Continuous Delivery of Neutralizing Antibodies Elevate CCL2 Levels in Mice Bearing MCF10CA1d Breast Tumor Xenografts.
Continuous Delivery of Neutralizing Antibodies Elevate CCL2 Levels in Mice Bearing MCF10CA1d Breast Tumor Xenografts.
复制标题
持续递送中和抗体可提高携带 MCF10CA1d 乳腺肿瘤异种移植物的小鼠中的 CCL2 水平。
DOI：
10.1016/j.tranon.2017.06.009
复制
发表时间：
2017
影响因子：
5
通讯作者：
Cheng,Nikki
中科院分区：
文献类型：
--
作者：
Yao,Min;Smart,Curtis;Hu,Qingting;Cheng,Nikki
趋化因子是可溶性小分子，在伤口愈合、感染和癌症进展中起关键作用。特别是，C-C基序趋化因子配体2（CCL 2）在多种癌症类型中的过表达与患者预后不良相关。动物研究表明，CCL 2向巨噬细胞和乳腺癌细胞发出信号，促进肿瘤生长、侵袭和转移，表明CCL 2是一个有希望的治疗靶点。然而，人类特异性中和抗体的有效性尚未得到充分评估。此外，关于使用中和抗体靶向CCL 2仍然存在争议，可能是由于药物递送模式。在这里，我们研究了持续递送人CCL 2中和抗体对乳腺癌进展的影响。携带MCF 10 CA 1d乳腺肿瘤异种移植物的裸鼠植入含有对照IgG或抗CCL 2的渗透泵，并在4周内分析CCL 2水平和肿瘤进展。尽管在体外抑制了CCL 2诱导的迁移，但CCL 2中和抗体并没有显著影响肿瘤生长、侵袭、巨噬细胞募集或肿瘤血管生成。CCL 2抗体不影响小鼠CCL 2水平，但显著增加循环血液和肿瘤间质液中的人CCL 2水平。CCL 2中和抗体在高浓度下短期降低培养细胞中的CCL 2水平。在培养的成纤维细胞和乳腺癌细胞中的CCL 2的酶联免疫吸附测定分析显示，中和抗体在培养基中螯合CCL 2。一旦去除抗体，CCL 2水平就恢复。这些研究揭示了CCL 2中和抗体作为治疗剂的局限性，对将CCL 2靶向转化为临床具有重要意义。
Chemokines are small soluble molecules that play critical roles in wound healing, infection, and cancer progression. In particular, overexpression of the C-C motif chemokine ligand 2 (CCL2) in multiple cancer types correlates with poor patient prognosis. Animal studies have shown that CCL2 signals to macrophages and breast cancer cells to promote tumor growth, invasion, and metastasis, indicating that CCL2 is a promising therapeutic target. However, the effectiveness of human-specific neutralizing antibodies has not been fully evaluated. Furthermore, controversies remain on the use of neutralizing antibodies to target CCL2 and could be due to mode of drug delivery. Here, we investigated the effects of continuous delivery of human CCL2-neutralizing antibodies on breast cancer progression. Nude mice bearing MCF10CA1d breast tumor xenografts were implanted with osmotic pumps containing control IgG or anti-CCL2 and analyzed for CCL2 levels and tumor progression over 4 weeks. Despite inhibiting CCL2-induced migrationin vitro, CCL2-neutralizing antibodies did not significantly affect tumor growth, invasion, macrophage recruitment, or tumor angiogenesis. CCL2 antibodies did not affect murine CCL2 levels but significantly increased human CCL2 levels in circulating blood and tumor interstitial fluid. CCL2-neutralizing antibodies reduced CCL2 levels in cultured cells short term at high concentrations. Enzyme-linked immunosorbent assay analysis of CCL2 in cultured fibroblasts and breast cancer cells revealed that the neutralizing antibodies sequestered CCL2 in the media. CCL2 levels were restored once the antibodies were removed. These studies reveal limitations in CCL2-neutralizing antibodies as a therapeutic agent, with important implications for translating CCL2 targeting to the clinic.
登录
查看更多内容
哺乳动物有髓神经纤维中钠通道的密度和髓鞘下轴突膜的性质。
DOI：
--
发表时间：
1977
影响因子：
11.1
作者：
J. M. Ritchie;R. Rogart
通讯作者：
R. Rogart
影响因子：
5.5
作者：
BOSTOCK, H;SEARS, TA;SHERRATT, RM
通讯作者：
SHERRATT, RM
氨基吡啶与鱿鱼轴突膜钾通道的相互作用。
影响因子：
3.4
作者：
J. Yeh;G. Oxford;C. Wu;Toshio Narahashi
通讯作者：
Toshio Narahashi
溶血磷脂酰胆碱脱髓鞘轴突中的跳跃传导先于髓鞘再生
影响因子：
4.4
作者：
Kenneth Smith;H. Bostock;Susan M. Hall
通讯作者：
Susan M. Hall
有髓纤维中轴膜和轴胶质关系的本体发生：膜可塑性的电生理学和冷冻断裂相关性。
影响因子：
--
作者：
S. Waxman;J. Black;R. Foster
通讯作者：
R. Foster