title: Disruption of Circulating Extracellular Vesicles as a Novel Therapeutic Strategy against Cancer Metastasis.
abstract: Metastasis is the main cause of cancer mortality for many types of cancer; however, difficulties remain in effectively preventing metastasis. It has been recently and widely reported that cancer-derived extracellular vesicles (EVs) contribute to cancer metastasis. Thus, therapeutic strategies targeting cancer-derived EVs hold great promise because of the possibility of EVs driving the cancer microenvironment toward metastasis. Here, we provide a novel strategy for therapeutic antibody treatment to target cancer-derived EVs and inhibit the metastasis of breast cancer in a mouse model, establishing a rationale for further clinical investigation. Treatment with human-specific anti-CD9 or anti-CD63 antibodies significantly decreased metastasis to the lungs, lymph nodes, and thoracic cavity, although no obvious effects on primary xenograft tumor growths were observed. In in vitro and in vivo experiments, the EVs incubated with the targeted antibodies were preferentially internalized by macrophages, suggesting that antibody-tagged cancer-derived EVs would be eliminated by macrophages. Our results suggested that therapeutic antibody administration effectively suppresses EV-triggered metastasis in cancer and that the removal of EVs could be a novel strategy for cancer therapy.
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Nishida-Aoki
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Naoomi
authors.initials: N
authors.lastname: Tominaga
authors.affiliation: Department of Functional Analysis, FIOC, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Takeshita
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Theoria Science Inc., 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sonoda
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yoshioka
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: tochiya@ncc.go.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D055252:Cell-Derived Microparticles / Q000378:metabolism; D004195:Disease Models, Animal; D000067128:Extracellular Vesicles / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D010587:Phagocytosis; D060245:Tetraspanin 29 / Q000276:immunology / Q000378:metabolism; D060149:Tetraspanin 30 / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060245:Tetraspanin 29; D060149:Tetraspanin 30
keywords: CD63; CD9; breast cancer; exosome; extracellular vesicles; metastasis; therapeutic antibody