Murakami Junichi, Li Tao-Sheng, Ueda Kazuhiro, Tanaka Toshiki, Hamano Kimikazu
Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, Japan.
Int J Cancer. 2009 Apr 1;124(7):1685-92. doi: 10.1002/ijc.24085.
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(+)/Flk-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 +/- 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.
有人提出，未成熟的祖细胞会因化疗诱导的骨髓抑制而从骨髓动员到外周血中。我们研究了未成熟祖细胞的动员如何影响化疗后的肿瘤生长。我们发现，给予100mg/kg环磷酰胺的小鼠外周血中CD34(+)/Flk-1(+)内皮祖细胞数量在给药1周后显著增加，而注射生理盐水的小鼠外周血中该细胞数量则无明显变化（分别为0.39±0.09%和0.20±0.10%；p<0.05）。接受化疗的小鼠肿瘤生长速度几乎比接受生理盐水注射的小鼠快1.3倍（分别为268±66mg和210±35mg；p<0.05）。肿瘤组织的组织学检查显示，接受化疗的小鼠肿瘤组织中的微血管密度显著更高，Ki67阳性细胞更多，但凋亡细胞显著更少（p<0.05）。此外，我们检测到接受化疗的小鼠肿瘤组织中骨髓来源的细胞显著多于接受生理盐水注射的小鼠，其中一些细胞CD34染色呈阳性，并定位于血管中。然而，通过CXCR4抗体中和对SDF-1/CXCR4轴进行为期1周的短暂破坏，阻断了骨髓来源的细胞向肿瘤组织的募集，并导致化疗后加速的肿瘤生长完全受到抑制。我们的结果表明，化疗诱导了内皮祖细胞的动员并加速了肿瘤生长，但短暂破坏SDF-1/CXCR4轴可通过阻断化疗后动员的内皮祖细胞的募集来防止肿瘤生长加速。
