The EGFR Ligands Amphiregulin and Heparin-Binding EGF-like Growth Factor Promote Peritoneal Carcinomatosis in CXCR4-Expressing Gastric Cancer
Autor: | Tadaaki Yamada, Kaname Yamashita, Kazuo Yasumoto, Koushiro Ohtsubo, Ivan Donev, Wei Wang, Shinji Tacheuchi, Seiji Yano, Hisatsugu Mouri, Atsuhiro Kawashima, Qi Li |
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Rok vydání: | 2011 |
Předmět: |
EGF Family of Proteins
Receptors CXCR4 Cancer Research Pathology medicine.medical_specialty Heparin-binding EGF-like growth factor Mice Nude Ligands Amphiregulin Mice Cell Movement Stomach Neoplasms Epidermal growth factor Cell Line Tumor Animals Humans Medicine Epidermal growth factor receptor Stomach cancer Peritoneal Neoplasms Cell Proliferation Glycoproteins Mice Inbred BALB C Cetuximab biology business.industry Cancer medicine.disease Chemokine CXCL12 ErbB Receptors Oncology Cancer cell Cancer research biology.protein Intercellular Signaling Peptides and Proteins business Heparin-binding EGF-like Growth Factor medicine.drug |
Zdroj: | Clinical Cancer Research. 17:3619-3630 |
ISSN: | 1557-3265 1078-0432 |
DOI: | 10.1158/1078-0432.ccr-10-2475 |
Popis: | 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 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. 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. ©2011 AACR. |
Databáze: | OpenAIRE |
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