Inhibition of accelerated tumor growth by blocking the recruitment of mobilized endothelial progenitor cells after chemotherapy
Inhibition of accelerated tumor growth by blocking the recruitment of mobilized endothelial progenitor cells after chemotherapy
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DOI：
10.1002/ijc.24085
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发表时间：
2009-04-01
影响因子：
6.4
通讯作者：
Hamano, Kimikazu
中科院分区：
文献类型：
--
作者：
Murakami, Junichi;Li, Tao-Sheng;Hamano, Kimikazu
有人认为，未成熟的祖细胞从骨髓中动员到外周血中是对化疗诱导的骨髓抑制的反应。我们研究了未成熟祖细胞的动员如何影响化疗后肿瘤的生长。我们发现，与生理盐水注射相比，给药100 mg/kg环磷酰胺1周后小鼠外周血CD34(+)/FIk-1（+）内皮祖细胞数量显著增加（分别为0.39 +/- 0.09%和0.20 +/- 0.10%,p < 0.05）。化疗小鼠的肿瘤生长速度比生理盐水小鼠快1.3倍（分别为268 +/- 6 mg和210 +/- 35 mg， p < 0.05）。肿瘤组织组织学检查显示，化疗组微血管密度明显高于生理盐水组，ki67阳性细胞增多，凋亡细胞明显少于生理盐水组（p < 0.05）。此外，我们在化疗小鼠的肿瘤组织中检测到比生理盐水小鼠更多的骨髓来源细胞，其中一些CD34染色阳性并定位于血管中。然而，在1周内，CXCR4抗体中和对SDF-1/CXCR4轴的短暂破坏阻断了骨髓源性细胞向肿瘤组织的募集，从而完全抑制了化疗后加速的肿瘤生长。我们的研究结果表明，化疗诱导内皮祖细胞的动员并加速肿瘤生长，但短暂破坏SDF-1/CXCR4轴可以通过阻断化疗后动员的内皮祖细胞的募集来阻止肿瘤的加速生长。(C) 21008 Wiley-Liss公司
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 CD34(+)/FIk-1(+) 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 +/- 6 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 I 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. (C) 21008 Wiley-Liss, Inc.