scholarly journals OncomiRs miR-106a and miR-17 negatively regulate the nucleoside-derived drug transporter hCNT1

2021 ◽  
Author(s):  
Clara Boces-Pascual ◽  
Aida Mata-Ventosa ◽  
Mireia Martín-Satué ◽  
Loreto Boix ◽  
Meritxell Gironella ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Family Member ◽  
Direct Relationship ◽  
Nucleoside Transporters ◽  
Ductal Adenocarcinoma ◽  
Drug Transporter ◽  
High Affinity ◽  
Digestive Cancers ◽  
Underlying Mechanisms

AbstractHigh-affinity uptake of natural nucleosides as well as nucleoside derivatives used in anticancer therapies is mediated by human concentrative nucleoside transporters (hCNTs). hCNT1, the hCNT family member that specifically transports pyrimidines, is also a transceptor involved in tumor progression. In particular, oncogenesis appears to be associated with hCNT1 downregulation in some cancers, although the underlying mechanisms are largely unknown. Here, we sought to address changes in colorectal and pancreatic ductal adenocarcinoma—both of which are important digestive cancers—in the context of treatment with fluoropyrimidine derivatives. An analysis of cancer samples and matching non-tumoral adjacent tissues revealed downregulation of hCNT1 protein in both types of tumor. Further exploration of the putative regulation of hCNT1 by microRNAs (miRNAs), which are highly deregulated in these cancers, revealed a direct relationship between the oncomiRs miR-106a and miR-17 and the loss of hCNT1. Collectively, our findings provide the first demonstration that hCNT1 inhibition by these oncomiRs could contribute to chemoresistance to fluoropyrimidine-based treatments in colorectal and pancreatic cancer. Graphic abstract

scholarly journals Islet Inflammation: The Link between Type 2 Diabetes and Pancreatic Cancer

2021 ◽  
Author(s):  
Alpana Mukhuty
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Protein Protein Interactions ◽  
Proinflammatory Response ◽  
Islet Inflammation ◽  
Underlying Mechanisms ◽  
And Migration

The role of islet inflammation in type 2 diabetes (T2DM) and pancreatic ductal adenocarcinoma (PDAC) is complex. About 80% of pancreatic cancer patients have glucose intolerance or T2D. Chronic type 2 diabetes increases risk for pancreatic cancer, but the mechanisms are unknown. In this context two hypotheses exist: (i) pancreatic cancer causes diabetes and (ii) diabetes promotes the development of pancreatic cancer. Pancreatic ductal adenocarcinoma is the most common and deadly form of pancreatic cancer that is associated with diabetes. There are many possibilities by which obesity links to pancreatic cancer. These possibilities include insulin resistance, hyperinsulinemia and inflammation. Adipose tissue deposition near pancreas (peri-pancreatic depot) increase proinflammatory response to a high fat or high calorie containing diet. Inflammatory processes in the islets act as main mediators during the development and progression of pancreatic cancer. Recently, studies have been carried out to investigate the underlying mechanisms that contribute to tumorigenesis induced by inflammation. Tumor-elicited inflammation, secretion of pro-inflammatory cytokines and migration of immune cells play the key roles in initiation, promotion and progression of malignant metastasis in pancreatic cancer. Initiation and progression of islet inflammation in diabetes and pancreatic cancer occurs as a result of various protein–protein interactions and genetic events. The increase in pancreatic cancer cases may be attributed to the obesity endemic and obesity mediated Type 2 diabetes. The existence of link between islet inflammation in chronic diabetes and pancreatic cancer cannot be ignored, although the details about the underlying mechanisms are not clear, and must be studied in detail.

scholarly journals A Proteomic Study on the Personalized Protein Corona of Liposomes. Relevance for Early Diagnosis of Pancreatic DUCTAL Adenocarcinoma and Biomarker Detection

2021 ◽  
Vol 2 (2) ◽  
pp. 82-93
Author(s):  
Luca Digiacomo ◽  
Francesca Giulimondi ◽  
Daniela Pozzi ◽  
Alessandro Coppola ◽  
Vincenzo La Vaccara ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Early Diagnosis ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Protein Corona ◽  
Detection Sensitivity ◽  
Ductal Adenocarcinoma ◽  
Protein Biomarkers ◽  
Ca 19.9 ◽  
Proteomic Study

