Abstract 3952: Cytochrome P450-derived eicosanoids regulate pancreatic cancer and metastasis.

Background: 20-hydroxeicosatetraenoic acid (20-HETE) and epoxyeicosatrenoic acids (EETs) are lipid autacoids biosynthesized by cytochrome P450 ω-hydroxylases (e.g. CYP4F2) and epoxygenases, respectively. These eicosanoids regulate inflammation, vascular tone and stimulate angiogenesis which is required for tumor growth and metastasis. However, despite their pleiotropic effects on cells, the role of these cytochrome P450-derived metabolites in pancreatic cancer has not been studied. We hypothesize that 20-HETE and EETs in the tumor microenvironment stimulate pancreatic cancer and metastasis. Methods and Results: Using genetic and pharmacological manipulation of endogenous 20-HETE and EET levels, we demonstrate that 20-HETE and EETs are critical for primary pancreatic tumor growth and metastasis. Native CYP4F2 protein was expressed in a series of human pancreatic tumor cell lines. Transgenic mice with endothelial-specific (tie2-promoter) overexpression of CYP4F2 were used to achieve increased endothelial levels of 20-HETE and stimulated pancreatic tumor growth. Systemic administration of 20-HETE and/or 14,15-EET by osmotic minipump stimulated primary human pancreatic cancer (Panc1) and murine pancreatic (PancOH7) tumor growth in both subcutaneous and orthotopic models. Inhibitors of soluble epoxide hydrolase, the enzyme that metabolizes EETs, elevated EET levels and promoted pancreatic tumor growth. Conversely, systemic administration of a 20-HETE antagonist (HET0016) and/or EET antagonist (14,15-EEZE) suppressed PancOH7 pancreatic tumor growth without toxic effects. Tie2-CYP4F2 transgenic mice exhibited spontaneous liver metastasis after resection of primary pancreatic (PancOH7) subcutaneous tumors. This is of interest because liver metastasis from the injection of pancreatic tumor cells is commonly only achieved by direct injection of tumor cells into the spleen or pancreas. Systemic administration of 20-HETE in WT mice stimulated a 4-fold increase in the number of surface lung metastases compared with control mice and led to an induction of liver and mediastinal lymph node metastasis 26-30 days after resection of the primary PancOH7 tumor. In contrast, the 20-HETE antagonist and/or EET antagonist prolonged survival in the PancOH7 resection metastasis model. Moreover, the 20-HETE antagonist and/or EET antagonist inhibited pancreatic tumor cell proliferation and viability induced by 20-HETE and 14,15-EET, respectively. Furthermore, the 20-HETE antagonist and/or EET antagonist suppressed tumor angiogenesis including a decrease in CD31-positive vessels and VEGF levels in PancOH7 pancreatic tumors. Conclusion: 20-HETE and EET production in the tumor microenvironment may be a critical regulator of pancreatic tumor growth and metastasis, offering a mechanistic rationale for using 20-HETE and EET antagonists as novel anti-cancer therapeutics for pancreatic cancer. Citation Format: Jessica A. Casper, Diane R. Bielenberg, Jennifer Cheng, Birgitta Schmidt, Bruce D. Hammock, Darryl C. Zeldin, Mark W. Kieran, Dipak Panigrahy. Cytochrome P450-derived eicosanoids regulate pancreatic cancer and metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3952. doi:10.1158/1538-7445.AM2013-3952