- 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
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.
- 著者
- KANOU Yasuhiko ABE Naoki ISHIDA Junji FUKAMIZU Akiyoshi SEO Hisao MURATA Yoshiharu
- 出版者
- Research Institute of Environmental Medicine, Nagoya University
- 雑誌
- Environmental medicine : annual report of the Research Institute of Environmental Medicine, Nagoya University (ISSN:02870517)
- 巻号頁・発行日
- vol.46, no.1/2, pp.55-57, 2002-12 (Released:2006-01-05)
ZAKI-4 inhibits the activity of calcineurin, a Ca^<2+>-dependent protein phosphatase. From ZAKI-4 gene, two isoforms, a and P are generated by an alternative splicing. In adult mice ZAKI-4 α mRNA was mainly expressed in brain whereas ZAKI-4 β mRNA wasubiquitously. To elucidate the specific function of ZAKI-4 isoforms, we plan to establish ZAKI-4 β knock out mice by homologousrecombination. For this purpose, mouse embryonic stem cells were electroporated with a targeting vector in which ZAKI-4 β sequencewas disrupted by cDNA coding neomycin resistance. Six independent clones out of 466 antibiotics-resistant colonies underwenthomologous recombination at the ZAKI-4 β locus. These clones will be used to establish the knock out mice.