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Lymphoma

Plasmin inhibitor reduces T-cell lymphoid tumor growth by suppressing matrix metalloproteinase-9-dependent CD11b+/F4/80+ myeloid cell recruitment

Leukemia volume 26, pages 332–339 (2012)Cite this article

Abstract

Activation of the fibrinolytic system during lymphoma progression is a well-documented clinical phenomenon. But the mechanism by which the fibrinolytic system can modulate lymphoma progression has been elusive. The main fibrinolytic enzyme, plasminogen (Plg)/plasmin (Plm), can activate matrix metalloproteinases (MMPs), such as MMP-9, which has been linked to various malignancies. Here we provide the evidence that blockade of Plg reduces T-cell lymphoma growth by inhibiting MMP-9-dependent recruitment of CD11b+F4/80+ myeloid cells locally within the lymphoma tissue. Genetic Plg deficiency and drug-mediated Plm blockade delayed T-cell lymphoma growth and diminished MMP-9-dependent CD11b+F4/80+ myeloid cell infiltration into lymphoma tissues. A neutralizing antibody against CD11b inhibited T-cell lymphoma growth in vivo, which indicates that CD11b+ myeloid cells have a role in T-cell lymphoma growth. Plg deficiency in T-cell lymphoma-bearing mice resulted in reduced plasma levels of the growth factors vascular endothelial growth-A and Kit ligand, both of which are known to enhance myeloid cell proliferation. Collectively, the data presented in this study demonstrate a previously undescribed role of Plm in lymphoproliferative disorders and provide strong evidence that specific blockade of Plg represents a promising approach for the regulation of T-cell lymphoma growth.

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Acknowledgements

We thank Stephanie C Napier, H Tachikawa, and A Furuhata (Juntendo University) and the FACS core facility for their help. Human recombinant tissue-type Plg activator was provided by the Eisai corporation (Japan). This work was supported by the Japan Society for the Promotion of Science and Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (KH; BH); grants from the Ministry of Health, Labour and Welfare (KH), Mitsubishi Pharma Research Foundation (KH), Kyowa Hakko Kirin Co., Ltd (KH), Japan Leukaemia Research Fund (KH), Novartis Foundation (BH) and Sagawa Foundation (BH); Program for Improvement of the Research Environment for Young Researchers (BH) funded by the Special Coordination Funds for Promoting Science and Technology of the MEXT, Japan.

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Author notes

  1. B Heissig and K Hattori: Share senior authorship.

Authors and Affiliations

  1. Laboratory of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    M Ishihara, C Nishida, Y Tashiro, I Gritli, J Rosenkvist, M Koizumi, B Heissig & K Hattori

  2. Frontier Research Initiative, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Y Okaji & B Heissig

  3. Laboratory of Stem Cell Therapy, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    R Yamamoto & H Nakauchi

  4. Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

    H Yagita

  5. Atopy (Allergy) Research Center, Juntendo University School of Medicine, Tokyo, Japan

    K Okumura, B Heissig & K Hattori

  6. Department of Hematology and Oncology, Kyoto University, Kyoto, Japan

    M Nishikori

  7. Kobe Research Projects on Thrombosis and Haemostasis, Kobe, Japan

    K Wanaka

  8. Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan

    Y Tsuda & Y Okada

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Correspondence to K Hattori.

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Ishihara, M., Nishida, C., Tashiro, Y. et al. Plasmin inhibitor reduces T-cell lymphoid tumor growth by suppressing matrix metalloproteinase-9-dependent CD11b+/F4/80+ myeloid cell recruitment. Leukemia 26, 332–339 (2012). https://doi.org/10.1038/leu.2011.203

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