| Project/Area Number |
16590336
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Aichi Cancer Center Research Institute |
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Principal Investigator |
NAKANISHI Hayao Aichi Cancer Center research Institute, Division of Oncological Pathology, Section Head, 腫瘍病理学部室長, 室長 (20207830)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | Gastric cnacer / Peritoneal metastasis / Mecirometastasia / TNF-alpha / Knockout mouse / Angiogenesis / ヒト化抗体 / 大腸癌 / 血管新生 / 乳斑 |
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| Research Abstract |
Peritoneal metastasis is the most important pattern of recurrence after curative resection in gastric cancer. The research goal of this project is to understand the molecular mechanisms of micrometastasis formation and subsequent peritoneal dissemination, and developed a new therapeutic approaches to protect patients from peritoneal recurrence. During this period (2004-2006), we demonstrated several findings as follows. We investigated whether peritoneal dissemination can be suppressed by the blockade of TNF-α using two mouse models such as TNF-α knockout (KO) mice/bone marrow chimera mice model and human gastric cancer xenograft model. We found that GFP-tagged Lewis carcinoma cells (P-29) disseminated into the whole peritoneal cavity including abdominal wall peritoneum in wild type C57BL mice after intraperitoneal injection, whereas in the TNF-α KO mice, tumor cells only metastasized to the omentum and mesentery in a milky spot-dependent manner without dissemination as well as growth
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stimulation, leading to the significant longer survival of KO mice than wild type mice. This ristricted peritoneal metastasis was canceled in chimeric KO mice transplanted with wild type bone marrow, in which TNF-α expressing leukocyte recruited into the peritoneal cavity. Addition of intraperitoneal chemotherapy with pacitaxel inhibited tumor growth in the peritoneal cavity and significantly increased survival time of KO mice rather than wild type mice because of inhibition of both growth and peritoneal dissemination of tumor cells. Furthermore, peritoneal dissemination of human gastric cancers tagged with GFP in nude mice was partially inhibited by the treatment with anti human TNF-α antibody (infliximab), resulting in a longer survival of the treated mice. These results indicate that TNF-α derived from host inflammatory leukocytes as well as tumor cells in the peritoneal cavity is responsible for peritoneal dissemination of tumor cells and suggest that anti TNF-α therapy in combination with chemotherapy would be a new potential therapeutic modality for protection of peritoneal dissemination and therefore prevention of peritoneal recurrence after curative surgery in gastric cancer patients. We are also developing ant-angiogenic therapy targeting to micrometastais with humanized anti-VEGE monoclonal antibody as well as a new drug delivery system to the peritoneal micrometastasis using mannose-coated liposome Less
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