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Clin Cancer Res. 2017 Nov 15;23(22):7130-7140. doi: 10.1158/1078-0432.CCR-17-0811. Epub 2017 Sep 12.

Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression In Vitro and In Vivo.

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Institut National de la Santé et de la Recherche Médicale, Unité Grenoble, Grenoble, France.
University Grenoble-Alpes, Grenoble, France.
Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, Grenoble, France.
Faculty of Medicine and Pharmacy, University Hassan II Casablanca and Ibn Rochd Hospital of Casablanca, Obstetrics and Gynecology Department, Casablanca, Morocco.
University Hospital of Grenoble, Department of Obstetrics and Gynaecology, and Laboratoire d'Aide à la Procréation-CECOS, La Tronche, France.
Department of Human Genetics, McGill University Health Centre Research Institute, Montréal, Quebec, Canada.
Department of Pharmacology, University of California, Irvine, California.
Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.
University of Lyon 1, University Hospital Lyon Sud, Department of Gynecological Surgery and Oncology, Obstetrics, Lyon, France.
French Reference Center for Gestational Trophoblastic Diseases, University Hospital Lyon Sud, Chemin du Grand Revoyet, Pierre Bénite, Lyon, France.
Joint Unit Hospices Civils de Lyon-bioMerieux, Cancer Biomarkers Research Group, University Hospital Lyon Sud, Lyon, France.
EA 7426 Pathophysiology of Injury-induced Immunosuppression, University of Lyon 1 Hospices Civils de Lyon bioMérieux, Hôpital Edouard Herriot, Lyon, France.
Centre National de la Recherche Scientifique, Unité Mixte de Recherche, Laboratoire de Chimie et Biologie des Métaux, Grenoble, France.
Institut National de la Santé et de la Recherche Médicale, Unité Grenoble, Grenoble, France.


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 recently identified endocrine gland-derived vascular endothelial growth factor (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 (×5) patients. EG-VEGF increased JEG3 proliferation, migration, and invasion in two-dimensional (2D) and three-dimensional (3D) culture systems. JEG3 injection in the placenta caused CC development with large metastases compared with 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 preclinical animal model of CC and presents evidence that EG-VEGF receptors can be targeted for CC therapy. This may provide safe and less toxic therapeutic options compared with the currently used multi-agent chemotherapies. Clin Cancer Res; 23(22); 7130-40. ©2017 AACR.

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