title: Trypsinogen 4 boosts tumor endothelial cells migration through proteolysis of tissue factor pathway inhibitor-2.
abstract: Proteases contribute to cancer in many ways, including tumor vascularization and metastasis, and their pharmacological inhibition is a potential anticancer strategy. We report that human endothelial cells (EC) express the trypsinogen 4 isoform of the serine protease 3 (PRSS3), and lack both PRSS2 and PRSS1. Trypsinogen 4 expression was upregulated by the combined action of VEGF-A, FGF-2 and EGF, angiogenic factors representative of the tumor microenvironment. Suppression of trypsinogen 4 expression by siRNA inhibited the angiogenic milieu-induced migration of EC from cancer specimens (tumor-EC), but did not affect EC from normal tissues. We identified tissue factor pathway inhibitor-2 (TFPI-2), a matrix associated inhibitor of cell motility, as the functional target of trypsinogen 4, which cleaved TFPI-2 and removed it from the matrix put down by tumor-EC. Silencing tumor-EC for trypsinogen 4 accumulated TFPI2 in the matrix. Showing that angiogenic factors stimulate trypsinogen 4 expression, which hydrolyses TFPI-2 favoring a pro-migratory situation, our study suggests a new pathway linking tumor microenvironment signals to endothelial cell migration, which is essential for angiogenesis and blood vessel remodeling. Abolishing trypsinogen 4 functions might be an exploitable strategy as anticancer, particularly anti-vascular, therapy.
authors: Laboratory of Biology and Treatment of Metastases, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors: Carmen
authors: C
authors: Ghilardi
authors: Laboratory of Biology and Treatment of Metastases, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors: Antonietta
authors: A
authors: Silini
authors: Laboratory of Biology and Treatment of Metastases, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors: Sara
authors: S
authors: Figini
authors: Laboratory of Biology and Treatment of Metastases, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors: Alessia
authors: A
authors: Anastasia
authors: Laboratory of Cancer Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors: Monica
authors: M
authors: Lupi
authors: Clinic of Obstetrics and Gynecology, University of Milan-Bicocca, San Gerardo Hospital, Monza, Italy.
authors: Robert
authors: R
authors: Fruscio
authors: Laboratory of Biology and Treatment of Metastases, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors: Raffaella
authors: R
authors: Giavazzi
authors: Laboratory of Biology and Treatment of Metastases, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors: Maria Rosa
authors: MR
authors: Bani
mesh_terms: D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014357:Trypsin / Q000235:genetics* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D006023:Glycoproteins; D042461:Vascular Endothelial Growth Factor A; C021240:tissue-factor-pathway inhibitor 2; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; C040749:PRSS3 protein, human; D014357:Trypsin
keywords: cancer microenvironment; endothelial cells; serine protease 3 (PRSS3)/trypsinogen 4; tissue factor pathway inhibitor 2 (TFPI-2); tumor angiogenesis