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Tumor-secreted anterior gradient-2 binds to VEGF and FGF2 and enhances their activities by promoting their homodimerization

Oncogene volume 36, pages 5098–5109 (2017)Cite this article

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Abstract

The importance of the tumor microenvironment in targeted anticancer therapies has been well recognized. Various protein factors participate in the cross-talk between tumor cells and non-malignant cells. Anterior gradient-2 (AGR2) is overexpressed in diverse human adenocarcinomas and it exists in both intracellular and extracellular spaces. Although intracellular AGR2 has been intensively investigated, the function of secreted AGR2, especially its exact mechanism of action is still poorly understood. Here we report that the secreted AGR2 promotes the angiogenesis and the invasion of vascular endothelial cells and fibroblasts by enhancing the activities of vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2). Further study indicated that AGR2 directly binds to these extracellular signaling molecules, and enhances their homodimerization. The extracellular AGR2 activity can be blocked to reduce angiogenesis and inhibit tumor growth in vitro and in vivo by a monoclonal antibody targeting the AGR2 self-dimerization region, and combined treatment with bevacizumab produced maximum inhibition effect. In conclusion, our investigation reveals a mechanism that directly links the secreted AGR2 with extracellular signaling networks, and we propose that the secreted AGR2 is a blockable molecular target, which acts as a chaperon-like enhancer to VEGF and FGF2.

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Abbreviations

AGR2:

anterior gradient-2

HUVECs:

human umbilical vein endothelial cells

BEV:

bevacizumab

TIF:

tumor interstitial fluid

αSMA:

alpha smooth muscle actin.

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Acknowledgements

This research was supported by National Natural Science Foundation of China No. 81373319; Shanghai Science and Technology Commission Foundation No. 14431903400; Guangdong Major Science and Technology Projects Foundation No. 2012A080202014.

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Author notes

  1. H Guo and Q Zhu: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China

    H Guo, Q Zhu, S B Merugu, H B Mangukiya, B Zhang, H Negi, R Rong, Z Wu & D Li

  2. Engineering Research Center of Cell and Therapeutic Antibody of Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China

    H Guo, Q Zhu, B Zhang & D Li

  3. Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China

    X Yu

  4. Department of Molecular Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA,

    N Smith & Z Li

  5. Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China

    K Cheng

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Correspondence to Z Wu or D Li.

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Guo, H., Zhu, Q., Yu, X. et al. Tumor-secreted anterior gradient-2 binds to VEGF and FGF2 and enhances their activities by promoting their homodimerization. Oncogene 36, 5098–5109 (2017). https://doi.org/10.1038/onc.2017.132

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  • DOI: https://doi.org/10.1038/onc.2017.132

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