Clinical Significance of chemokines and its receptors in peritoneal carcinomatosis of gastric cancer

腹膜癌转移是进展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，我们假设它们也可能参与胃癌腹膜癌转移的发展。人胃癌细胞株，这都是非常有效的产生恶性腹水裸鼠腹腔接种后，选择性表达CXCR 4 mRNA和蛋白。特别是，NUGC 4细胞对其配体CXCL 12（也称为基质衍生因子-1a，SDF-1a）表现出强烈的迁移反应。CXCL 12促进NUGC 4细胞增殖，并使蛋白激酶B/Akt和细胞外信号调节激酶（ERK）磷酸化水平迅速增加。我们还证明，AMD 3100（一种特异性CXCR 4拮抗剂）可有效减少接种NUGC 4细胞的裸鼠的肿瘤生长和腹水形成。此外，我们还检查了人类临床样本。腹膜癌转移患者的恶性腹水中含有高浓度的CXCL 12（平均4.67 ng/mL）。免疫组化结果显示，33例有腹膜转移的原发性胃癌中，22例CXCR 4表达阳性（67%），而16例有其他远处转移的胃癌中，仅4例CXCR 4表达阳性（25%）。值得注意的是，26例CXCR 4表达原发性肿瘤中有22例发生腹膜转移（85%）。原发性胃癌CXCR 4阳性与腹膜癌转移的发生密切相关。总的来说，我们的研究结果强烈表明，CXCR 4/CXC 12轴在胃癌腹膜癌转移的发展中起着重要作用。因此，CXCR 4可能成为胃癌腹膜转移的潜在治疗靶点。

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.