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¹ Department of Surgery and Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
² Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan
³ Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0075, Japan
⁴ Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115

CORRESPONDENCE Hideaki Tahara: tahara{at}ims.u-tokyo.ac.jp

Carcinogenesis reflects the dynamic interplay of transformed cells and normal host elements, but cancer treatments typically target each compartment separately. Within the tumor microenvironment, the secreted protein milk fat globule epidermal growth factor–8 (MFG-E8) stimulates disease progression through coordinated _vβ₃ integrin signaling in tumor and host cells. MFG-E8 enhances tumor cell survival, invasion, and angiogenesis, and contributes to local immune suppression. We show that systemic MFG-E8 blockade cooperates with cytotoxic chemotherapy, molecularly targeted therapy, and radiation therapy to induce destruction of various types of established mouse tumors. The combination treatments evoke extensive tumor cell apoptosis that is coupled to efficient dendritic cell cross-presentation of dying tumor cells. This linkage engenders potent antitumor effector T cells but inhibits FoxP3⁺ T reg cells, thereby achieving long-term protective immunity. Collectively, these findings suggest that systemic MFG-E8 blockade might intensify the antitumor activities of existing therapeutic regimens through coordinated cell-autonomous and immune-mediated mechanisms.

© 2009 Jinushi et al.
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This article has been cited by other articles:

• Jinushi, M., Sato, M., Kanamoto, A., Itoh, A., Nagai, S., Koyasu, S., Dranoff, G., Tahara, H. (2009). Milk fat globule epidermal growth factor-8 blockade triggers tumor destruction through coordinated cell-autonomous and immune-mediated mechanisms. JCB 185: i8-i8 [Full Text]  

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