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The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy

Oncogene volume 31, pages 3254–3264 (2012)Cite this article

Abstract

Immature and unstable tumor vasculature provides an aberrant tumor microenvironment and leads to resistance of tumors to conventional therapy. Hence, normalization of tumor vessels has been reported to improve the effect of immuno-, chemo- and radiation therapy. However, the humoral factors, which can effectively induce maturation of tumor vasculature, have not been elucidated. In this study, we found that the novel peptide apelin and its receptor APJ can induce the morphological and functional maturation of blood vessels in tumors. This apelin-induced tumor vascular maturation enhances the efficacy of cancer dendritic cell-based immunotherapy and significantly suppresses tumor growth by promoting the infiltration of invariant natural killer T cells into the central region of the tumor and thereby robustly inducing apoptosis of tumor cells. Additionally, we showed APJ expression to be enhanced in the tumor endothelium in comparison with normal-state endothelial cells. These findings provide a new target for tumor vascular-specific maturation, which is expected to improve the efficacy of conventional cancer therapies.

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Acknowledgements

We thank Ms C Takeshita, Ms K Fukuhara and Ms N Fujimoto for technical assistance. Financial support: This work was supported by Grant-in-Aid for Research Activity Start-up (KAKENHI 21890124) from the Japan Society for the Promotion of Science (JSPS) and Research; a grant from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; and the YASUDA Medical Foundation.

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  1. H Kidoya and N Kunii: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

    H Kidoya, H Naito, F Muramatsu & N Takakura

  2. Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan

    N Kunii & Y Okamoto

  3. Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan

    N Kunii & T Nakayama

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  1. H Kidoya
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Correspondence to N Takakura.

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Kidoya, H., Kunii, N., Naito, H. et al. The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy. Oncogene 31, 3254–3264 (2012). https://doi.org/10.1038/onc.2011.489

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