TY - JOUR
T1 - Lysophosphatidic acid induces lymphangiogenesis and IL-8 production in vitro in human lymphatic endothelial cells
AU - Mu, Hong
AU - Calderone, Tiffany L.
AU - Davies, Michael A.
AU - Prieto, Victor G.
AU - Wang, Hua
AU - Mills, Gordon B.
AU - Bar-Eli, Menashe
AU - Gershenwald, Jeffrey E.
N1 - Funding Information:
Disclosures: G.B.M. receives research funding from LPATH, Inc., biotechnology (San Diego, CA). The other authors have no potential conflicts of interest to disclose.
Funding Information:
Supported in part by an American Cancer Society Research Scholar grant ( RSG-05-250-01-CSM to J.E.G.), the Grossman Family Foundation (J.E.G.), the University of Texas MD Anderson Cancer Center Melanoma Specialized Programs in Research Excellence ( NIH SPORE grant P50 CA93459 ), and the MD Anderson's Cancer Center Support Grant ( NIH CCSG CA016672 ). M.A.D. is the Goodfellow Scholar of the MD Anderson Physician-Scientist Program.
PY - 2012/5
Y1 - 2012/5
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajpath.2012.03.003
DO - 10.1016/j.ajpath.2012.03.003
M3 - Article
C2 - 22465753
AN - SCOPUS:84860234451
SN - 0002-9440
VL - 180
SP - 2170
EP - 2181
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -