Lysophosphatidic acid induces lymphangiogenesis and IL-8 production in vitro in human lymphatic endothelial cells

Hong Mu, Tiffany L. Calderone, Michael A. Davies, Victor G. Prieto, Hua Wang, Gordon B. Mills, Menashe Bar-Eli, Jeffrey E. Gershenwald

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

The bioactive phospholipid lysophosphatidic acid (LPA) and its receptors LPA 1-3 are aberrantly expressed in many types of human cancer. LPA has been reported to induce tumor cell proliferation, migration, and cytokine production. However, whether LPA exerts an effect on lymphatic endothelial cells (LECs) or on lymphangiogenesis, a process of new lymphatic vessel formation that is associated with increased metastasis and poor prognosis in cancer patients, has been unknown. Here, we show that LPA induces cell proliferation, survival, migration, and tube formation, and promotes lymphangiogenesis in vitro in human dermal LECs. In addition, LPA induces IL-8 expression by enhancing IL-8 promoter activity via activation of the NF-κB pathway in LECs. Using IL-8 siRNA and IL-8 neutralizing antibody, we revealed that IL-8 plays an important role in LPA-induced lymphangiogenesis in vitro. Moreover, using siRNA inhibition, we discovered that LPA-induced lymphangiogenesis in vitro and IL-8 production are mediated via the LPA 2 receptor in LECs. Finally, using human sentinel afferent lymphatic vessel explants, we demonstrated that LPA up-regulates IL-8 production in the LECs of lymphatic endothelia. These studies provide the first evidence that LPA promotes lymphangiogenesis and induces IL-8 production in LECs; we also reveal a possible new role of LPA in the promotion of tumor progression, as well as metastasis, in different cancer types.

Original languageEnglish (US)
Pages (from-to)2170-2181
Number of pages12
JournalAmerican Journal of Pathology
Volume180
Issue number5
DOIs
StatePublished - May 2012
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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