In conclusion we established that tightening of the endothelial barrier achieved sequel to Epac activation in HDMECs reduced the trans-endothelial migration of the NB (SK-N-BE2C and SK-N-AS) cells, which potentially may serve as a therapeutic mechanism for the Epac pathway in the treatment of the high-risk neuroblastoma patients as they often developed the refractory or recurrent osteomedullary form of NB disease. Here, RAPGEF4 is linked to neuroblastoma.