title: Lysophosphatidic acid induces lymphangiogenesis and IL-8 production in vitro in human lymphatic endothelial cells.
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.
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Mu
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Calderone
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.forename: Victor G
authors.initials: VG
authors.lastname: Prieto
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Menashe
authors.initials: M
authors.lastname: Bar-Eli
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Gershenwald
mesh_terms: D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D042583:Lymphangiogenesis / Q000187:drug effects* / Q000502:physiology; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000187:drug effects / Q000378:metabolism; D008246:Lysophospholipids / Q000008:administration & dosage / Q000494:pharmacology*; D008545:Melanoma / Q000378:metabolism / Q000556:secondary; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000502:physiology; D021701:Sentinel Lymph Node Biopsy; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016209:Interleukin-8; D008246:Lysophospholipids; D016328:NF-kappa B; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid