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

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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.

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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.

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Authors and Affiliations

  1. Liver Cancer Institute and Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People’s Republic of China

    **ao-Dong Zhu, Hui-Chuan Sun, Ling-Qun Kong, Zong-Tao Chai, Lu Lu, Ju-Bo Zhang, Dong-Mei Gao, Wei-Zhong Wu, Lu Wang & Zhao-You Tang

  2. Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, 200032, People’s Republic of China

    **ao-Dong Zhu, Hui-Chuan Sun, Ling-Qun Kong, Zong-Tao Chai, Lu Lu, Ju-Bo Zhang, Dong-Mei Gao, Wei-Zhong Wu, Lu Wang & Zhao-You Tang

  3. Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China

    Hua-**ang Xu & Wen-Quan Wang

  4. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China

    Hua-**ang Xu & Wen-Quan Wang

  5. Department of Hepatobiliary Surgery, Tian** Medical University Cancer Institute and Hospital, Tian**, 300060, People’s Republic of China

    Wei Zhang

  6. Laboratory of Cancer Prevention and Therapy, Tian**, 300060, People’s Republic of China

    Wei Zhang

  7. Department of General Surgery, **nhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, People’s Republic of China

    Peng-Yuan Zhuang

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  1. **ao-Dong Zhu
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  14. Zhao-You Tang
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Correspondence to Zhao-You Tang.

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**ao-Dong Zhu and Hui-Chuan Sun have contributed equally to this work.

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Zhu, XD., Sun, HC., Xu, HX. et al. Antiangiogenic therapy promoted metastasis of hepatocellular carcinoma by suppressing host-derived interleukin-12b in mouse models. Angiogenesis 16, 809–820 (2013). https://doi.org/10.1007/s10456-013-9357-6

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