| Budget Amount *help |
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Research Abstract |
Peritoneal carcinomatosis is a frequent cause of death in patients with advanced gastric carcinoma. Since chemokines are now considered to play an important role in the metastasis of various malignancies, we hypothesized that they may also be involved in the development of peritoneal carcinomatosis by gastric carcinoma. Human gastric carcinoma cell lines, which were all highly efficient in generating malignant ascites in nude mice upon intraperitoneal inoculation, selectively expressed CXCR4 mRNA and protein. In particular, NUGC4 cells showed vigorous migratory responses to its ligand CXCL12 (also called stromal-derived factor-1a, SDF-1a). CXCL12 enhanced proliferation and rapid increases in phosphorylation of protein kinase B/Akt and extracellular signal-regulated kinase (ERK) of NUGC4 cells. We also demonstrated that AMD3100 (a specific CXCR4 antagonist) effectively reduced tumor growth and ascitic fluid formation in nude mice inoculated with NUGC4 cells. In addition, we examined human clinical samples. Malignant ascites fluids from patients with peritoneal carcinomatosis contained high concentrations of CXCL12 (average, 4.67 ng/mL). Moreover, immunohistochemical analysis demonstrated that 22 of 33 primary gastric tumors with peritoneal metastasis were positive for CXCR4 expression (67%), whereas only 4 of 16 with other distant metastasis were positive (25%). Notably, 22 of 26 CXCR4-expressing primary tumors developed peritoneal metastases (85%). CXCR4-positivity of primary gastric carcinomas significantly correlated with the development of peritoneal carcinomatosis. Collectively, our results strongly suggest that the CXCR4/CXC12 axis plays an important role in the development of peritoneal carcinomatosis from gastric carcinoma. Thus, CXCR4 may be a potential therapeutic target for peritoneal carcinomatosis of gastric carcinoma.
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