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Targeting VEGF and interleukin-6 for controlling malignant effusion of primary effusion lymphoma

  • Original Article - Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma that shows malignant effusion most commonly seen in advanced AIDS patients. In this study, we clarified the potential role of VEGF and IL-6 in PEL fluid retention and evaluated the efficacy of humanized anti-VEGF monoclonal antibody (mAb), bevacizumab, and humanized anti-IL-6 receptor mAb, tocilizumab, against PEL.

Methods

The production of VEGF and IL-6, and the expression of IL-6Rα in PEL cell lines were examined. The antiproliferative effect of bevacizumab and tocilizumab on PEL cells was evaluated in vitro. The effect of tocilizumab on VEGF was also examined. An intraperitoneal xenograft mouse model was used for in vivo efficacy.

Results

Although we found the production of VEGF and IL-6, and the expression of IL-6Rα in PEL cell lines, bevacizumab and tocilizumab did not inhibit the proliferation of PEL cells in vitro. Tocilizumab decreased VEGF mRNA and VEGF production by inhibiting Stat3 phosphorylation and Stat3 binding to VEGF promoter. In a PEL xenograft mouse model that showed profuse ascites, bevacizumab suppressed ascites formation completely, indicating the critical role of VEGF for PEL fluid retention. Tocilizumab also significantly inhibited ascites formation in vivo. Moreover, these mAbs improved the overall survival of treated mice.

Conclusions

IL-6-VEGF axis contributed to fluid retention, and bevacizumab and tocilizumab could be effective molecular targeting therapies for PEL.

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Acknowledgments

We thank Ms. I. Suzu and Ms. S. Fujikawa for technical assistance and Ms. Y. Endo for secretarial assistance. This work was supported by a Health and Labour Sciences Research Grant from the Ministry of Health, Labour, and Welfare of Japan (H25-AIDS-I-002), the Global COE program, “Global Education and Research Center Aiming at the Control of AIDS,” and Grants-in-Aid for Science Research (No. 25114711) from the Ministry of Education, Science, Sports, and Culture of Japan.

Conflict of interest

The authors have declared that no conflict of interest exists.

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Authors and Affiliations

  1. Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan

    Hiroki Goto, Eriko Kudo, Ryusho Kariya, Manabu Taura & Seiji Okada

  2. Department of Pathology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan

    Harutaka Katano

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  1. Hiroki Goto
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  2. Eriko Kudo
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Correspondence to Seiji Okada.

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Goto, H., Kudo, E., Kariya, R. et al. Targeting VEGF and interleukin-6 for controlling malignant effusion of primary effusion lymphoma. J Cancer Res Clin Oncol 141, 465–474 (2015). https://doi.org/10.1007/s00432-014-1842-9

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  • DOI: https://doi.org/10.1007/s00432-014-1842-9

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