期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 180, 期 5, 页码 2170-2181出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2012.03.003
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资金
- American Cancer Society [RSG-05-250-01-CSM]
- Grossman Family Foundation
- University of Texas MD Anderson Cancer Center Melanoma Specialized Programs in Research Excellence (NIH SPORE) [P50 CA93459]
- MD Anderson's Cancer Center (NIH CCSG) [CA016672]
- MD Anderson Physician-Scientist Program
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-kappa B 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, 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. (Am J Pathol 2012, 180:2170-2181; DOI: 10.1016/j.ajpath.2012.03.003)
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