J Clin Invest.
Pharmacological modulation of EET levels controls primary tumor growth and metastasis.
(A) Systemic administration of an sEH inhibitor (tAUCB) stimulates primary LLC-GFP tumor growth. Images show representative tumors after 13 days of treatment. n = 6 mice/group; *P = 0.007. Scale bar: 1 cm. (B) Immunofluorescence double staining for VEGF and GFP (tumor cells) shows increased tumor cell expression of VEGF in LLC-GFP tumor cells from tAUCB- versus vehicle-treated mice. Green, GFP-stained tumor cells; red, VEGF-containing cells. Colocalization of red and green fluorescence (yellow) indicates tumor cells expressing VEGF (arrows). tAUCB-treated tumors have an increase in MECA-32–positive ECs (green). Scale bars: 20 μm. (C) Systemic administration of tAUCB and TUPS (10 mg/kg/d each) increases spontaneous B16F10 axillary lymph node metastasis 21 days after B16F10 resection. Representative axillary lymph nodes after 21 days of treatment are shown. Scale bars: 1 cm. n = 6 mice/group; *P = 0.029 versus control. (D) The EET antagonist 14,15-EEZE (0.21 mg/mouse) inhibits primary LLC growth (left panel), prolongs survival (middle panel), and reduces plasma VEGF levels (right panel) in a spontaneous LLC lung metastasis model. n = 5 mice/group; *P = 0.017, **P = 0.035, ***P = 0.044. (E) The EET antagonist 14,15-EEZE-mSI (0.21 mg/mouse) inhibits 14,15-EET–induced (15 μg/kg/d) spontaneous LLC metastasis. The stable EET metabolite 14,15-DHET (15 μg/kg/d) does not stimulate metastasis. Representative photographs on day 12 after LLC resection are shown. Scale bars: 1 cm. n = 5 mice/group; *P < 0.001, **P = 0.003 versus 14,15-EET.