Eicosanoids in the pancreatic tumor microenvironment: a multicellular, multifaceted progression

Eicosanoids, oxidized fatty acids that serve as cell-signaling molecules, have been broadly implicated in tumorigenesis. To identify eicosanoids relevant to pancreatic tumorigenesis, we profiled normal pancreas and pancreatic ductal adenocarcinoma (PDAC) in mouse models and patient samples using mass spectrometry. We interrogated RNA sequencing datasets for eicosanoid synthase or receptor expression. Findings were confirmed by immunostaining. In murine models, we identified elevated levels of PGD2, prostacyclin, and thromboxanes in PDAC while PGE2, 12-HHTre, HETEs, and HDoHEs are elevated specifically in tumors. Analysis of scRNA-seq datasets suggests that PGE2 and prostacyclins are derived from fibroblasts, PGD2 and thromboxanes from myeloid cells, and PGD2 and 5-HETE from tuft cells. In patient samples, we identified a transition from PGD2 to PGE2-producing enzymes in the epithelium during the transition to PDAC, fibroblast/tumor expression of PTGIS, and myeloid/tumor cell expression of TBXAS1. Altogether, our analyses identify key changes in eicosanoid species during pancreatic tumorigenesis and the cell types responsible for their synthesis.

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Role of the 807 C/T Polymorphism of the α2 Gene in Platelet GP Ia Collagen Receptor Expression and Function

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614605 ◽

1999 ◽

Vol 81 (06) ◽

pp. 951-956 ◽

Cited By ~ 59

Author(s):

J. Corral ◽

R. González-Conejero ◽

J. Rivera ◽

F. Ortuño ◽

P. Aparicio ◽

...

Keyword(s):

Venous Thrombosis ◽

Cell Types ◽

Receptor Expression ◽

Case Control Studies ◽

Platelet Surface ◽

Vitro Analysis ◽

And Function ◽

In Vitro Analysis

SummaryThe variability of the platelet GP Ia/IIa density has been associated with the 807 C/T polymorphism (Phe 224) of the GP Ia gene in American Caucasian population. We have investigated the genotype and allelic frequencies of this polymorphism in Spanish Caucasians. The T allele was found in 35% of the 284 blood donors analyzed. We confirmed in 159 healthy subjects a significant association between the 807 C/T polymorphism and the platelet GP Ia density. The T allele correlated with high number of GP Ia molecules on platelet surface. In addition, we observed a similar association of this polymorphism with the expression of this protein in other blood cell types. The platelet responsiveness to collagen was determined by “in vitro” analysis of the platelet activation and aggregation response. We found no significant differences in these functional platelet parameters according to the 807 C/T genotype. Finally, results from 3 case/control studies involving 302 consecutive patients (101 with coronary heart disease, 104 with cerebrovascular disease and 97 with deep venous thrombosis) determined that the 807 C/T polymorphism of the GP Ia gene does not represent a risk factor for arterial or venous thrombosis.

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Myeloid-Derived Suppressor Cells and Pancreatic Cancer: Implications in Novel Therapeutic Approaches

Cancers ◽

10.3390/cancers11111627 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1627 ◽

Cited By ~ 5

Author(s):

Anita Thyagarajan ◽

Mamdouh Salman A. Alshehri ◽

Kelly L.R. Miller ◽

Catherine M. Sherwin ◽

Jeffrey B. Travers ◽

...

Keyword(s):

