Research Papers:

Trypsinogen 4 boosts tumor endothelial cells migration through proteolysis of tissue factor pathway inhibitor-2

Carmen Ghilardi, Antonietta Silini, Sara Figini, Alessia Anastasia, Monica Lupi, Robert Fruscio, Raffaella Giavazzi and MariaRosa Bani _

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Oncotarget. 2015; 6:28389-28400. https://doi.org/10.18632/oncotarget.4949

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Carmen Ghilardi1, Antonietta Silini1, Sara Figini1, Alessia Anastasia1, Monica Lupi2, Robert Fruscio3, Raffaella Giavazzi1 and MariaRosa Bani1

1 Laboratory of Biology and Treatment of Metastases, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

2 Laboratory of Cancer Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

3 Clinic of Obstetrics and Gynecology, University of Milan-Bicocca, San Gerardo Hospital, Monza, Italy

Correspondence to:

MariaRosa Bani, email:

Raffaella Giavazzi, email:

Keywords: endothelial cells, cancer microenvironment, tumor angiogenesis, serine protease 3 (PRSS3)/trypsinogen 4, tissue factor pathway inhibitor 2 (TFPI-2)

Received: March 11, 2015 Accepted: July 02, 2015 Published: July 22, 2015


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.

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