the islet
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    Regulatory T Cells in Pancreatic Cancer: Of Mice and Men
    (MDPI, 2022-01-01) Reyes, Carmen Mota; Demir, Elke; Cifcibasi, Kaan; Istvanffy, Rouzanna; Friess, Helmut; Demir, Ihsan Ekin
    Simple Summary Regulatory T cells (Treg) are a major immunosuppressive cell subset in the pancreatic tumor microenvironment. Tregs influence tumor growth by acting either directly on cancer cells or via the inhibition of effector immune cells. Treg cells form a partially redundant network with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) that confer robustness to tumor immunosuppression and resistance to immunotherapy. The results obtained in preclinical studies, whereupon Treg depletion, MDSCs concomitantly decreased in early tumors whereas an inverse association was seen in advanced PCa, urge a comprehensive analysis of the immunosuppressive profile of PCa throughout tumorigenesis. One relevant context to analyse these compensatory mechanisms may be patients with locally advanced PCa undergoing neoadjuvant therapy (neoTx). In order to understand these dynamics and to uncover stage-specific actional strategies involving Tregs, pre-clinical models that allow the administration of neoTx to different stages of PCa may be a very useful platform. Regulatory T cells (Treg) are one of the major immunosuppressive cell subsets in the pancreatic tumor microenvironment. Tregs influence tumor growth by acting either directly on cancer cells or via the inhibition of effector immune cells. Treg cells mechanisms form a partially redundant network with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) that confer robustness to tumor immunosuppression and resistance to immunotherapy. The results obtained in preclinical studies where after Treg depletion, MDSCs concomitantly decreased in early tumors whereas an inverse association was seen in advanced PCa, urge a comprehensive analysis of the immunosuppressive profile of PCa throughout tumorigenesis. One relevant context to analyse these complex compensatory mechanisms may be the tumors of patients who underwent neoTx. Here, we observed a parallel decrease in the numbers of both intratumoral Tregs and MDSC after neoTx even in locally advanced PCa. NeoTx also led to decreased amounts of alpha SMA(+) myofibroblastic cancer-associated fibroblasts (myCAF) and increased proportions of CD8(+) cytotoxic T lymphocytes in the tumor. In order to understand these dynamics and to uncover stage-specific actional strategies involving Tregs, pre-clinical models that allow the administration of neoTx to different stages of PCa may be a very useful platform.
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    Circulating annexin A2 as a biomarker in patients with pancreatic cancer
    (WOLTERS KLUWER MEDKNOW PUBLICATIONS, 2020-01-01) Karabulut, Mehmet; Afsar, Cigdem Usul; Serilmez, Murat; Karabulut, Senem
    Background: Pancreatic cancer (PC) is a highly lethal malignancy. There are only few predictive or prognostic markers for PC. This study was conducted to investigate the serum levels of annexin A2 (AnxA2) in patients with PC and its relationship with tumor progression and known prognostic parameters. Materials and Methods: Serum samples were obtained on the first admission before any treatment. Serum AnxA2 levels were determined using enzyme-linked immunosorbent assay. Age- and sex-matched healthy controls were included in the analysis. All statistical tests were carried out using two-sided test, and P <= 0.05 was considered statistically significant. Results: The median age at diagnosis was 59 years. The most common metastatic site was liver in 23 patients with metastasis (n = 19, 83\%). At the end of the observation period, thirty-two patients (97\%) were dead. Thirty-nine percent of 23 metastatic patients who received palliative chemotherapy (CTx) were CTx responsive. Median overall survival of the whole group was 41.3 +/- 8.3 weeks (95\% confidence interval = 25-58 weeks). The baseline serum AnxA2 levels were significantly higher in patients with PC than in the control group (P = 0.01). Serum AnxA2 levels were significantly higher in the patients with high erythrocyte sedimentation rate (P = 0.04). Conversely, serum AnxA2 concentration had no prognostic role on survival (P = 0.18). Conclusions: AnxA2 is identified as a novel secretory biomarker for PC, but it has no role as a prognostic or predictive marker.
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    Clinical Significance of Serum NEDD9 Levels in Patients with Pancreatic Cancer
    (MDPI, 2018-01-01) Afsar, Cigdem Usul; Karabulut, Mehmet; Karabulut, Senem; Ozal, Safiye Tokgoz; Cikot, Murat; Serilmez, Murat; Tas, Faruk
    Introduction: Pancreatic cancer (PC) is a lethal malignancy. Various diagnostic, predictive, and prognostic biomarkers have been evaluated. This study was conducted to investigate the serum levels of neural precursor cell expressed developmentally downregulated protein 9 (NEDD9) in patients with PC and the relationship between tumor progression and known prognostic parameters. Materials and Methods: Serum samples were obtained on first admission before any treatment. Serum NEDD9 levels were determined using enzyme-linked immunosorbent assay (ELISA). Age- and sex-matched healthy controls were included in the analysis. Results: In a three year period, 32 patients with a pathologically-confirmed diagnosis of PC were enrolled in this study. The median age at diagnosis was 61 years, range 38 to 84 years