title: The EGFR ligands amphiregulin and heparin-binding egf-like growth factor promote peritoneal carcinomatosis in CXCR4-expressing gastric cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Divisions of Surgical Oncology and Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. kyasu@staff.kanazawa-u.ac.jp
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yasumoto
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Yamada
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Kawashima
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.forename: Ivan Shterev
authors.initials: IS
authors.lastname: Donev
authors.forename: Shinji
authors.initials: S
authors.lastname: Tacheuchi
authors.forename: Hisatsugu
authors.initials: H
authors.lastname: Mouri
authors.forename: Kaname
authors.initials: K
authors.lastname: Yamashita
authors.forename: Koushiro
authors.initials: K
authors.lastname: Ohtsubo
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
mesh_terms: D066258:Amphiregulin; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism* / Q000494:pharmacology; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010534:Peritoneal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D066255:EGF Family of Proteins; D006023:Glycoproteins; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D019718:Receptors, CXCR4; C512478:EGFR protein, human; D066246:ErbB Receptors