Lymphangiogenesis (growth of new lymphatic vessels) is thought to play an important role in cancer lymphatic spread to the regional lymph nodes. However, the molecular pathways involved in lymphangiogenesis and their regulation are still unclear. Recently, there has been a significant advance in the studies of the lymphatic system and lymphangiogenesis as several novel specific lymphatic markers are discovered. Here, the effects of several cytokines on the lymphatic expression of human endothelial cells were studied. Amongst these cytokines, interleukin-7 (IL-7) was found to have significant impact on the lymphatic expression as it induced the expression of podoplanin, prox-1 and LYVE-1 in endothelial cells. Furthermore, IL-7 enhanced endothelial cell growth, migration and generation of lymphatic tubules in vitro via upregulating the expression of the lymphangiogenic growth factor and vascular endothelial growth factor-D. The specificity of these effects of IL-7 was confirmed using blocking anti-bodies and ribozyme transgene technology. These effects of IL-7 were totally abolished when IL-7R null endothelial cell mutants were used. IL-7 activated its transmembrane receptor, IL-7R, on endothelial cells, as well as its downstream signalling intermediates, Jak-1, Jak-3, PI3-K and Stat-5. Selective inhibition of these intermediates using specific inhibitors showed that IL-7 induced the afore-mentioned effects via a Wortmannin sensitive pathway. Collectively, these results demonstrate, for the first time, that IL-7 is a lymphangiogenic growth factor by inducing the lymphangiogenic properties of endothelial cells. This might have a significant impact on the lymphatic spread of solid tumours. Furthermore, interruption of IL-7 signalling might provide an attractive therapeutic option in cancer lymphatic metastasis.

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