Survival Rates ◽

Suppressor Cells ◽

Cell Types ◽

Therapeutic Agents ◽

Ductal Adenocarcinoma ◽

Cancer Therapies ◽

Myeloid Derived Suppressor Cells ◽

Tumor Resistance ◽

Cellular Mechanisms ◽

Immunosuppressive Cell

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating human malignancy with poor prognosis and low survival rates. Several cellular mechanisms have been linked with pancreatic carcinogenesis and also implicated in inducing tumor resistance to known therapeutic regimens. Of various factors, immune evasion mechanisms play critical roles in tumor progression and impeding the efficacy of cancer therapies including PDAC. Among immunosuppressive cell types, myeloid-derived suppressor cells (MDSCs) have been extensively studied and demonstrated to not only support PDAC development but also hamper the anti-tumor immune responses elicited by therapeutic agents. Notably, recent efforts have been directed in devising novel approaches to target MDSCs to limit their effects. Multiple strategies including immune-based approaches have been explored either alone or in combination with therapeutic agents to target MDSCs in preclinical and clinical settings of PDAC. The current review highlights the roles and mechanisms of MDSCs as well as the implications of this immunomodulatory cell type as a potential target to improve the efficacy of therapeutic regimens for PDAC.

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Metabolic activation and colitis pathogenesis is prevented by lymphotoxin β receptor expression in neutrophils

Mucosal Immunology ◽

10.1038/s41385-021-00378-7 ◽

2021 ◽

Author(s):

Thomas Riffelmacher ◽

Daniel A. Giles ◽

Sonja Zahner ◽

Martina Dicker ◽

Alexander Y. Andreyev ◽

...

Keyword(s):

Severe Disease ◽

Metabolic Activation ◽

Cell Types ◽

Receptor Expression ◽

Neutrophil Accumulation ◽

Functional Studies ◽

Mitochondrial Ros ◽

Tnf Superfamily ◽

Β Receptor ◽

Lymphotoxin Beta Receptor

AbstractInflammatory bowel disease is characterized by an exacerbated intestinal immune response, but the critical mechanisms regulating immune activation remain incompletely understood. We previously reported that the TNF-superfamily molecule TNFSF14 (LIGHT) is required for preventing severe disease in mouse models of colitis. In addition, deletion of lymphotoxin beta receptor (LTβR), which binds LIGHT, also led to aggravated colitis pathogenesis. Here, we aimed to determine the cell type(s) requiring LTβR and the mechanism critical for exacerbation of colitis. Specific deletion of LTβR in neutrophils (LTβRΔN), but not in several other cell types, was sufficient to induce aggravated colitis and colonic neutrophil accumulation. Mechanistically, RNA-Seq analysis revealed LIGHT-induced suppression of cellular metabolism, and mitochondrial function, that was dependent on LTβR. Functional studies confirmed increased mitochondrial mass and activity, associated with excessive mitochondrial ROS production and elevated glycolysis at steady-state and during colitis. Targeting these metabolic changes rescued exacerbated disease severity. Our results demonstrate that LIGHT signals to LTβR on neutrophils to suppress metabolic activation and thereby prevents exacerbated immune pathogenesis during colitis.

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Syndecans and Pancreatic Ductal Adenocarcinoma

Biomolecules ◽

10.3390/biom11030349 ◽

2021 ◽

Vol 11 (3) ◽

pp. 349

Author(s):

Nausika Betriu ◽

Juan Bertran-Mas ◽

Anna Andreeva ◽

Carlos E. Semino

Keyword(s):

Extracellular Matrix ◽

Pancreatic Ductal Adenocarcinoma ◽

Cell Types ◽

Ductal Adenocarcinoma ◽

Physiological Processes ◽

Extracellular Matrix Components ◽

Detection And Diagnosis ◽

And Migration ◽

Early Detection And Diagnosis

Pancreatic Ductal Adenocarcinoma (PDAC) is a fatal disease with poor prognosis because patients rarely express symptoms in initial stages, which prevents early detection and diagnosis. Syndecans, a subfamily of proteoglycans, are involved in many physiological processes including cell proliferation, adhesion, and migration. Syndecans are physiologically found in many cell types and their interactions with other macromolecules enhance many pathways. In particular, extracellular matrix components, growth factors, and integrins collect the majority of syndecans associations acting as biochemical, physical, and mechanical transducers. Syndecans are transmembrane glycoproteins, but occasionally their extracellular domain can be released from the cell surface by the action of matrix metalloproteinases, converting them into soluble molecules that are capable of binding distant molecules such as extracellular matrix (ECM) components, growth factor receptors, and integrins from other cells. In this review, we explore the role of syndecans in tumorigenesis as well as their potential as therapeutic targets. Finally, this work reviews the contribution of syndecan-1 and syndecan-2 in PDAC progression and illustrates its potential to be targeted in future treatments for this devastating disease.