Due to late diagnosis, high incidence of metastasis, and poor survival rate, pancreatic cancer is one of the most leading cause of cancer-related death. Although manifold recent efforts have been done to achieve an early diagnosis of pancreatic cancer, CA-19.9 is currently the unique biomarker that is adopted for the detection, despite its limits in terms of sensitivity and specificity. To identify potential protein biomarkers for pancreatic ductal adenocarcinoma (PDAC), we used three model liposomes as nanoplatforms that accumulate proteins from human plasma and studied the composition of this biomolecular layer, which is known as protein corona. Indeed, plasma proteins adsorb on nanoparticle surface according to their abundance and affinity to the employed nanomaterial, thus even small differences between healthy and PDAC protein expression levels can be, in principle, detected. By mass spectrometry experiments, we quantified such differences and identified possible biomarkers for PDAC. Some of them are already known to exhibit different expressions in PDAC proteomes, whereas the role of other relevant proteins is still not clear. Therefore, we predict that the employment of nanomaterials and their protein corona may represent a useful tool to amplify the detection sensitivity of cancer biomarkers, which may be used for the early diagnosis of PDAC, with clinical implication for the subsequent therapy in the context of personalized medicine.

scholarly journals Roles of autophagy and metabolism in pancreatic cancer cell adaptation to environmental challenges

2017 ◽  
Vol 313 (5) ◽  
pp. G524-G536 ◽  
Author(s):  
Sandrina Maertin ◽  
Jason M. Elperin ◽  
Ethan Lotshaw ◽  
Matthias Sendler ◽  
Steven D. Speakman ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Oxidative Phosphorylation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Environmental Stresses ◽  
Ductal Adenocarcinoma ◽  
Cell Adaptation ◽  
Autophagy Inhibition ◽  
Dependent Mechanism

Pancreatic ductal adenocarcinoma (PDAC) displays extensive and poorly vascularized desmoplastic stromal reaction, and therefore, pancreatic cancer (PaCa) cells are confronted with nutrient deprivation and hypoxia. Here, we investigate the roles of autophagy and metabolism in PaCa cell adaptation to environmental stresses, amino acid (AA) depletion, and hypoxia. It is known that in healthy cells, basal autophagy is at a low level, but it is greatly activated by environmental stresses. By contrast, we find that in PaCa cells, basal autophagic activity is relatively high, but AA depletion and hypoxia activate autophagy only weakly or not at all, due to their failure to inhibit mechanistic target of rapamycin. Basal, but not stress-induced, autophagy is necessary for PaCa cell proliferation, and AA supply is even more critical to maintain PaCa cell growth. To gain insight into the underlying mechanisms, we analyzed the effects of autophagy inhibition and AA depletion on PaCa cell metabolism. PaCa cells display mixed oxidative/glycolytic metabolism, with oxidative phosphorylation (OXPHOS) predominant. Both autophagy inhibition and AA depletion dramatically decreased OXPHOS; furthermore, pharmacologic inhibitors of OXPHOS suppressed PaCa cell proliferation. The data indicate that the maintenance of OXPHOS is a key mechanism through which autophagy and AA supply support PaCa cell growth. We find that the expression of oncogenic activation mutation in GTPase Kras markedly promotes basal autophagy and stimulates OXPHOS through an autophagy-dependent mechanism. The results suggest that approaches aimed to suppress OXPHOS, particularly through limiting AA supply, could be beneficial in treating PDAC. NEW & NOTEWORTHY Cancer cells in the highly desmoplastic pancreatic ductal adenocarcinoma confront nutrient [i.e., amino acids (AA)] deprivation and hypoxia, but how pancreatic cancer (PaCa) cells adapt to these conditions is poorly understood. This study provides evidence that the maintenance of mitochondrial function, in particular, oxidative phosphorylation (OXPHOS), is a key mechanism that supports PaCa cell growth, both in normal conditions and under the environmental stresses. OXPHOS in PaCa cells critically depends on autophagy and AA supply. Furthermore, the oncogenic activation mutation in GTPase Kras upregulates OXPHOS through an autophagy-dependent mechanism.

