Abstract
Eicosanoids are bioactive lipids derived from arachidonic acid, which have emerged as key regulators of a wide variety of pathophysiological processes in recent times and are implicated as mediators of gastrointestinal cancer. In this study, we investigated the systemic levels of lipoxygenase (LOX)-derived lipoxin A4 and B4, together with resolvin D1 and D2 in patients with pancreatic adenocarcinoma (n = 68), as well as in healthy individuals (n = 32). Systemic concentrations of the aforementioned immunoresolvents were measured using an enzyme-linked immunosorbent assay (ELISA). In this study, we observed that compared with concentrations in healthy individuals, the peripheral concentrations of the aforementioned eicosanoids were significantly elevated (2- to 10-fold) in patients with pancreatic cancer (in all cases p<0.00001). No significant association was observed between eicosanoid levels and the TNM clinical staging. Furthermore, we observed no significant differences in concentrations of the analyzed bioactive lipids between patients diagnosed with early-stage (TNM stage I-II) and more advanced disease (TNM stage III-IV). Receiver operating characteristic (ROC) curve analysis of each aforementioned immunoresolvent showed area under the curve values ranging between 0.79 and 1.00. Sensitivity, specificity, as well as positive and negative predictive values of the eicosanoids involved in the detection/differentiation of pancreatic adenocarcinoma ranged between 56.8% and 100%. In summary, our research is the first study that provides clinical evidence to support a systemic imbalance in LOX-derived lipoxins and resolvins as the mechanism underlying the pathogenesis of pancreatic adenocarcinoma. This phenomenon occurs regardless of the clinical TNM stage of the disease. Furthermore, our study is the first to preliminarily highlight the role of peripheral levels of immunoresolvents, particularly resolvin D1, as potential novel biomarkers of pancreatic cancer in humans.
Highlights
Pancreatic adenocarcinoma is an extremely aggressive and invariably fatal malignancy in humans
We observed that peripheral levels of lipoxin A4 and B4 were significantly higher in patients with pancreatic adenocarcinoma than in healthy individuals
They are expected to be significant mediators of carcinogenesis, because uncontrolled chronic inflammation is known to be associated with the development of solid malignancies [24,25,26,27]
Summary
Pancreatic adenocarcinoma is an extremely aggressive and invariably fatal malignancy in humans. Among the various eicosanoids generated via the aforementioned enzymatic pathways, bioactive lipids such as leukotrienes, hydroxyeicosatetraenoic acids, lipoxins, and resolvins have gained much attention as significant contributors to malignancies This effect is mainly associated with their actions on immune cell function and modulation of both initiation (leukotrienes) and resolution (lipoxins, resolvins) of inflammatory processes [9,10,11,12]. LOX-derived lipoxins and resolvins participate in resolution of inflammation; several experimental studies have shown their benefits in suppression of chronic inflammation-induced tumorigenesis [13, 14] These results support the potential application of these immunoresolvents as promising preventive or anti-cancer agents [15,16,17,18]; limited information is available regarding their role in the development of pancreatic adenocarcinoma in humans
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