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Tumor-derived exosomal long noncoding RNA LINC01133, regulated by Periostin, contributes to pancreatic ductal adenocarcinoma epithelial-mesenchymal transition through the Wnt/β-catenin pathway by silencing AXIN2

Oncogene ◽

10.1038/s41388-021-01762-0 ◽

2021 ◽

Vol 40 (17) ◽

pp. 3164-3179

Author(s):

Yang Liu ◽

Tianchi Tang ◽

Xiaosheng Yang ◽

Peng Qin ◽

Pusen Wang ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Noncoding Rna ◽

Pancreatic Tumor ◽

Epithelial Mesenchymal Transition ◽

Noncoding Rnas ◽

Ductal Adenocarcinoma ◽

Overall Survival Rate ◽

Poor Overall Survival ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies and rapidly progressive diseases. Exosomes and long noncoding RNAs (lncRNAs) are emerging as vital mediators in tumor cells and their microenvironment. However, the detailed roles and mechanisms of exosomal lncRNAs in PDAC progression remain unknown. Here, we aimed to clarify the clinical significance and mechanisms of exosomal lncRNA 01133 (LINC01133) in PDAC. We analyzed the expression of LINC01133 in PDAC and found that exosomal LINC01133 expression was high and positively correlated with higher TNM stage and poor overall survival rate of PDAC patients. Further research demonstrated that Periostin could increase exosome secretion and then enhance LINC01133 expression. In addition, Periostin increased p-EGFR, p-Erk, and c-myc expression, and c-myc could bind to the LINC01133 promoter region. These findings suggested that LINC01133 can be regulated by Periostin via EGFR pathway activity. We also observed that LINC01133 promoted the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of pancreatic cancer cells. We subsequently evaluated the effect of LINC01133 on the Wnt/β-catenin pathway and confirmed that LINC01133 can interact with Enhancer Of Zeste Homolog 2 (EZH2) and then promote H3K27 trimethylation. This can further silence AXIN2 and suppress GSK3 activity, ultimately activating β-catenin. Collectively, these data indicate that exosomal LINC01133 plays an important role in pancreatic tumor progression, and targeting LINC01133 may provide a potential treatment strategy for PDAC.

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Applying Probe Electrospray Ionization Mass Spectrometry to Cytological Diagnosis: A Preliminary Study by Using Cultured Lung Cancer Cells

Acta Cytologica ◽

10.1159/000516639 ◽

2021 ◽

pp. 1-10

Author(s):

Yuki Morimoto ◽

Takeshi Oya ◽

Mayuko Ichimura-Shimizu ◽

Minoru Matsumoto ◽

Hirohisa Ogawa ◽

...

Keyword(s):

Mass Spectrometry ◽

Electrospray Ionization ◽

Squamous Cell ◽

Cultured Cells ◽

Sample Pretreatment ◽

Cell Types ◽

Diagnostic Tools ◽

Ionization Mass ◽

Diagnostic Modality ◽

Probe Electrospray Ionization

Objectives: Cytology and histology are 2 indispensable diagnostic tools for cancer diagnosis, which are rapidly increasing in importance with aging populations. We applied mass spectrometry (MS) as a rapid approach for swiftly acquiring nonmorphological information of interested cells. Conventional MS, which primarily rely on promoting ionization by pre-applying a matrix to cells, has the drawback of time-consuming both on data acquisition and analysis. As an emerging method, probe electrospray ionization-MS (PESI-MS) with a dedicated probe is capable to pierce sample and measure specimen in small amounts, either liquid or solid, without the requirement for sample pretreatment. Furthermore, PESI-MS is timesaving compared to the conventional MS. Herein, we investigated the capability of PESI-MS to characterize the cell types derived from the respiratory tract of human tissues. Study Design: PESI-MS analyses with DPiMS-2020 were performed on various type of cultured cells including 5 lung squamous cell carcinomas, 5 lung adenocarcinomas, 5 small-cell carcinomas, 4 malignant mesotheliomas, and 2 normal controls. Results: Several characteristic peaks were detected at around m/z 200 and 800 that were common in all samples. As expected, partial least squares-discriminant analysis of PESI-MS data distinguished the cancer cell types from normal control cells. Moreover, distinct clusters divided squamous cell carcinoma from adenocarcinoma. Conclusion: PESI-MS presented a promising potential as a novel diagnostic modality for swiftly acquiring specific cytological information.

