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. 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. Cancer Discov; 2(5); 434-49.

Circulating Endothelial Progenitors and Tumor Resistance to Vascular-Targeting Therapies

“…Although the first CEP spike occurs a few hours after the administration of the VDA in both naïve and tumor-bearing mice, as previously reported (9), the second CEP spike occurs 3 to 4 days after the administration of VDA and is specifically observed in tumor-bearing mice (12). Of importance, the authors also detected bimodal CEP kinetics in cancer patients treated with a clinically validated VDA (ombrabulin).…”

“…Perhaps most importantly, future studies should also formally demonstrate that CEPs give rise to the bone marrow-derived ECs that incorporate in the tumor blood vessels. Because CEPtracing experiments (16) were not performed, the current study (12) provides only indirect evidence that the late CEP spike gives rise to the pool of bone marrow-derived ECs.…”

“…However, it also raises important questions. One key issue is represented by the ill-defined nature of the CEPs described in this study (12). Indeed, it is unclear from the data presented whether the second wave of cells mobilized in response to the VDA (late CEP spike) truly represent bona fide cell progenitors, that is, immature cells endowed with clonogenic activity.…”

“…The study of Taylor and colleagues (12) attests to the significance of "CEP rebounds" for tumor resistance to VDA therapy in mouse models of cancer. However, it also raises important questions.…”

“…These findings suggest that the therapeutic efficacy of VDAs may be improved by blocking drug-induced CEP rebounds into the tumor vasculature. In this issue of Cancer Discovery, Taylor and colleagues (12) report carefully performed studies that provide novel insight into the involvement of CEPs in tumor resistance to the VDA combretastatin-A4-phosphate (CA-4-P).…”