Figure 6. Tumor endothelium manages angiogenesis and blood vessel remodeling through theangiogenic factors-mediated trypsinogen 4 up-regulation and cleavage ofextracellular TFPI-2.

The cartoon shows the proposed scenario: the tumor microenvironment (VEGF-A, FGF-2 and EGF provided by the cancer cells and stroma) triggers and sustains the expression of trypsinogen 4 by the endothelium. Upon secretion and activation, trypsinogen 4 cleaves TFPI-2, particularly rich in the endothelial ECM. The displacement of TPFI-2 permits EC migration and hence favors angiogenesis and blood vessel remodeling. The mechanism of release and activation of trypsinogen 4 remains to be elucidated, although there is evidence indicating its activation by cathepsin B [7].