Inhibition of accelerated tumor growth by blocking the recruitment of mobilized endothelial progenitor cells after chemotherapy

Abstract

It has been suggested that immature progenitor cells mobilize from bone marrow into the peripheral blood in response to the chemotherapy-induced myelosuppression. We investigated how the mobilization of immature progenitor cells affects tumor growth after chemotherapy. We found significantly increased numbers of CD34α/Flk-1α endothelial progenitor cells in the peripheral blood of mice 1 week after the administration of 100 mg/ kg cyclophosphamide vs. a saline injection (0.39 ± 0.09% vs. 0.20 ± 0.10%, respectively; p < 0.05). Tumor growth in the mice given chemotherapy was almost 1.3-fold faster than that in the mice given saline (268 ± 66 mg vs. 210 ± 3 5 mg, respectively; p<0.05). Histological examination of tumor tissue revealed significantly higher microvessel density and more Ki67-positive cells, but significantly fewer apoptotic cells, in the mice given chemotherapy than in those given saline (p<0.05). Furthermore, we detected significantly more bone marrow-derived cells, some of which stained positively for CD34 and were localized in the vessels, in tumor tissue from the mice given chemotherapy than in that from the mice given saline. However, the transient disruption of the SDF-1/ CXCR4 axis by the antibody neutralization of CXCR4, which occurred over 1 week, blocked the recruitment of bone marrow- derived cells into the tumor tissue, and resulted in complete inhibition of accelerated tumor growth after chemotherapy. Our results show that chemotherapy induced the mobilization of endothelial progenitor cells and accelerated tumor growth, but that transient disruption of the SDF-1/CXCR4 axis could prevent accelerated tumor growth by blocking the recruitment of mobilized endothelial progenitor cells after chemotherapy. © 2008 Wiley-Liss, Inc.