Differential effects of vascular endothelial growth factor receptor-2 inhibitor ZD6474 on circulating endothelial progenitors and mature circulating endothelial cells: implications for use as a surrogate marker of antiangiogenic activity.
OBJECTIVE
Circulating endothelial cells (CEC) comprise at least two distinct populations: bone marrow-derived circulating endothelial progenitors (CEP) and mature CECs derived from existing vasculature. We hypothesized that antiangiogenic agents may have differential effects on CEPs and mature CECs and that these changes may serve as a marker of biological activity.


METHODS
The effect of angiogenesis inhibitors on CECs was evaluated by flow cytometry after vascular endothelial growth factor (VEGF)-induced mobilization and in mice bearing Lewis lung carcinoma (LLC). Tumor angiogenesis was evaluated in parallel by immunohistochemistry.


RESULTS
In nontumor-bearing mice, VEGF administration increased both mature CECs and CEPs. This increase was inhibited by the VEGF receptor 2 inhibitor ZD6474 as well as the VEGF inhibitor-soluble Flt-1. ZD6474 had no significant effect on CECs in the absence of exogenous VEGF stimulation. In contrast, LLC-bearing mice had an increase in mature CECs but not CEPs after 3 days of treatment with ZD6474. The increase in mature CECs was dose-dependent, accompanied by a decrease in tumor microvessel density, and preceded reduction in tumor volume. Treatment of LLC-bearing mice with the vascular targeting agent ZD6126 also increased mature CECs.


CONCLUSIONS
VEGF inhibitors can have differential effects on mature CECs and CEPs, and agents inhibiting tumor angiogenesis may cause a concomitant increase in mature CECs. This increase occurs in tumor-bearing but not in nontumor-bearing mice, suggesting that tumor endothelium is a potential source of mature CECs. Therefore, assessing both mature CECs and CEPs may provide insights into the mechanism of antiangiogenic agents and serve as an early surrogate marker of biological activity.
Beaudry
Paul
P
Children's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Force
Jeremy
J
Naumov
George N
GN
Wang
Andrew
A
Baker
Cheryl H
CH
Ryan
Anderson
A
Soker
Shay
S
Johnson
Bruce E
BE
Folkman
Judah
J
Heymach
John V
JV
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000097:blood / Q000098:blood supply / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism
D010880:Piperidines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D019009:Proto-Oncogene Proteins c-kit; D040301:Vascular Endothelial Growth Factor Receptor-2; D017493:Leukocyte Common Antigens; C452423:vandetanib