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Exosomal Cargo May Hold the Key to Improving Reproductive Outcomes in Dairy Cows

International Journal of Molecular Sciences ◽

10.3390/ijms22042024 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2024

Author(s):

Natalie Turner ◽

Pevindu Abeysinghe ◽

Pawel Sadowski ◽

Murray D. Mitchell

Keyword(s):

Mass Spectrometry ◽

Dairy Cows ◽

Bioactive Peptides ◽

Cell Types ◽

Dairy Herds ◽

Dairy Farmers ◽

Early Biomarkers ◽

Health And Disease ◽

Place Of Origin ◽

Quantitative Profiling

The reproductive status of dairy cows remains a challenge for dairy farmers worldwide, with impaired fertility linked to a significant reduction in herd profitability, due in part to impaired immunity, increased metabolic pressure, and longer postpartum anestrous interval (PPAI). Exosomes are nanovesicles released from a variety of cell types and end up in circulation, and carry proteins, bioactive peptides, lipids, and nucleic acids specific to the place of origin. As such, their role in health and disease has been investigated in humans and animals. This review discusses research into exosomes in the context of reproduction in dairy herds and introduces recent advances in mass-spectrometry (MS) based proteomics that have a potential to advance quantitative profiling of exosomal protein cargo in a search for early biomarkers of cattle fertility.

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The Biology of Vasopressin

Biomedicines ◽

10.3390/biomedicines9010089 ◽

2021 ◽

Vol 9 (1) ◽

pp. 89

Author(s):

Samantha Sparapani ◽

Cassandra Millet-Boureima ◽

Joshua Oliver ◽

Kathy Mu ◽

Pegah Hadavi ◽

...

Keyword(s):

Parental Behavior ◽

Cell Types ◽

G Protein Coupled Receptors ◽

Receptor Expression ◽

Evolutionarily Conserved ◽

Terrestrial Environments ◽

Intracellular Vesicles ◽

G Protein Coupled ◽

Neuropsychiatric Conditions ◽

Vasopressin Synthesis

Vasopressins are evolutionarily conserved peptide hormones. Mammalian vasopressin functions systemically as an antidiuretic and regulator of blood and cardiac flow essential for adapting to terrestrial environments. Moreover, vasopressin acts centrally as a neurohormone involved in social and parental behavior and stress response. Vasopressin synthesis in several cell types, storage in intracellular vesicles, and release in response to physiological stimuli are highly regulated and mediated by three distinct G protein coupled receptors. Other receptors may bind or cross-bind vasopressin. Vasopressin is regulated spatially and temporally through transcriptional and post-transcriptional mechanisms, sex, tissue, and cell-specific receptor expression. Anomalies of vasopressin signaling have been observed in polycystic kidney disease, chronic heart failure, and neuropsychiatric conditions. Growing knowledge of the central biological roles of vasopressin has enabled pharmacological advances to treat these conditions by targeting defective systemic or central pathways utilizing specific agonists and antagonists.

