Development of molecular target therapy for gastric cancer targeted for the CXCR4/CXCL12 axis and HB-EGF

在这项研究中，我们发现在恶性腹水中有丰富的EGFR配体，即双调节蛋白和HB-EGF。双调蛋白显著促进表达CXCR4的人胃癌NUGC4细胞的增殖，而HB-EGF显著诱导成纤维细胞迁移。此外，HB-EGF和CXCL12共同促进表达CXCR4的NUGC4细胞分泌依赖于TACE的两调节素。西妥昔单抗是一种抗EGFR的单抗，可以有效地减少肿瘤生长和腹水形成，从而显著延长接种NUGC4细胞的裸鼠的生存时间。我们的发现为在胃癌腹膜癌病发展过程中针对肿瘤细胞及其微环境的治疗提供了新的见解(《临床癌症研究报告2011》)。

In this study, we showed that the EGFR ligands, amphiregulin and HB-EGF, are abundant in malignant ascites. Amphiregulin strongly enhanced the proliferation of CXCR4-expressing human gastric cancer NUGC4 cells, whereas HB-EGF markedly induced migration of fibroblasts. Moreover, HB-EGF and CXCL12 together enhanced TNF□-converting enzyme (TACE)-dependent amphiregulin shedding from functional CXCR4-expressing NUGC4 cells. Cetuximab, an anti-EGFR monoclonal antibody, effectively reduced tumor growth and ascites formation, and therefore dramatically prolonged survival in nude mice inoculated with NUGC4 cells. Our findings provide a novel insight into treatments that target tumor cells and their microenvironments during the development of peritoneal carcinomatosis from gastric cancer (Clin Cancer Res 2011 in press).