title: Reversing resistance to vascular-disrupting agents by blocking late mobilization of circulating endothelial progenitor cells.
abstract: The prevailing concept is that immediate mobilization of bone marrow-derived circulating endothelial progenitor cells (CEP) is a key mechanism mediating tumor resistance to vascular-disrupting agents (VDA). Here, we show that administration of VDA to tumor-bearing mice induces 2 distinct peaks in CEPs: an early, unspecific CEP efflux followed by a late yet more dramatic tumor-specific CEP burst that infiltrates tumors and is recruited to vessels. Combination with antiangiogenic drugs could not disrupt the early peak but completely abrogated the late VDA-induced CEP burst, blunted bone marrow-derived cell recruitment to tumors, and resulted in striking antitumor efficacy, indicating that the late CEP burst might be crucial to tumor recovery after VDA therapy. CEP and circulating endothelial cell kinetics in VDA-treated patients with cancer were remarkably consistent with our preclinical data. These findings expand the current understanding of vasculogenic "rebounds" that may be targeted to improve VDA-based strategies.
  
  
  CONCLUSIONS
  Our findings suggest that resistance to VDA therapy may be strongly mediated by late, rather than early, tumor-specific recruitment of CEPs, the suppression of which resulted in increased VDA-mediated antitumor efficacy. VDA-based therapy might thus be significantly enhanced by combination strategies targeting late CEP mobilization.
authors.affiliation: Translational Research Laboratory, University of Paris-Sud, INSERM U981, Villejuif, France.
authors.forename: Melissa
authors.initials: M
authors.lastname: Taylor
authors.forename: Fanny
authors.initials: F
authors.lastname: Billiot
authors.forename: Virginie
authors.initials: V
authors.lastname: Marty
authors.forename: Valérie
authors.initials: V
authors.lastname: Rouffiac
authors.forename: Patrick
authors.initials: P
authors.lastname: Cohen
authors.forename: Elodie
authors.initials: E
authors.lastname: Tournay
authors.forename: Paule
authors.initials: P
authors.lastname: Opolon
authors.forename: Fawzia
authors.initials: F
authors.lastname: Louache
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.forename: Corinne
authors.initials: C
authors.lastname: Laplace-Builhé
authors.forename: Philippe
authors.initials: P
authors.lastname: Vielh
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Françoise
authors.initials: F
authors.lastname: Farace
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors