Zoledronic acid inhibits infiltration of tumor-associated macrophages and angiogenesis following transcatheter arterial chemoembolization in rat hepatocellular carcinoma models

Zhou,Da‑Yong; Qin,Jie; Huang,Jian; Wang,Feng; Xu,Guo‑Peng; Lv,Yan‑Tian; Zhang,Ji‑Bin; Shen,Li‑Ming

doi:10.3892/ol.2017.6717

Zoledronic acid inhibits infiltration of tumor-associated macrophages and angiogenesis following transcatheter arterial chemoembolization in rat hepatocellular carcinoma models

Authors:
- Da‑Yong Zhou
- Jie Qin
- Jian Huang
- Feng Wang
- Guo‑Peng Xu
- Yan‑Tian Lv
- Ji‑Bin Zhang
- Li‑Ming Shen
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Affiliations: Department of Interventional Radiology and Vascular Surgery, Suzhou Municipal Hospital Affiliated to Nanjing Medical University, Suzhou, Jiangsu 215002, P.R. China, Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China, Department of Pathology, Suzhou Municipal Hospital Affiliated to Nanjing Medical University, Suzhou, Jiangsu 215002, P.R. China, Department of Respiration, Suzhou Municipal Hospital Affiliated to Nanjing Medical University, Suzhou, Jiangsu 215002, P.R. China, Department of Radiology, Suzhou Municipal Hospital Affiliated to Nanjing Medical University, Suzhou, Jiangsu 215002, P.R. China
Published online on: August 3, 2017 https://doi.org/10.3892/ol.2017.6717
Pages: 4078-4084
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hepatic transcatheter arterial chemoembolization (TACE), a minimally invasive procedure to block the blood supply of tumors and release of cytotoxic agents, is preferentially applied to patients with hepatocellular carcinoma (HCC) who are not able to receive radical treatments. However, the long‑term effects of TACE are unsatisfactory, as the microenvironment following procedure stimulates tumor angiogenesis, which promotes recurrence and metastasis of residual tumors. Tumor associated macrophages (TAMs) have been revealed to stimulate tumor growth and angiogenesis associated with poor prognosis in HCC. The present study focused on the changes in TAMs following TACE, and explored the effects of TACE in combination with the TAM inhibitor zoledronic acid (ZA) in rat HCC models. Orthotropic HCC rats were divided into three groups: Sham TACE, TACE alone and TACE combined with ZA treatment. At 7 or 14 days following TACE, tumor growth was evaluated by magnetic resonance imaging (MRI). Infiltration of TAMs was assessed by histological analysis and flow cytometry. Tumor angiogenesis was measured as the mean vessel density, and initial slope was calculated from dynamic contrast enhancement MRI. Local and systemic levels of vascular endothelial growth factor (VEGF) were determined by western blotting or an ELISA, respectively. The results revealed that TACE inhibited tumor growth at 7 days following the procedure, but this inhibition was attenuated at 14 days following the procedure compared with the sham TACE control. If combined with ZA treatment, TACE exhibited a stable inhibition effect on tumor growth until the end of observation. Investigation of the underlying mechanisms demonstrated that TACE combined with ZA treatment inhibited infiltration of F4/80 positive TAMs and tumor angiogenesis compared with the TACE alone group at 14 days following the procedure. Additionally, the combination treatment significantly inhibited secretion of VEGF in the present models. In conclusion, ZA treatment enhanced the effects of TACE through inhibiting TAM infiltration and tumor angiogenesis in rat HCC models.

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