title: Zoledronic acid prevents the tumor-promoting effects of mesenchymal stem cells via MCP-1 dependent recruitment of macrophages.
abstract: 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.
authors: Key Laboratory of Molecular Imaging of the Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China.
authors: Xiao-Hua
authors: XH
authors: Jia
authors: Key Laboratory of Molecular Imaging of the Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China.
authors: Yang
authors: Y
authors: Du
authors: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors: Duo
authors: D
authors: Mao
authors: School of Life Science and Technology, Xidian University, Shaanxi, Xi'an 710071, China.
authors: Zhong-Liang
authors: ZL
authors: Wang
authors: State Key Laboratory of Oncology in South China, Department of Neurosurgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors: Zhen-Qiang
authors: ZQ
authors: He
authors: Department of General Surgery, the Chinese PLA General Hospital, Beijing 100039, China.
authors: Jing-Dan
authors: JD
authors: Qiu
authors: Key Laboratory of Molecular Imaging of the Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China.
authors: Xi-Bo
authors: XB
authors: Ma
authors: Key Laboratory of Molecular Imaging of the Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China.
authors: Wen-Ting
authors: WT
authors: Shang
authors: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors: Dan
authors: D
authors: Ding
authors: Key Laboratory of Molecular Imaging of the Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China.|Beijing Key Laboratory of Molecular Imaging, Beijing 100190, China.
authors: Jie
authors: J
authors: Tian
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D037181:Lectins, C-Type / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements / Q000379:methods; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D018932:Chemokine CCL2; D016207:Cytokines; D004164:Diphosphonates; D007093:Imidazoles; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D000077211:Zoledronic Acid; D008156:Luciferases
keywords: breast carcinoma; mesenchymal stem cells; monocyte chemotactic protein-1; tumor associated macrophages; zoledronic acid