title: Endothelial precursor cell-based therapy to target the pathologic angiogenesis and compensate tumor hypoxia.
abstract: Hypoxia-inducing pathologies as cancer develop pathologic and inefficient angiogenesis which rules tumor facilitating microenvironment, a key target for therapy. As such, the putative ability of endothelial precursor cells (EPCs) to specifically home to hypoxic sites of neovascularization prompted to design optimized, site-specific, cell-mediated, drug-/gene-targeting approach. Thus, EPC lines were established from aorta-gonad-mesonephros (AGM) of murine 10.5 dpc and 11.5 dpc embryo when endothelial repertoire is completed. Lines representing early endothelial differentiation steps were selected: MAgEC10.5 and MagEC11.5. Distinct in maturation, they differently express VEGF receptors, VE-cadherin and chemokine/receptors. MAgEC11.5, more differentiated than MAgEC 10.5, displayed faster angiogenesis in vitro, different response to hypoxia and chemokines. Both MAgEC lines cooperated to tube-like formation with mature endothelial cells and invaded tumor spheroids through a vasculogenesis-like process. In vivo, both MAgEC-formed vessels established blood flow. Intravenously injected, both MAgECs invaded Matrigel(TM)-plugs and targeted tumors. Here we show that EPCs (MAgEC11.5) target tumor angiogenesis and allow local overexpression of hypoxia-driven soluble VEGF-receptor2 enabling drastic tumor growth reduction. We propose that such EPCs, able to target tumor angiogenesis, could act as therapeutic gene vehicles to inhibit tumor growth by vessel normalization resulting from tumor hypoxia alleviation.
authors.affiliation: Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, Kraków 30387, Poland.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Collet
authors.affiliation: Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, Kraków 30387, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Szade
authors.affiliation: Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, Kraków 30387, Poland.
authors.forename: Witold
authors.initials: W
authors.lastname: Nowak
authors.affiliation: Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, Kraków 30387, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Klimkiewicz
authors.affiliation: Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France.
authors.forename: Bouchra
authors.initials: B
authors.lastname: El Hafny-Rahbi
authors.affiliation: Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, Kraków 30387, Poland.
authors.forename: Karol
authors.initials: K
authors.lastname: Szczepanek
authors.affiliation: Division of Hematopoietic Stem Cells, Kyushu University Faculty of Medical Sciences, Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sugiyama
authors.affiliation: Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France.
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Weglarczyk
authors.affiliation: Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Foucault-Collet
authors.affiliation: Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France.
authors.forename: Alan
authors.initials: A
authors.lastname: Guichard
authors.affiliation: Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, Kraków 30387, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Mazan
authors.affiliation: Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France.
authors.forename: Mahdi
authors.initials: M
authors.lastname: Nadim
authors.affiliation: Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Fasani
authors.affiliation: Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lamerant-Fayel
authors.affiliation: Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Grillon
authors.affiliation: Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Petoud
authors.affiliation: Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Beloeil
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, Kraków 30387, Poland; Malopolska Biotechnology Centre, Jagiellonian University, Gronostajowa 7A, Kraków 30387, Poland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Jozkowicz
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, Kraków 30387, Poland; Malopolska Biotechnology Centre, Jagiellonian University, Gronostajowa 7A, Kraków 30387, Poland. Electronic address: jozef.dulak@uj.edu.pl.
authors.forename: Jozef
authors.initials: J
authors.lastname: Dulak
authors.affiliation: Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France; Malopolska Biotechnology Centre, Jagiellonian University, Gronostajowa 7A, Kraków 30387, Poland. Electronic address: claudine.kieda@cnrs-orleans.fr.
authors.forename: Claudine
authors.initials: C
authors.lastname: Kieda
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D066026:Endothelial Progenitor Cells / Q000502:physiology*; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000628:therapy*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Cell gene therapy; Endothelial precursor cells; Pathologic angiogenesis/vasculogenesis; Tumor targeting