Contribution of Granulocyte Colony-Stimulating Factor to the Acute Mobilization of Endothelial Precursor Cells by Vascular Disrupting Agents

Abstract

Vascular disrupting agents (VDA) cause acute shutdown of abnormal established tumor vasculature, followed by massive intratumoral hypoxia and necrosis. However, a viable rim of tumor tissue invariably remains from which tumor regrowth rapidly resumes. We have recently shown that an acute systemic mobilization and homing of bone marrow-derived circulating endothelial precursor (CEP) cells could promote tumor regrowth following treatment with either a VDA or certain chemotherapy drugs. The molecular mediators of this systemic reactive host process are unknown. Here, we show that following treatment of mice with OXi-4503, a second-generation potent prodrug derivative of combretastatin-A4 phosphate, rapid increases in circulating plasma vascular endothelial growth factor, stromal derived factor-1 (SDF-1), and granulocyte colonystimulating factor (G-CSF) levels are detected. With the aim of determining whether G-CSF is involved in VDA-induced CEP mobilization, mutant G-CSF-R À/À mice were treated with OXi-4503. We found that as opposed to wild-type controls, G-CSF-R À/À mice failed to mobilize CEPs or show induction of SDF-1 plasma levels. Furthermore, Lewis lung carcinomas grown in such mice treated with OXi-4503 showed greater levels of necrosis compared with tumors treated in wild-type mice. Evidence for rapid elevations in circulating plasma G-CSF, vascular endothelial growth factor, and SDF-1 were also observed in patients with VDA (combretastatin-A4 phosphate)-treated cancer. These results highlight the possible effect of druginduced G-CSF on tumor regrowth following certain cytotoxic drug therapies, in this case using a VDA, and hence G-CSF as a possible therapeutic target.

Reversing Resistance to Vascular-Disrupting Agents by Blocking Late Mobilization of Circulating Endothelial Progenitor Cells

“…Functional analyses in the syngeneic C57Bl/6 mouse model transplanted with GFP + -tagged bone marrow showed a significant correlation between the late CEP burst detected in peripheral blood and tumor recruitment and infiltration of GFP but within a limited time-frame almost always restricted to the first 24 hours after drug administration (16,46,47). We confirmed the existence of an early (within 2-4 hours) VDAinduced CEP peak in both non-tumor-bearing and tumorbearing animals.…”

TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice

“…The number of F4/80 + TAMs was also significantly increased in CA4P-treated tumors ( Tumor expression of CXCL12 (SDF1) by both tumor and stromal cells (identified on the basis of cell morphology) increased 24 hours after CA4P treatment ( Figure 2A and Supplemental Figure 3) and was consistent with the hypoxic upregulation of CXCL12 (16) and raised plasma levels of CXCL12 seen in CA4P-treated patients (17). Ninety percent of tumor TEMs and 60% of TIE2 -TAMs expressed the CXCL12 receptor, CXCR4, in MMTV-PyMT tumors ( Figure 2B).…”

Phase I Safety, Pharmacokinetic and Pharmacodynamic Evaluation of the Vascular Disrupting Agent Ombrabulin (AVE8062) in Patients with Advanced Solid Tumors

“…Given the variations in timing of responses, it may be valuable to conduct CEC and CEP measures at multiple time points to determine optimal timing for use of this parameter as a biomarker. The cytokines G-CSF and SDF-1, previously implicated in the acute mobilization of endothelial progenitor cells by VDAs (27,30), showed no evidence of being reliable biomarkers of ombrabulin activity. The use of CECs, VEGF, and MMP-9 as biomarkers of ombrabulin activity merits further exploration, as does the use of dynamic contrast-enhanced (DCE) techniques to correlate tumoral vascular changes with antitumor activity (see Supplementary text for a preliminary DCE analysis of this study).…”