Role of the CXCL12/CXCR4 axis in peritoneal carcinomatosis of gastric cancer
Role of the CXCL12/CXCR4 axis in peritoneal carcinomatosis of gastric cancer
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DOI：
10.1158/0008-5472.can-05-3393
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发表时间：
2006-02-15
期刊：
影响因子：
11.2
通讯作者：
Saiki, I
中科院分区：
文献类型：
--
作者：
Yasumoto, K;Koizumi, K;Saiki, I
腹膜癌是晚期胃癌患者常见的死亡原因。由于趋化因子现在被认为在各种恶性肿瘤的转移中起重要作用，我们假设它们可能参与胃癌引起的腹膜癌的发展。人胃癌细胞系选择性表达CXCR4 mRNA和蛋白，在裸鼠体内接种后均能高效产生恶性腹水。特别是，NUGC4细胞高水平表达CXCR4 mRNA，并对其配体CXCL12表现出强烈的迁移反应。CXCL12增强了NUGC4细胞的增殖，并迅速增加了蛋白激酶B/Akt和细胞外信号调节激酶的磷酸化。我们还发现AMD3100（一种特异性CXCR4拮抗剂）在接种了NUGC4细胞的裸鼠中有效地抑制肿瘤生长和腹水形成。此外，我们检查了人类临床样本。腹膜癌患者的恶性腹水含有高浓度的CXCL12 （4.67 ng/mL）。此外，免疫组化分析显示33例伴有腹膜转移的原发性胃肿瘤中22例（67%）表达CXCR4阳性，而16例伴有其他远处转移的肿瘤中只有4例（25%）表达CXCR4阳性。值得注意的是，26例表达cxcr4的原发肿瘤中有22例发生腹膜转移（85%）。原发性胃癌中CXCR4阳性与腹膜癌的发生有显著相关性（P < 0.001）。综上所述，我们的研究结果强烈提示CXCR4/CXC12轴在胃癌腹膜癌的发展中起重要作用。因此，CXCR4可能是胃癌腹膜癌病的潜在治疗靶点。
Peritoneal carcinomatosis is a frequent cause of death in patients with advanced gastric carcinoma. Because chemokines are now considered to play an important role in the metastasis of various malignancies, we hypothesized that they may 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 i.p. inoculation, selectively expressed CXCR4 mRNA and protein. In particular, NUGC4 cells expressed CXCR4 mRNA at high levels and showed vigorous migratory responses to its ligand CXCL12. CXCL12 enhanced proliferation and rapid increases in phosphorylation of protein kinase B/Akt and extracellular signal-regulated kinase of NUGC4 cells. We also showed that AMD3100 (a specific CXCR4 antagonist) effectively reduced tumor growth and ascitic fluid formation in nude mice inoculated with NUGC4 cells. Additionally, we examined human clinical samples. Malignant ascitic fluids from patients with peritoneal carcinomatosis contained high concentrations of CXCL12 (4.67 ng/mL). Moreover, immunohistochemical analysis showed 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 (P < 0.001). 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.