Divisions of Surgical Oncology and Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Clin Cancer Res. 2011 Jun 1;17(11):3619-30. doi: 10.1158/1078-0432.CCR-10-2475. Epub 2011 Apr 11.
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.
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.
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 TNFα-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.
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.
腹膜转移是进展期胃癌患者死亡的最主要原因，通常与恶性腹水有关。我们之前的研究表明，趋化因子受体 4（CXCR4）/趋化因子配体 12（CXCL12）轴参与胃癌腹膜转移的发生。在此，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转移的发生。
在表达 CXCR4 的人胃癌细胞和纤维母细胞、临床样本（原发肿瘤和腹水）以及动物模型中，检测了 ErbB 家族受体和/或 EGFR 配体表达的功能相关性。
高浓度的 EGFR 配体，如双调蛋白和肝素结合表皮生长因子样生长因子（HB-EGF）以及 CXCL12 存在于恶性腹水中。具有高腹膜转移潜能的人胃癌细胞系和原发肿瘤表达高水平的 EGFR 和 CXCR4mRNA 和蛋白。双调蛋白和 HB-EGF 均增强了高度表达 CXCR4 的胃癌 NUGC4 细胞的增殖、迁移和功能性 CXCR4 表达。双调蛋白强烈增强了 NUGC4 细胞的增殖，而 HB-EGF 则显著诱导纤维母细胞的迁移。此外，HB-EGF 和 CXCL12 共同增强了 TNFα 转换酶（TACE）依赖性 NUGC4 细胞中双调蛋白的脱落。在小鼠实验性腹膜转移模型中，西妥昔单抗能有效抑制肿瘤生长和腹水形成。
我们的研究结果强烈表明，EGFR 配体双调蛋白和 HB-EGF 通过与 CXCL12/CXCR4 轴相互作用，在胃癌腹膜转移的发生中发挥重要作用，提示这两个轴可能是胃癌腹膜转移的潜在治疗靶点。
