Previously we reported that EL Kras mice fed diets rich

Previously, we reported that EL-Kras mice-fed diets rich in omega-6 FAs demonstrated increased pancreatic mast cell infiltration [16]. Significantly, increased infiltration of mast cells into the tumor microenvironment correlates with a poor prognosis [15]. Soucek et al.[25] demonstrated that mast cells mediate expansion of islet-cell tumors in mice and are essential for tumor maintenance. Ma et al.[26] showed that PDAC cells promote mast cell migration and activation in vitro, and when mast cell migration is blocked in vivo in an orthotopic PDAC mouse model, PDAC growth is inhibited. In this report, we demonstrate a significant association between 5LO expression and mast cell infiltration in human PDAC tumors. We also show that EL-Kras/5LO mice not only have reduced pancreatic mast cell infiltration but were resistant to the effects of omega-6 FA-rich diets to induce pancreatic mast cell infiltration, indicating that 5LO is important in regulating mast cell infiltration in vivo. Our results suggest that the absence of 5LO decreases lesion development and mast cell infiltration in EL-Kras mice, and it abrogates the effect of omega-6 FAs on lesion formation. Overall, our results indicate that 5LO contributes to the inflammatory microenvironment of precancerous pancreatic lesions. Preclinical animal studies have shown that the 5LO inhibitor Zileuton can inhibit tumor growth and reduce tumor mass in an orthotopic mouse model of colon cancer and in chemically induced pancreatic tumors in hamsters [27], [28]. As a drug that is well tolerated in KPT-9274 australia patients and is approved by the Food and Drug Administration, Zileuton may be an ideal chemopreventive therapy for obese patients at risk for pancreatic cancer [10]. Our future work will explore Zileuton chemoprevention in developing neoplastic lesions in EL-Kras mice.
Acknowledgment The authors gratefully acknowledge the contribution of Carolyn Pelham and Kevin Adrian for their outstanding care and oversight of mice for the duration of this diet study. The research described herein was generously supported by funds provided by the Barnum Foundation and Zell Family Foundation at Northwestern University, the Nathan and Isabel Miller Family Foundation, the IDP Foundation, National Institutes of HealthR21 CA123041-01 (P.J.G.), and National Institutes of HealthR01 CA161283-01 (P.J.G.).
Introduction Recent positron emission tomography (PET) data indicate that the normal human brain consumes 17.8mg/day of arachidonic acid, and that this consumption increases in the brains of Alzheimer's disease (AD) patients (for review, see Rapoport, 2008). A portion of intracellular free arachidonic acid is metabolized by cyclooxygenases (e.g., cyclooxygenase-1, COX-1; cyclooxygenase-2, COX-2) and lipoxygenases (e.g., 5-lipoxygenase; 5-LOX) to generate biologically active prostaglandins and leukotrienes, respectively. In the central nervous system (CNS), both COXs and 5-LOX have been associated with pathobiological mechanisms accompanying aging and neurodegeneration (Choi et al., 2009, Chu and Praticò, 2009, Phillis et al., 2006). A recent study of COX-2 and 5-LOX single nucleotide polymorphisms (SNPs) in AD performed on 341 AD patients and 190 controls from Northern Italy found a significant difference in the distribution of the −765G COX-2 and −1708A 5-LOX alleles between AD cases and controls — both alleles were overrepresented in AD patients and underrepresented in controls (Listì et al., 2010). These authors suggested that the identified alleles of COX-2 and 5-LOX could be risk factors for AD. Since in the periphery, the most prominent function of COXs and 5-LOX is in inflammation, i.e., they are considered “inflammatory” enzymes, findings of the presence and overactivation and overexpression of these enzymes in AD are typically referred to as evidence for an inflammatory basis for AD pathobiology. Furthermore, both COXs and 5-LOX contribute to atherogenesis and it has been proposed that these pathways may be at the core of the co-morbidity of cardiovascular and neurological disorders such as AD (Chu and Praticò, 2009, Praticò and Dogné, 2009). However, both COX and 5-LOX may influence CNS functioning via mechanisms unrelated to the role these proteins play in inflammation. For example, COX-2, which is predominantly expressed in pyramidal neurons in contrast to COX-1, which is mostly present in microglia, regulates neuroplasticity via its conversion of arachidonic acid to classic prostaglandins but also by favoring oxidative metabolism of endocannabinoids to novel prostaglandins (Yang and Chen, 2008). On the other hand, 5-LOX appears to be capable of regulating the brain's amyloid-beta levels by influencing gamma-secretase (Firuzi et al., 2008).