著者

Iida Noriho Nakamoto Yasunari Baba Tomohisa Nakagawa Hidetoshi Mizukoshi Eishiro Naito Makoto Mukaida Naofumi Kaneko Shuichi

出版者

American Association for Cancer Research

雑誌

Cancer Research (ISSN:00085472)

巻号頁・発行日

vol.70, no.16, pp.6556-6565, 2010-08-15

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Several chemokines are used for immunotherapy against cancers because they can attract immune cells such as dendritic and cytotoxic T cells to augment immune responses. Radiofrequency ablation (RFA) is used to locally eliminate cancers such as hepatocellular carcinoma (HCC), renal cell carcinoma, and lung cancer. Because HCC often recurs even after an eradicative treatment with RFA, additional immunotherapy is necessary. We treated tumor-bearing mice by administering ECI301, an active variant of CC chemokine ligand 3, after RFA. Mice were injected s.c. with BNL 1ME A.7R.1, a murine hepatoma cell line, in the bilateral flank. After the tumor became palpable, RFA was done on the tumor of one flank with or without ECI301. RFA alone eliminated the treated ipsilateral tumors and retarded the growth of contralateral non-RFA-treated tumors accompanied by massive T-cell infiltration. Injection of ECI301 augmented RFA-induced antitumor effect against non-RFA-treated tumors when administered to wild-type or CCR5-deficient but not CCR1-deficient mice. ECI301 also increased CCR1-expressing CD11c+ cells in peripheral blood and RFA-treated tumors after RFA. Deficiency of CCR1 impairs accumulation of CD11c+, CD4+, and CD8+ cells in RFA-treated tumors. Furthermore, in IFN-ã-enzyme-linked immunospot assay, ECI301 augmented tumor-specific responses after RFA whereas deficiency of CCR1 abolished this augmentation. Thus, we proved that ECI301 further augments RFA-induced antitumor immune responses in a CCR1-dependent manner. ©2010 AACR.

著者

Du Wa Takuwa Noriko Yoshioka Kazuaki Okamoto Yasuo Gonda Koichi Sugihara Kazushi Fukamizu Akiyoshi Asano Masahide Takuwa Yoh

出版者

American Association for Cancer Research

雑誌

Cancer Research (ISSN:00085472)

巻号頁・発行日

vol.70, no.2, pp.772-781, 2010-01-15

被引用文献数

6 96

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Sphingosine-1-phosphate (S1P) has been implicated in tumor angiogenesis by acting through the Gi-coupled chemotactic receptor S1P1. Here, we report that the distinct receptor S1P2 is responsible for mediating the G12/13/Rho-dependent inhibitory effects of S1P on Akt, Rac, and cell migration, thereby negatively regulating tumor angiogenesis and tumor growth. By using S1P2LacZ/+ mice, we found that S1P2 was expressed in both tumor and normal blood vessels in many organs, in both endothelial cells (EC) and vascular smooth muscle cells, as well as in tumor-associated, CD11b-positive bone marrow-derived cells (BMDC). Lewis lung carcinoma or B16 melanoma cells implanted in S1P2-deficient (S1P2-/-) mice displayed accelerated tumor growth and angiogenesis with enhanced association of vascular smooth muscle cells and pericytes. S1P2-/- ECs exhibited enhanced Rac activity, Akt phosphorylation, cell migration, proliferation, and tube formation in vitro. Coinjection of S1P2-/- ECs and tumor cells into wild-type mice also produced a relative enhancement of tumor growth and angiogenesis in vivo. S1P2-/- mice were also more efficient at recruiting CD11b-positive BMDCs into tumors compared with wild-type siblings. Bone marrow chimera experiments revealed that S1P2 acted in BMDCs to promote tumor growth and angiogenesis. Our results indicate that, in contrast to endothelial S1P1, which stimulates tumor angiogenesis, S1P 2 on ECs and BMDCs mediates a potent inhibition of tumor angiogenesis, suggesting a novel therapeutic tactic for anticancer treatment. ©2010 AACR.