Abstract
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.
Highlights
Gastric cancer is the second leading cause of cancerrelated deaths worldwide, with peritoneal carcinomatosis, often associated with malignant ascites, being the most frequent cause of death in patients with advanced gastric cancer [1,2,3]
Our results strongly suggest that the epidermal growth factor receptor (EGFR) ligands amphiregulin and heparin-binding EGF-like growth factor (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
To determine whether EGFR ligands are present in malignant ascites from patients with gastric cancer, we assayed the concentrations of the EGFR ligands EGF, transforming growth factor a (TGFa), HB-EGF, and amphiregulin in these samples and in nonmalignant peritoneal exudates (Table 1)
Summary
Gastric cancer is the second leading cause of cancerrelated deaths worldwide, with peritoneal carcinomatosis, often associated with malignant ascites, being the most frequent cause of death in patients with advanced gastric cancer [1,2,3]. Gastric cancer patients may be due to the direct dissemination of cancer cells into the peritoneal cavity. We have previously shown that the CXCR4/CXCL12 axis is involved in the development of peritoneal carcinomatosis with malignant ascites from gastric cancer [5]. Other tumor-associated factors, in addition to CXCL12, may be necessary to promote the malignant potential and survival of cancer cells [6]. The development of effective therapies targeting peritoneal carcinomatosis from gastric cancer requires further understanding of the processes and molecules leading to its initiation and progression
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