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Identification of S100A14 as a metastasis-promoting molecule in a murine organotropic metastasis model

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Abstract

Cancer metastasis shows great diversity in target organs, routes and molecular mechanisms depending on the type of cancer and even on the individual patients. To identify key molecules involved in metastasis, we constructed a murine model system including multiple sublines with different organotropism and pathways of metastasis. We selected metastatic sublines from a murine mammary tumor cell line MCH66. Using this model, we extracted metastasis-related molecules by gene expression screening methods and verified their metastasis-promoting effects by gene knockdown or overexpression experiments. For the candidates promoting metastasis, we analyzed molecular functions involved in metastasis: cell growth, motility and invasive activity. We established a metastasis model including low metastatic sublines (66C8, 66LM, 66-4) and highly metastatic counterparts with various organotropism, such as to the lung (66Lu10), liver (HM-KAN5) and general organs (66HM and its clones: HM1-6 and HM1-7). The sublines basically exhibited the invasion-independent metastasis pathway characterized by endothelial cell-covered tumor emboli, whereas 66HM and HM-KAN5 showed an alternative metastasis pathway based on invasion in part and in whole, respectively. Comprehensive gene analysis extracted several molecular candidates responsible for metastasis. S100A14 was identified as one of the promissing candidates promoting lung-metastasis, which was verified by gene knockdown experiments in vivo. In addition, in vivo and in vitro functional analyses demonstrated that S100A14 enhanced scattering, motility and invasiveness of mouse tumor cells. Our model system may be adaptable to the diversity of metastasis in human cancers and useful for exploring the molecular mechanism responsible for metastasis.

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All data generated or analyzed during this study are included in this published article.

Abbreviations

SLPI:

Secretory leukocyte protease inhibitor

RAGE:

Receptor for advanced glycation end products

SSH:

Suppressive subtractive hybridization

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Funding

This work was supported by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (16K08727).

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Authors and Affiliations

  1. Division of Pathology, Shizuoka Cancer Center, Shizuoka, 411-8777, Japan

    Takashi Sugino, Masato Abe, Koji Muramatsu, Takuma Oishi, Yuko Kakuda & Takuya Kawata

  2. Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan

    Naoki Ichikawa-Tomikawa, Mizuko Tanaka & Tomiko Miura

  3. Department of Cardiology, Southern TOHOKU General Hospital, Koriyama, Japan

    Namiko Shishito

  4. Division of Immunotherapy, Shizuoka Cancer Center Research Institute, Shizuoka, Japan

    Yasuto Akiyama

Authors
  1. Takashi Sugino
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  2. Naoki Ichikawa-Tomikawa
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  3. Mizuko Tanaka
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  4. Namiko Shishito
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  5. Tomiko Miura
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  6. Masato Abe
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  7. Koji Muramatsu
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  8. Takuma Oishi
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  9. Yuko Kakuda
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  10. Takuya Kawata
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  11. Yasuto Akiyama
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Contributions

The authors contributed as follows: TS, NIT, MT and NS: were involved in the study concept and experimental design; TS, NS, TM, MA and KM: performed molecular and animal experiments; TO, YK and TK: helped with the analysis and interpretation of data (statistical analysis, biostatistics, computational analysis); YA: supervised the whole process. TS and NS: wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Takashi Sugino.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

All animal studies were carried out under the control of the Animal Care and Use Committee in accordance with the Guidelines for Animal Experiments of Fukushima Medical University and Shizuoka Cancer Center.

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Sugino, T., Ichikawa-Tomikawa, N., Tanaka, M. et al. Identification of S100A14 as a metastasis-promoting molecule in a murine organotropic metastasis model. Clin Exp Metastasis 36, 411–422 (2019). https://doi.org/10.1007/s10585-019-09979-w

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  • DOI: https://doi.org/10.1007/s10585-019-09979-w

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