Ablation of 5-lipoxygenase mitigates pancreatic lesion development

Abstract

Background Pancreatic ductal adenocarcinoma (PDAC), which continues to have a dismal prognosis, is associated with a pronounced fibro-inflammatory response. Inflammation in vivo can be mediated by 5-lipoxygenase (5LO), an enzyme that converts omega-6 fatty acids to eicosanoids, including leukotriene B4 (LTB4). We have previously shown that diets rich in omega-6 fatty acids (FA) increase pancreatic lesions and mast cell infiltration in EL-Kras mice. In this study, we evaluated the role of 5LO in generating higher levels of LTB4 from human cells and in mediating lesion development and mast cell infiltration in EL-Kras mice. Materials and Methods Human pancreatic ductal epithelial (HPDE) and cancer cells were treated with omega-6 FA in vitro. EL-Kras mice lacking 5LO (EL-Kras/5LO−/−) mice were generated and fed standard chow or omega-6 FA diets. Pancreatic lesion frequency and mast cell infiltration were compared to EL-Kras/5LO+/+ mice. Human PDAC tumors were evaluated for 5LO expression and mast cells. Results HPDE and cancer cells treated with omega-6 FA generated increased LTB4 levels in vitro. EL-Kras/5LO−/− developed fewer pancreatic lesions and had decreased mast cell infiltration when compared to EL-Kras/5LO+/+ mice. Human PDAC tumors with increased 5LO expression demonstrate increased mast cell infiltration. Additionally, diets rich in omega-6 FA failed to increase pancreatic lesion development and mast cell infiltration in EL-Kras/5LO−/− mice. Conclusions The expansion of mutant Kras-induced lesions via omega-6 FA is dependent on 5LO, and 5LO functions downstream of mutant Kras to mediate inflammation, suggesting that 5LO may be a potential chemo-preventive and therapeutic target in pancreatic cancer.

Cross-Talk between Cancer Cells and the Tumour Microenvironment: The Role of the 5-Lipoxygenase Pathway

“…This was further supported in human pancreatic ductal adenocarcinoma where increased 5-LO immunostaining was associated with increased mast cell numbers [111]. Therefore targeting myeloid 5-LO signalling may be an effective therapeutic strategy for polyposis and potentially colorectal and pancreatic cancer [110,111]. …”

“…Zileuton treated polyps were found to have significantly lower levels of infiltrating macrophages, mast cells, MDSCs (>50%–60% lower) which Gounaris et al suggest is responsible for the lower incidence of polyps in these mice. In another study, pancreatic ductal adenocarcinoma lesions were significantly less frequent in 5-LO knockout mice and a decrease of infiltrating pancreatic mast cells was also noted [ 111 ]. This was further supported in human pancreatic ductal adenocarcinoma where increased 5-LO immunostaining was associated with increased mast cell numbers [ 111 ].…”

“…In another study, pancreatic ductal adenocarcinoma lesions were significantly less frequent in 5-LO knockout mice and a decrease of infiltrating pancreatic mast cells was also noted [ 111 ]. This was further supported in human pancreatic ductal adenocarcinoma where increased 5-LO immunostaining was associated with increased mast cell numbers [ 111 ]. Therefore targeting myeloid 5-LO signalling may be an effective therapeutic strategy for polyposis and potentially colorectal and pancreatic cancer [ 110 , 111 ].…”

The yin and yang of leukotriene B 4 mediated inflammation in cancer

“…Treating mice with Zileuton, an inhibitor of 5-LO was found to reduce systemic inflammation and polyp burden of small intestine/colon in a murine model of polyposis supporting above human studies [50]. Deletion of the key enzymes in LTB 4 biosynthesis, 5-LO or LTA 4 H significantly abrogated tumor burden in K-ras–driven pancreatic ductal adenocarcinoma [51] or in xenograft mouse model of human pancreatic cancer [52]. Interestingly, an inhibitor of 5-LO was also shown to induce differentiation of glioma-stem-like cells thereby reducing the tumorigenecity of the xenografts [53].…”

Is it time for a new classification of mast cells? What do we know about mast cell heterogeneity?

“…Increased expression of immunoglobulin free light chains, that can trigger MC activation, is also found in areas of MC infiltration in pancreatic cancer . Moreover, 5‐lipoxygenase (5LO) upregulation has been associated with MC accumulation . A potential pro‐tumoral role for MCs in the progression of PDAC has been corroborated by studies with cancer cell lines and in different murine models.…”