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Angiogenesis

, Volume 16, Issue 4, pp 809–820 | Cite as

Antiangiogenic therapy promoted metastasis of hepatocellular carcinoma by suppressing host-derived interleukin-12b in mouse models

  • Xiao-Dong Zhu
  • Hui-Chuan Sun
  • Hua-Xiang Xu
  • Ling-Qun Kong
  • Zong-Tao Chai
  • Lu Lu
  • Ju-Bo Zhang
  • Dong-Mei Gao
  • Wen-Quan Wang
  • Wei Zhang
  • Peng-Yuan Zhuang
  • Wei-Zhong Wu
  • Lu Wang
  • Zhao-You TangEmail author
Original Paper

Abstract

Antiangiogenic therapy, specially sorafenib, has become the standard of care for patients with advanced hepatocellular carcinoma (HCC), however, the improvement in survival time is not satisfactory. Previous studies have found that, in some circumstances, antiangiogenic therapy promoted tumor metastasis and the mechanistic studies were mainly focus on cancer-cell-autonomous manners. In two experimental metastasis models with tail-vein injection with hepatoma cells and an orthotopic HCC mouse model, we found that pretreatment with two vascular endothelial growth factor receptor (VEGFR) inhibitors, sunitinib and sorafenib, facilitated tumor cell survival in blood stream and promoted lung metastasis from tumors that were subsequently incubated after drug discontinuation, indicating that host response joined into the pro-metastatic effects. An antibody microarray identified that interleukin (IL)-12b was decreased in the peripheral blood of the mice treated with the two VEGFR inhibitors. IL-12b suppression in macrophages and dendritic cells from host organs was found to play a crucial role in treatment-induced metastasis. Supplement with recombinant mouse IL-12b or restoration of IL-12b expression in the host by zoledronic acid, which was previously reported to enhance IL-12 expression in vitro and in vivo, alleviated the metastasis-promoting effects of sunitinib and sorafenib. These studies suggest that host response to VEGFR inhibitors facilitates HCC metastasis and restoration of IL-12b expression could translate into clinical benefits.

Keywords

Sorafenib Sunitinib Zoledronic acid Macrophages Dendritic cells 

Notes

Acknowledgments

This work was jointly supported by Shanghai Natural Science Foundation (12ZR1442300), National Natural Science Foundation of China (No. 81020108025 and 81101564), the National Key Project for Infectious Diseases (2012ZX10002-012), and the National “211” Project for Higher Education.

Supplementary material

10456_2013_9357_MOESM1_ESM.docx (233 kb)
Supplementary material 1 (DOCX 232 kb)

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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Xiao-Dong Zhu
    • 1
    • 2
  • Hui-Chuan Sun
    • 1
    • 2
  • Hua-Xiang Xu
    • 3
    • 4
  • Ling-Qun Kong
    • 1
    • 2
  • Zong-Tao Chai
    • 1
    • 2
  • Lu Lu
    • 1
    • 2
  • Ju-Bo Zhang
    • 1
    • 2
  • Dong-Mei Gao
    • 1
    • 2
  • Wen-Quan Wang
    • 3
    • 4
  • Wei Zhang
    • 5
    • 6
  • Peng-Yuan Zhuang
    • 7
  • Wei-Zhong Wu
    • 1
    • 2
  • Lu Wang
    • 1
    • 2
  • Zhao-You Tang
    • 1
    • 2
    Email author
  1. 1.Liver Cancer Institute and Zhongshan HospitalFudan UniversityShanghaiPeople’s Republic of China
  2. 2.Key Laboratory for Carcinogenesis and Cancer InvasionChinese Ministry of EducationShanghaiPeople’s Republic of China
  3. 3.Department of Pancreatic and Hepatobiliary SurgeryFudan University Shanghai Cancer CenterShanghaiPeople’s Republic of China
  4. 4.Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiPeople’s Republic of China
  5. 5.Department of Hepatobiliary SurgeryTianjin Medical University Cancer Institute and HospitalTianjinPeople’s Republic of China
  6. 6.Laboratory of Cancer Prevention and TherapyTianjinPeople’s Republic of China
  7. 7.Department of General Surgery, Xinhua Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiPeople’s Republic of China

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