41 Cathepsin D Expression in Pancreatic Ductal Adenocarcinoma (PDAC) Cells Increases Proliferation and Reduces Survival of Pancreatic Cancer Patients

2015 ◽  
Vol 148 (4) ◽  
pp. S-13
Author(s):  
Ujjwal M. Mahajan ◽  
Enno Langhoff ◽  
Eithne Costello ◽  
William Greenhalf ◽  
Christopher Halloran ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Patients ◽  
Cathepsin D ◽  
Ductal Adenocarcinoma

Precursors of pancreatic cancer in background of chronic opisthorchiasis

2021 ◽  
Vol 22 (1) ◽  
pp. 118-121
Author(s):  
V. U. Rayn ◽  
◽  
M. A. Persidskiy ◽  
E. V. Malakhova ◽  
I. V. Anuchina ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Disease Free Survival ◽  
Morphological Data ◽  
Small Samples ◽  
Ductal Adenocarcinoma ◽  
Preneoplastic Lesions ◽  
Opisthorchis Felineus ◽  
Disease Free

Aim. To establish the association between pancreatic cancer precursor lesions and chronic opisthorchiasis. Materials and methods. A single center case-control study was conducted at a low-volume pancreatic surgery center in Khanty-Mansiysk. We retrospectively collected morphological data from 47 pancreatoduodenectomies performed for pancreatic ductal adenocarcinoma. The study group included 23 cases of pancreatic ductal adenocarcinoma with concomitant chronic Opisthorchis felineus invasion which were compared to 24 controls consisting of “pure” cancer. Qualitative analysis was performed using χ2 Pearson criterion. Exact Fisher test was used for small samples. Time to progression and overall survival rates were calculated using Kaplan-Meier survival analysis. Data were collected and analyzed in Statistica 7.0. Results. PanINs were seen in 41,7% pancreata resected for ductal adenocarcinoma of the head and in 95,7% cases of pancreatic cancer in background of chronic opisthorchiasis (р = 0,000; 95% CI 3,5-268). PanIN high grade were observed only in opisthorchiasis group. In mixed pathology invasive cancer component tended to be more dedifferentiated and advanced when compared to pure cancer group (p = 0,029). Median disease free survival was 9 mo. in both groups and overall survival was 13 mo. in non-opisthorchiasis group and 15,3 mo. in opisthorchiasis group (р = 0,437). Conclusion. Chronic opisthorchiasis is associated with pancreatic intraepithelial neoplasia. Pancreatic ductal adenocarcinoma in background of opisthorchiasis with preneoplastic lesions tend to be more advanced in stage and poorly differentiated. Disease free and overall survival have no statistically significant differences in patients with and without Opisthorchis felineus invasion.

scholarly journals Role of Oxidative and Nitro-Oxidative Damage in Silver Nanoparticles Cytotoxic Effect against Human Pancreatic Ductal Adenocarcinoma Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Ewelina Barcińska ◽  
Justyna Wierzbicka ◽  
Agata Zauszkiewicz-Pawlak ◽  
Dagmara Jacewicz ◽  
Aleksandra Dabrowska ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Pancreatic Cancer ◽  
Silver Nanoparticles ◽  
Oxidative Damage ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cytotoxic Effect ◽  
Mrna Level ◽  
Ductal Adenocarcinoma ◽  
Adenocarcinoma Cells

Pancreatic ductal adenocarcinoma is one of the most aggressive human malignancies, where the 5-year survival rate is less than 4% worldwide. Successful treatment of pancreatic cancer is a challenge for today’s oncology. Several studies showed that increased levels of oxidative stress may cause cancer cells damage and death. Therefore, we hypothesized that oxidative as well as nitro-oxidative stress is one of the mechanisms inducing pancreatic cancer programmed cell death. We decided to use silver nanoparticles (AgNPs) (2.6 and 18 nm) as a key factor triggering the reactive oxygen species (ROS) and reactive nitrogen species (RNS) in pancreatic ductal adenocarcinoma cells (PANC-1). Previously, we have found that AgNPs induced PANC-1 cells death. Furthermore, it is known that AgNPs may induce an accumulation of ROS and alteration of antioxidant systems in different type of tumors, and they are indicated as promising agents for cancer therapy. Then, the aim of our study was to evaluate the implication of oxidative and nitro-oxidative stress in this cytotoxic effect of AgNPs against PANC-1 cells. We determined AgNP-induced increase of ROS level in PANC-1 cells and pancreatic noncancer cell (hTERT-HPNE) for comparison purposes. We found that the increase was lower in noncancer cells. Reduction of mitochondrial membrane potential and changes in the cell cycle were also observed. Additionally, we determined the increase in RNS level: nitric oxide (NO) and nitric dioxide (NO2) in PANC-1 cells, together with increase in family of nitric oxide synthases (iNOS, eNOS, and nNOS) at protein and mRNA level. Disturbance of antioxidant enzymes: superoxide dismutase (SOD1, SOD2, and SOD3), glutathione peroxidase (GPX-4) and catalase (CAT) were proved at protein and mRNA level. Moreover, we showed cells ultrastructural changes, characteristic for oxidative damage. Summarizing, oxidative and nitro-oxidative stress and mitochondrial disruption are implicated in AgNPs-mediated death in human pancreatic ductal adenocarcinoma cells.

