Our results demonstratefor the first time that i) endothelial cells express the trypsinogen 4 isoform of the serine protease PRSS3; ii) trypsinogen 4 cleaves TFPI-2, and iii) displaces it from the extracellular matrix of tumor-EC; iv) theangiogenic milieu dictates the up-regulation of trypsinogen 4 which is essential for the migration of tumor-EC. This evidence concerns the gene TFPI2 and neoplasm.