A Proliferation-inducing Ligand (APRIL) Acts as an Angiogenic Factor by Inducing Vascular Endothelial Growth Factor (VEGF)

Angiogenesis, the generation of new capillary blood vessels from pre-existing vessels, occurs under normal and patho logical conditions.Although angiogenesis in physiological processes is tightly regulated by a balance of stimulatory factors and inhibitory factors, disrupted balance effect plays a leading role in the progress of diseases such as tumor growth, rheumatoid arthritis and various blood vesselrelated pathology.1-3Tumor growth relies on angiogenesis to receive an adequate supply of nutrients and oxygen.In addition, the newly formed blood vessels provide a way for tumor cells to enter the circulation and to metastasize to distant organs.Therefore, treatment of cancer with antiangiogenic agents will control cancer cell growth and meta stasis.Among a variety of angiogenic factors, VEGF and basic fibroblast growth factor (bFGF) have a prominent activity in tumor metastasis and mortality.4Specially, VEGF expression is induced in various cancer by stimuli including hypoxia, activation of IGF-IR, or p53 loss of function and transcriptional activation of VEGF gene is mediated by hypoxia-inducible factor-1 (HIF-1)5,6 or nuclear factor kappa B (NF-xB).7Members of the TNF cytokine family are critically impli cated in various biological responses, including infections, inflammation, autoimmune diseases, and tissue homeostasis.8,9APRIL, a new member of the TNF family, is abundantly expressed in many tumor cells and tissues.10-12APRIL has been known to stimulate tumor cell and leukemia cell growth,10,12-14 regulate tumor cell apoptosis,11,15 or activate NF-xB.16,17However, the function of APRIL in tumor cells is not yet clear.Since angiogenesis process is composed of various steps including endothelial cell migration through extracellular matrix, we investigated the effect of APRIL on endothelial cell migration.HEK 293 cells were transfected with APRIL expression plasmid and then transfected cells were selected as described in experimental section.After confirmation of protein expression of APRIL (Fig. 1A), conditioned medium (CM) from the selected cells was obtained.In a chemotaxis chamber, human umbilical vein endothelial cells (HUVECs) were treated with CM from stably transfected cells for 2 h and HUVECs that had been migrated through membrane pores were counted under microscope.CM derived from stable APRIL-transfected cells (APRIL-CM) showed signi ficantly induced migratory effect, compared to that of control-CM (Fig. 1B).Thus, this result suggests that APRIL-CM has