Reversing resistance to vascular-disrupting agents by blocking late mobilization of circulating endothelial progenitor cells.

Abstract

UNLABELLED 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. SIGNIFICANCE 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.

DOI: 10.1158/2159-8290.CD-11-0171

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@article{Taylor2012ReversingRT, title={Reversing resistance to vascular-disrupting agents by blocking late mobilization of circulating endothelial progenitor cells.}, author={Melissa Taylor and Fanny Billiot and Virginie Marty and Valerie Rouffiac and Patrick Cohen and Elodie Tournay and Paule Opolon and Fawzia Louache and Gilles Vassal and Corinne Laplace-Builhe and Philippe Vielh and Jean-Charles Soria and Françoise Farace}, journal={Cancer discovery}, year={2012}, volume={2 5}, pages={434-49} }