Zoledronic acid prevents the tumor-promoting effects of mesenchymal stem cells via MCP-1 dependent recruitment of macrophages.
Zoledronic acid prevents the tumor-promoting effects of mesenchymal stem cells via MCP-1 dependent recruitment of macrophages.
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唑来膦酸通过 MCP-1 依赖性巨噬细胞募集阻止间充质干细胞的促肿瘤作用
DOI：
10.18632/oncotarget.4658
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发表时间：
2015-09-22
期刊：
影响因子：
--
通讯作者：
Tian J
中科院分区：
文献类型：
--
作者：
Jia XH;Du Y;Mao D;Wang ZL;He ZQ;Qiu JD;Ma XB;Shang WT;Ding D;Tian J
唑来膦酸（ZA）已在临床试验中作为早期乳腺癌的附加治疗进行了测试。然而，ZA发挥其抗肿瘤活性的机制仍不清楚。本研究的目的是研究ZA是否通过调节肿瘤微环境中的间充质干细胞（MSC）-单核细胞趋化蛋白1（MCP-1）-巨噬细胞轴来预防肿瘤生长。为了解决这个问题，MDA-MB-231-FLUC人乳腺癌细胞被培养并单独或与MSC偶联注射到裸鼠的乳房脂肪垫中。MSC用ZA处理或未处理。采用体内生物发光成像（BLI）法测定肿瘤生长情况，并采用CD 206抗体免疫组化法检测肿瘤组织中肿瘤相关巨噬细胞（TAMs）。实时荧光定量PCR检测ZA对MSC细胞因子相关基因表达的影响。在这项研究中，我们发现ZA治疗的小鼠显示出肿瘤生长的显着延迟。此外，我们的数据显示，ZA通过损害TAM募集和肿瘤血管化来削弱MSC促进肿瘤生长的能力。此外，发现ZA降低MSC的MCP-1表达，因此减少TAM向肿瘤部位的募集，从而抑制肿瘤生长。总而言之，我们的研究表明ZA可以阻止MSC的促肿瘤作用。ZA的抗肿瘤作用是通过降低MSC的MCP-1表达，从而进一步减少TAM向肿瘤部位的浸润，从而抑制肿瘤生长。
Zoledronic acid (ZA) has been tested in clinical trials as an additive therapy for early-stage breast cancer. However, the mechanism by which ZA exerts its antitumor activity is still unclear. The aim of this study is to investigate whether the prevention of tumor growth by ZA is through regulating the mesenchymal stem cells (MSC)-monocyte chemotactic protein 1 (MCP-1)-macrophages axis in the tumor microenvironment. To address this issue, MDA-MB-231-FLUC human breast cancer cells were cultured and injected either alone, or coupled with MSC into the mammary fat pads of nude mice. MSC were treated with either ZA or untreated. Tumor growth was determined by using an in vivo bioluminescence imaging (BLI) and the tumor-associated macrophages (TAMs) in tumor tissues were immunohistochemically analyzed by using CD206 antibody. The effects of ZA on the cytokine related gene expression of MSC were assessed by using real-time PCR. In this study, we found that ZA-treated mice showed a significant delay in tumor growth. In addition, our data revealed that ZA weakened the ability of MSC to promote tumor growth by impairing TAMs recruitment and tumor vascularization. Furthermore, it was found that ZA decreased MCP-1 expression of MSC, and therefore reduced the recruitment of TAMs to the tumor sites and hence inhibited the tumor growth. Altogether, our study demonstrated ZA can prevent the tumor-promoting effects of MSC. The antitumor effects of ZA were caused by decreasing the MCP-1 expression of MSC, which further decreased the infiltration of TAMs into tumor sites, and therefore inhibited the tumor growth.