Antagonism of EG-VEGF receptors as targeted therapy for choriocarcinoma progression in vitro and in vivo

Traboulsi, Wael;Sergent, Frederic;Boufettal, Houssine;Brouillet, Sophie;Slim, Rima;Hoffmann, Pascale;Benlahfid, Mohammed;Zhou, qun yong;BALBONI, GIANFRANCO;ONNIS, VALENTINA;Bolze, Pierre Adrien;Salomon, Aude;Sauthier, Philippe;Mallet, François;Aboussaouira, Touria;Feige, Jean Jacques;Benharouga, Mohamed;Alfaidy, Nadia

2017-01-01

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Abstract

Purpose: Choriocarcinoma (CC) is the most malignant gestational trophoblastic disease that often develops from complete hydatidiform moles (CHM). Neither the mechanism of CC development nor its progression is yet characterized. We have recently identified EG-VEGF as a novel key placental growth factor that controls trophoblast proliferation and invasion. EG-VEGF acts via two receptors PROKR1 and PROKR2. Here, we demonstrate that EG-VEGF receptors can be targeted for CC therapy. Experimental design: Three approaches were used, i) a clinical investigation comparing circulating EG-VEGF in Control (n=20) and in distinctive CHM (n=38) and CC (n=9) cohorts, ii) an in vitro study investigating EG-VEGF effects on the CC cell line JEG3, and iii) an in vivo study including the development of a novel CC mouse model, through a direct injection of JEG3-luciferase into the placenta of gravid SCID-mice. Results: Both placental and circulating EG-VEGF levels were increased in CHM and CC (x5) patients. EG-VEGF increased JEG3 proliferation, migration and invasion, in 2D and 3D culture systems. JEG3 injection in the placenta caused CC development with large metastases compared to their injection into the uterine horn. Treatment of the animal model with EG-VEGF receptor's antagonists significantly reduced tumor development and progression and preserved pregnancy. Antibody-array and immunohistological analyses further deciphered the mechanism of the antagonist's actions. Conclusions: Our work describes a novel pre-clinical animal model of CC and brings evidences that EG-VEGF receptors can be targeted for CC therapy. This may provide safe and less toxic therapeutic options compared to the currently used multi-agent chemotherapies.