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

在本研究中，我们发现EGFR配体双调节蛋白和HB-EGF在恶性腹水中含量丰富。Amphiregulin强烈促进表达cxcr4的人胃癌细胞的增殖，而HB-EGF则显著诱导成纤维细胞的迁移。此外，HB-EGF和CXCL12共同增强了功能性表达cxcr4的NUGC4细胞中TNF□转换酶（TACE）依赖性双调节蛋白的脱落。西妥昔单抗（Cetuximab）是一种抗egfr单克隆抗体，可有效降低NUGC4细胞接种裸鼠的肿瘤生长和腹水形成，从而显着延长存活时间。我们的研究结果为胃癌腹膜癌发病过程中靶向肿瘤细胞及其微环境的治疗提供了新的见解（clincancer Res 2011 in press）。

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).