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Pregnancy-enhanced Ca2+ responses to ATP in uterine artery endothelial cells is due to greater capacitative Ca2+ entry rather than altered receptor coupling

Journal of Endocrinology ◽

10.1677/joe.1.06635 ◽

2006 ◽

Vol 190 (2) ◽

pp. 373-384 ◽

Cited By ~ 18

Author(s):

Shannon M Gifford ◽

Fu-Xian Yi ◽

Ian M Bird

Keyword(s):

Endothelial Cells ◽

Uterine Artery ◽

Purinergic Receptor ◽

Cell Types ◽

P2y Receptors ◽

Receptor Expression ◽

Receptor Subtype ◽

Initial Transient ◽

Receptor Coupling ◽

Specific Variation

Uterine artery endothelial cells (UAEC) derived from pregnant (P-UAEC) and nonpregnant (NP-UAEC) ewes retain pregnancy-specific differences in cell signaling as well as vasodilator production through passage 4. In particular, when P- and NP-UAEC are stimulated with ATP over a 2.5 min recording period, they exhibit similar initial transient peaks in the intracellular free Ca2+ concentration ([Ca2+]i), but the P-UAEC show a heightened sustained phase. In order to establish whether thiswas due to an altered subclass of purinergic receptor (P2), both the dose dependencyof [Ca2+]i responses to ADP and UTP and the profile of purinergic receptor expression are determined in NP- and P-UAEC. Our findings indicate that while several isoforms of P2X and P2Y receptors are present, it is P2Y2 that is responsible for the ATP-induced initial transient peak in both cell types. We also characterized several key components of the ATP-induced Ca2+ signaling cascade, including the inositol 1,4,5-trisphosphate receptor and G-proteins, but could not confirm any pregnancy-specific variation in the protein expression that correlated with pregnancy-specific differences in prolonged Ca2+ signaling. We thus investigated whether such a difference may be inherent to the cell itself rather than specific to the purinergic receptor-signaling pathway. Using thapsigargin (Tg), we were able to demonstrate that the initial Tg-sensitive intracellular pool of Ca2+is nearly identical with the capacity in both cell types, but the P-UAEC is nonetheless capable of greater capacitative Ca2+ entry (CCE) than NP-UAEC. Furthermore, CCE induced by Tg could be dramatically inhibited by 2-aminoethoxydiphenyl borate, suggesting a role for store-operated channels in the ATP-induced [Ca2+]i response. We conclude that changes at the level of capacitative entry mechanisms rather than switching of receptor subtype or coupling to phospholipase C underlies pregnancy adaptation of UAEC at the level of Ca2+signaling.

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Fibronectin is overproduced by keloid fibroblasts during abnormal wound healing

Molecular and Cellular Biology ◽

10.1128/mcb.9.4.1642-1650.1989 ◽

1989 ◽

Vol 9 (4) ◽

pp. 1642-1650

Author(s):

M Babu ◽

R Diegelmann ◽

N Oliver

Keyword(s):

Wound Healing ◽

State Level ◽

Cell Types ◽

Relative Increase ◽

Receptor Expression ◽

Glucocorticoid Treatment ◽

Fibronectin Receptor ◽

Coordinate Regulation ◽

Extracellular Matrix Components ◽

Keloid Fibroblasts

Wound healing in certain individuals leads to the development of keloid tumors which exhibit abnormal collagen metabolism and an increased abundance of extracellular matrix components. Comparison of fibronectin levels in fibroblasts derived from keloids and normal dermis revealed a relative increase in intracellular and extracellular fibronectin in the keloid-derived cells. While fibronectin was similarly processed, compartmentalized, and degraded by both cell types, fibronectin biosynthesis was found to be accelerated as much as fourfold in keloid fibroblasts due to a corresponding increase in the amount of accumulated fibronectin mRNA. These changes account for the elevated steady-state level of the molecule in keloid fibroblasts and suggest that increased fibronectin in keloid lesions is due to overproduction by the wound-healing fibroblasts. Glucocorticoid treatment stimulated fibronectin biosynthesis in both normal and keloid fibroblasts. However, the amount of stimulation was less for the keloid-derived cells, indicating a limitation on maximal rates of fibronectin biosynthesis. These observations suggest that separate mechanisms act to control basal and maximal rates of fibronectin production. Biosynthesis of the 140-kilodalton fibronectin receptor was also found to be increased in keloid fibroblasts, suggesting some level of coordinate regulation for fibronectin and fibronectin receptor expression.

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