Research Papers:

Zoledronic acid prevents the tumor-promoting effects of mesenchymal stem cells via MCP-1 dependent recruitment of macrophages

Xiao-Hua Jia, Yang Du, Duo Mao, Zhong-Liang Wang, Zhen-Qiang He, Jing-Dan Qiu, Xi-Bo Ma, Wen-Ting Shang, Dan Ding and Jie Tian _

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Oncotarget. 2015; 6:26018-26028. https://doi.org/10.18632/oncotarget.4658

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Xiao-Hua Jia1,*, Yang Du1,*, Duo Mao2, Zhong-Liang Wang3, Zhen-Qiang He4, Jing-Dan Qiu5, Xi-Bo Ma1, Wen-Ting Shang1, Dan Ding2, Jie Tian1,6

1Key Laboratory of Molecular Imaging of the Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China

2State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China

3School of Life Science and Technology, Xidian University, Shaanxi, Xi’an 710071, China

4State Key Laboratory of Oncology in South China, Department of Neurosurgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, China

5Department of General Surgery, the Chinese PLA General Hospital, Beijing 100039, China

6Beijing Key Laboratory of Molecular Imaging, Beijing 100190, China

*These authors have contributed equally to this work

Correspondence to:

Jie Tian, e-mail: [email protected]

Keywords: zoledronic acid, mesenchymal stem cells, breast carcinoma, tumor associated macrophages, monocyte chemotactic protein-1

Received: March 29, 2015     Accepted: July 23, 2015     Published: August 03, 2015


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.

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