CXCR4 antibody treatment suppresses metastatic spread to the lung of intratibial human osteosarcoma xenografts in mice.
CXCR4 antibody treatment suppresses metastatic spread to the lung of intratibial human osteosarcoma xenografts in mice.
复制标题
DOI：
10.1007/s10585-013-9632-3
复制
发表时间：
2014-03
影响因子：
4
通讯作者：
Fuchs B
中科院分区：
文献类型：
--
作者：
Brennecke P;Arlt MJ;Campanile C;Husmann K;Gvozdenovic A;Apuzzo T;Thelen M;Born W;Fuchs B
目前，原发性转移性骨肉瘤（OS）的手术和新辅助化疗联合治疗无效，受影响患者的5年生存率低于20%。在实验性OS转移模型中的研究指出CXCR 4/CXCL 12归巢轴是OS转移抑制治疗的新靶点。本研究首次在自发转移的人143 B OS细胞系来源的原位异种移植小鼠模型中研究了CXCR 4阻断原理。与亲本非转移性HOS细胞不同，高转移性143 B细胞在细胞表面表达功能性CXCR 4受体，如本研究中通过基因转录物的RT/PCR、通过使用单克隆抗CXCR 4抗体12 G5（mAb 12 G5）的FACS分析以及通过CXCL 12对AKT和ERK磷酸化的时间和剂量依赖性刺激所揭示的。在Boyden室跨孔迁移测定中，与HOS细胞相比，143 B的显著（p < 0.05）更高的CXCL 12剂量依赖性趋化反应表明CXCL 12/CXCR 4归巢轴在143 B细胞肺转移中的关键作用。静脉推注mAb 12 G5重复治疗143 B细胞衍生的胫骨内肿瘤小鼠确实显著抑制了lacZ转导的143 B细胞的X-半乳糖苷酶肺微转移的数量（p < 0.01）。抗体治疗对原发性肿瘤生长也有轻微的抑制作用，与明显较少的骨质溶解相关，但它不影响肺大转移的发生数量。总之，这些结果证明了高亲和力CXCR 4阻断剂在转移性OS中用于OS肿瘤细胞归巢抑制治疗的相当大的潜力，作为当前（新）辅助化疗的补充。
Current combined surgical and neo-adjuvant chemotherapy of primary metastatic osteosarcoma (OS) is ineffective, reflected by a 5-year survival rate of affected patients of less than 20 %. Studies in experimental OS metastasis models pointed to the CXCR4/CXCL12 homing axis as a novel target for OS metastasis-suppressive treatment. The present study investigated for the first time the CXCR4-blocking principle in a spontaneously metastasizing human 143B OS cell line-derived orthotopic xenograft mouse model. The highly metastatic 143B cells, unlike the parental non-metastatic HOS cells, express functional CXCR4 receptors at the cell surface, as revealed in this study by RT/PCR of gene transcripts, by FACS analysis with the monoclonal anti CXCR4 antibody 12G5 (mAb 12G5) and by CXCL12 time- and dose-dependent stimulation of AKT and ERK phosphorylation. A significantly (p < 0.05) higher CXCL12 dose-dependent chemotactic response of 143B compared to HOS cells in a Boyden chamber trans-well migration assay suggested a crucial role of the CXCL12/CXCR4 homing axis in 143B cell lung metastasis. Repetitive treatment of mice with 143B cell-derived intratibial tumors given intravenous bolus injections of mAb12G5 indeed inhibited significantly (p < 0.01) the number of X-gal-stainable lung micrometastases of lacZ-transduced 143B cells. Antibody treatment had also a mild inhibitory effect on primary tumor growth associated with remarkably less osteolysis, but it did not affect the number of developing lung macrometastases. In conclusion, these results demonstrate considerable potential of high-affinity CXCR4-blocking agents for OS tumor cell homing suppressive treatment in metastasizing OS complementary to current (neo)-adjuvant chemotherapy.