scholarly journals PancREatic Cancer and Individualised Supervised Exercise (PRECISE): a feasibility trial protocol for patients with resectable pancreatic ductal adenocarcinoma

2020 ◽  
Vol 2 ◽  
pp. 22
Author(s):  
Dominic O'Connor ◽  
Malcolm Brown ◽  
Roy Bowdery ◽  
Martin Eatock ◽  
Claire Hulme ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Adjuvant Chemotherapy ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Exercise Intervention ◽  
Feasibility Trial ◽  
Ductal Adenocarcinoma ◽  
Moderate Intensity ◽  
Moderate Intensity Exercise ◽  
Supervised Exercise ◽  
Health And Social Care

Background: Patients with resectable pancreatic ductal adenocarcinoma (PDAC), undergoing adjuvant chemotherapy can experience an array of complications including fatigue, pain and the loss of physical function. Accumulating evidence from largely early stage breast cancer studies supports exercise as an adjunct therapy to help mitigate treatment complications. However, there is a lack of evidence of its feasibility in pancreatic cancer. The purpose of this study is to explore the initial feasibility of delivering a supervised, individualized, and progressive concurrent exercise intervention to individuals with resectable PDAC who are undergoing adjuvant therapy. Methodology: Ten patients with resectable PDAC undergoing adjuvant chemotherapy will be recruited. Clinical care teams will screen patients against inclusion criteria to determine eligibility. All enrolled participants will complete a 16-week, supervised, tailored, moderate intensity exercise intervention consisting of aerobic and muscle strengthening activities. The primary outcome will be feasibility of delivering a supervised exercise intervention. Secondary outcomes will include measures of physical fitness, fatigue, and quality of life. Outcomes will be measured at baseline (T1), 16 weeks (T2) and 3 months (T3). The feasibility, acceptability and potential utility of the supervised exercise intervention will be explored qualitatively through semi-structured interviews with key stakeholders (e.g. active participants, eligible participants that declined participation and the research staff including exercise physiologists and recruiting clinicians).  The use of health and social care services, medications and personal expenses incurred during the trial will also be used to determine cost-effectiveness of this intervention and a potential further RCT in PDAC. Discussion: The overall aim of this study is to determine the utility of a supervised, tailored, moderate intensity exercise intervention in PDAC patients undergoing adjuvant chemotherapy.  This feasibility study will help inform the design of future randomised controlled trials to determine the efficacy of the exercise intervention in PDAC.

scholarly journals KIF4A Regulates the Progression of Pancreatic Ductal Adenocarcinoma through Proliferation and Invasion

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Jing Chen ◽  
Cui-Cui Zhao ◽  
Fei-Ran Chen ◽  
Guo-Wei Feng ◽  
Fei Luo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Disease Free Survival ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion

Background. Pancreatic cancer is a malignant tumor of the digestive tract, which is difficult to diagnose and treat due to bad early diagnosis. We aimed to explore the role of kinesin superfamily 4A (KIF4A) in pancreatic ductal adenocarcinoma (PDAC). Methods. We first used the bioinformatic website to screen the data of pancreatic cancer in TCGA, and KIF4A protein was detected among the 86 specimens of patients in our hospital combined with clinic-pathological characteristics and survival analysis. KIF4A loss-expression cell lines were established by RNA interference (RNAi). In addition, we performed in vitro cell assays to detect the changes in cell proliferation, migration, and invasion. The proteins involved in the proliferation and metastasis of cancer cells were also detected by western blot. The above results could be proved in vivo. Further, the correlation between KIF4A and CDC5L was analyzed by TCGA and IHC data. Results. We first found a high expression of KIF4A in pancreatic cancer, suggesting a role of KIF4A in the development of pancreatic cancer. KIF4A was found to be differentially expressed ( P < 0.05 ) among the 86 specimens of patients in our hospital and was significantly associated with PDAC TNM stages and tumor size. High KIF4A expression also significantly worsened overall survival (OS) and disease-free survival rate (DFS) ( P < 0.05 , respectively). In addition, cell proliferation, migration, and invasion were inhibited by the KIF4A-shRNA group compared with the control ( P < 0.05 , respectively). In the end, knockdown of KIF4A could inhibit tumor development and metastasis in vivo. Further, the positive correlation between KIF4A and CDC5L existed, and KIF4A might promote pancreatic cancer proliferation by affecting CDC5L expression. Conclusion. In conclusion, the high expression level of KIF4A in PDAC was closely related to poor clinical and pathological status, lymphatic metastasis, and vascular invasion. KIF4A might be involved in promoting the development of PDAC in vitro and in vivo, which might be a new therapeutic target of PDAC.

