The EGFR Ligands Amphiregulin and Heparin-Binding EGF-like Growth Factor Promote Peritoneal Carcinomatosis in CXCR4-Expressing Gastric Cancer
The EGFR Ligands Amphiregulin and Heparin-Binding EGF-like Growth Factor Promote Peritoneal Carcinomatosis in CXCR4-Expressing Gastric Cancer
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DOI：
10.1158/1078-0432.ccr-10-2475
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发表时间：
2011-06-01
影响因子：
11.5
通讯作者：
Yano, Seiji
中科院分区：
文献类型：
--
作者：
Yasumoto, Kazuo;Yamada, Tadaaki;Yano, Seiji
目的：腹膜癌是晚期胃癌患者最常见的死亡原因，常伴有恶性腹水。我们之前发现CXCR4/CXCL12轴参与胃癌腹膜癌的发展。在这里，我们研究了表皮生长因子受体（EGFR）配体是否也参与胃癌腹膜癌的发展。实验设计：在表达cxcr4的人胃癌细胞和成纤维细胞、临床样本（原发性肿瘤和腹水）和动物模型中检测ErbB受体家族和/或EGFR配体表达的功能参与。结果：恶性腹水中存在高浓度的EGFR配体双调节蛋白、肝素结合egf样生长因子（HB-EGF）及CXCL12。人胃癌细胞系和原发胃肿瘤具有高发生腹膜癌的潜力，表达高水平的EGFR和CXCR4 mRNA和蛋白。在高表达CXCR4的胃癌细胞中，双调节蛋白和HB-EGF均能增强CXCR4的增殖、迁移和功能表达。Amphiregulin强烈促进了NUGC4细胞的增殖，而HB-EGF则显著诱导成纤维细胞的迁移。此外，HB-EGF和CXCL12共同增强了ngc4细胞中TNF α转换酶（TACE）依赖性双调节蛋白的脱落。在实验性小鼠腹膜癌模型中，西妥昔单抗有效地抑制肿瘤生长和腹水形成。结论：我们的研究结果强烈提示EGFR配体amphiregulin和HB-EGF与CXCL12/CXCR4轴相互作用，在胃癌腹膜癌的发展过程中发挥了重要作用，提示这两个轴可能是胃癌腹膜癌的潜在治疗靶点。临床癌症研究；17 (11);3619 - 30。AACR (C) 2011。
Purpose: Peritoneal carcinomatosis, often associated with malignant ascites, is the most frequent cause of death in patients with advanced gastric cancer. We previously showed that the CXCR4/CXCL12 axis is involved in the development of peritoneal carcinomatosis from gastric cancer. Here, we investigated whether epidermal growth factor receptor (EGFR) ligands are also involved in the development of peritoneal carcinomatosis from gastric cancer.Experimental Design: The functional involvement of expression of the ErbB family of receptors and/or EGFR ligands was examined in CXCR4-expressing human gastric cancer cells and fibroblasts, clinical samples (primary tumors and ascites), and an animal model.Results: High concentration of the EGFR ligands amphiregulin and heparin-binding EGF-like growth factor (HB-EGF), as well as of CXCL12, were present in malignant ascites. Human gastric cancer cell lines and primary gastric tumors, with high potential to generate peritoneal carcinomatosis, expressed high levels of EGFR and CXCR4 mRNA and protein. Both amphiregulin and HB-EGF enhanced the proliferation, migration, and functional CXCR4 expression in highly CXCR4-expressing gastric cancer NUGC4 cells. Amphiregulin strongly enhanced the proliferation of NUGC4 cells, whereas HB-EGF markedly induced the migration of fibroblasts. Moreover, HB-EGF and CXCL12 together enhanced TNF alpha-converting enzyme (TACE)-dependent amphiregulin shedding from NUGC4 cells. In an experimental peritoneal carcinomatosis model in mice, cetuximab effectively reduced tumor growth and ascites formation.Conclusions: Our results strongly suggest that the EGFR ligands amphiregulin and HB-EGF play an important role, interacting with the CXCL12/CXCR4 axis, in the development of peritoneal carcinomatosis from gastric cancer, indicating that these two axes may be potential therapeutic targets for peritoneal carcinomatosis of gastric carcinoma. Clin Cancer Res; 17(11); 3619-30. (C)2011 AACR.