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BMP4/Thrombospondin-1 loop paracrinically inhibits tumor angiogenesis and suppresses the growth of solid tumors

Oncogene volume 33, pages 3803–3811 (2014)Cite this article

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Abstract

Bone morphogenetic protein 4 (BMP4) has potential as an anticancer agent. Recent studies have suggested that BMP4 inhibits the survival of cancer stem cells (CSCs) of neural and colon cancers. Here, we showed that BMP4 paracrinically inhibited tumor angiogenesis via the induction of Thrombospondin-1 (TSP1), and consequently suppressed tumor growth in vivo. Although HeLa (human cervical cancer), HCI-H460-LNM35 (highly metastatic human lung cancer) and B16 (murine melanoma) cells did not respond to the BMP4 treatment in vitro, the growth of xeno- and allografts of these cells was suppressed via reductions in tumor angiogenesis after intraperitoneal treatment with BMP4. When we assessed the mRNA expression of major angiogenesis-related factors in grafted tumors, we found that the expression of TSP1 was significantly upregulated by BMP4 administration. We then confirmed that BMP4 was less effective in suppressing the tumor growth of TSP1-knockdown cancer cells. Furthermore, we found that BMP4 reduced vascular endothelial growth factor (VEGF) expression in vivo in a TSP1-dependent manner, which indicates that BMP4 interfered with the stabilization of tumor angiogenesis. In conclusion, the BMP4/TSP1 loop paracrinically suppressed tumor angiogenesis in the tumor microenvironment, which subsequently reduced the growth of tumors. BMP4 may become an antitumor agent and open a new field of antiangiogenic therapy.

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Acknowledgements

We thank Dr Takashi Koda and Ms Kiyomi Kaneki for assisting in analysis of microarray data, Mr Daichi Yamanaka for operating of FACS sorting and Ms Shigeko Shimizu for preparing of immunohistochemistry. RT is a Research Fellow of the Japan Society of the Promotion of Science. This work was supported by the Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists (22-400024), Grant-in-Aid for Young Scientist (23701047), Grant-in-Aid for Scientific Research on Innovative Areas (24116509), the Takeda Science Foundation and a Grant-in-Aid Special Project Research on Cancer-Bioscience (17014020) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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  1. R Tsuchida and T Osawa: These authors equally contributed to this work.

Authors and Affiliations

  1. Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan

    R Tsuchida, T Osawa, F Wang, R Nishii, S Tsuchida, M Muramatsu, Y Yuasa & M Shibuya

  2. Department of Pediatrics, Tokyo Medical and Dental University, 1-5-45 Yushima, Tokyo, Japan

    R Tsuchida & R Nishii

  3. Laboratory for System Biology and Medicine, RCAST, University of Tokyo, Tokyo, Japan

    T Osawa, T Inoue, Y Wada & T Minami

  4. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    F Wang

  5. Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, USA

    B Das

  6. Department of Pediatrics, University of Tokyo Hospital, Tokyo, Japan

    S Tsuchida

  7. Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA

    M Muramatsu

  8. Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

    T Takahashi

  9. Institute of Physiology and Medicine, Jobu University, 270-1 Shin-machi, Takasaki, Gunma, Japan

    M Shibuya

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  1. R Tsuchida
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Correspondence to R Tsuchida or M Shibuya.

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RT, TO and MS designed the research; RT, TO, FW, RN, ST, MM, TT, TI and YW performed the experiments; RT, TO, BD and MS analyzed the data and wrote the paper; and TM and YY provided valuable help.

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Tsuchida, R., Osawa, T., Wang, F. et al. BMP4/Thrombospondin-1 loop paracrinically inhibits tumor angiogenesis and suppresses the growth of solid tumors. Oncogene 33, 3803–3811 (2014). https://doi.org/10.1038/onc.2013.358

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