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Epoxyeicosanoid regulation of tumor lymphangiogenesis
Author(s) -
Mudge Dayna,
Bielenberg Diane R.,
Serhan Karolina,
Hwang Sung Hee,
Hammock Bruce D.,
Kieran Mark W.,
Panigrahy Dipak
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb457
Subject(s) - lymphangiogenesis , cancer research , lymphatic endothelium , metastasis , vascular endothelial growth factor c , primary tumor , lymphatic system , angiogenesis , medicine , chemistry , cancer , pathology , vascular endothelial growth factor a , vascular endothelial growth factor , vegf receptors
Epoxyeicosatrienoic acids (EETs) are lipid autacoids biosynthesized by cytochrome P450 epoxygenases. We recently demonstrated EETs stimulate multiorgan and lymph node metastasis. However, the mechanism of EETs in tumor metastasis is unknown. We hypothesize that EETs stimulate lymph node metastasis via tumor lymphangiogenesis. Using two murine tumor lines, B16F10 melanoma and T241 fibrosarcoma, each transfected with VEGFC we demonstrate EETs stimulate primary tumor growth via lymphangiogenesis. Systemic administration of 14,15‐EET and/or 20‐HETE accelerated growth of both primary tumors. Conversely, systemic administration of EET antagonist (14,15‐EEZE) and/or 20‐HETE antagonist (HET0016) regressed established primary B16F10‐VEGFC tumors. Immunohistochemistry studies revealed an increase in podoplanin‐positive and LYVE‐1‐positive vessels in tumors treated with 14,15‐EET. 14,15‐EET and 11,12‐EET stimulated lymphatic endothelial cell proliferation, viability and migration, as well as increased the production of VEGFC by tumor cells. 14,15‐EEZE and/or siRNA to VEGFR3 inhibited spontaneous lung metastasis and the combination showed additive inhibition. EETs and 20‐HETE stimulate tumor lymphangiogenesis, offering a mechanistic rationale for using EET and 20‐HETE antagonists as novel anticancer therapeutics to inhibit lymph node metastasis and tumor lymphangiogenesis.