The Role of Nanoliposomal Irinotecan Plus Fluorouracil and Folinic Acid as Second-Line Treatment Option in Patients With Metastatic Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Se Jun Park ◽  
Hyunho Kim ◽  
Kabsoo Shin ◽  
Tae Ho Hong ◽  
Ja Hee Suh ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Adverse Events ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Real World ◽  
Median Overall Survival ◽  
Ductal Adenocarcinoma ◽  
Nanoliposomal Irinotecan ◽  
Previously Treated ◽  
Grade 3

Abstract BackgroundAccording to the NAPOLI-1 trial, nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) showed improved overall survival compared to fluorouracil alone for patients with metastatic pancreatic cancer who previously treated gemcitabine-based therapy. In that trial, Asian patients had frequent dose modification due to hematological toxicity. There has been limited information on the clinical benefit and toxicity of this regimen in a real-world setting. Herein, we assessed real-world experience of nal-IRI plus 5-FU/LV in patients with advanced pancreatic cancer after gemcitabine failure.MethodsWe conducted a single institution retrospective analysis of response, survival and safety in patients who had been treated with nal-IRI with 5-FU/LV. Patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy received nal-IRI (80mg/m2) with 5-FU/LV every 2 weeks. ResultsFifty-one patients received nal-IRI plus 5-FU/LV between January 2015 and December 2020. The median age was 67 years, and males were 58.8%. A total of 40 (78.4%) and 11 (21.6%) patients had received one and two lines of prior chemotherapy before enrollment, respectively. Median progression-free survival was 2.8 months (95% confidence interval [CI] 1.8-3.7) and median overall survival was 7.0 months (95% CI 6.0-7.9). Chemotherapy doses were reduced or delayed in 33 (64.7%) patients during the first 6 weeks and median relative dose intensity was 0.87. Thirty-six (70.6%) patients experienced any grade 3 or 4 adverse events. Most common grade 3 or 4 adverse event was neutropenia (58.8%) and most non-hematologic adverse events were under grade 2. Since the start of first-line chemotherapy, median overall survival was 16.3 months (95% CI 14.1-18.4).ConclusionsNal-IRI plus 5-FU/LV seems to be effective, with manageable toxicities, after gemcitabine-based treatment in patients with metastatic pancreatic ductal adenocarcinoma. Trial registration Retrospectively registered

scholarly journals Omics Approaches in Pancreatic Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1052
Author(s):  
Iranzu González-Boja ◽  
Antonio Viúdez ◽  
Saioa Goñi ◽  
Enrique Santamaria ◽  
Estefania Carrasco-García ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Survival Rate ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Curative Intent ◽  
Pancreatic Cancers ◽  
Wide Range ◽  
Prevention And Treatment ◽  
Shed Light

Pancreatic ductal adenocarcinoma, which represents 80% of pancreatic cancers, is mainly diagnosed when treatment with curative intent is not possible. Consequently, the overall five-year survival rate is extremely dismal—around 5% to 7%. In addition, pancreatic cancer is expected to become the second leading cause of cancer-related death by 2030. Therefore, advances in screening, prevention and treatment are urgently needed. Fortunately, a wide range of approaches could help shed light in this area. Beyond the use of cytological or histological samples focusing in diagnosis, a plethora of new approaches are currently being used for a deeper characterization of pancreatic ductal adenocarcinoma, including genetic, epigenetic, and/or proteo-transcriptomic techniques. Accordingly, the development of new analytical technologies using body fluids (blood, bile, urine, etc.) to analyze tumor derived molecules has become a priority in pancreatic ductal adenocarcinoma due to the hard accessibility to tumor samples. These types of technologies will lead us to improve the outcome of pancreatic ductal adenocarcinoma patients.

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