Involvement of SDF-1alpha/CXCR4 axis in the enhanced peritoneal metastasis of epithelial ovarian carcinoma.
Epithelial ovarian carcinoma (EOC) spreads by implantation of tumor cells onto the human peritoneal mesothelial cells (HPMCs) lining the peritoneal cavity. The aim of this study was to determine whether the stromal cell-derived factor-1alpha (SDF-1alpha)/CXCR4 axis is involved in the interaction of EOC cells with HPMCs in peritoneal metastasis. Clinically, we first evaluated CXCR4 expression in sections from 36 primary EOCs using immunohistochemistry. We next examined whether SDF-1alpha played roles in EOC progression, including in proliferation, cell motility, attachment to HPMCs, and the in vivo development of peritoneal metastasis through CXCR4. Of the 36 carcinomas, 16 cases (44.4%) were positive for CXCR4 immunoexpression. Positive CXCR4 expression significantly predicted poorer overall survival compared with negative expression (p = 0.0069). We found CXCR4 expression in both EOC cells and HPMCs. In contrast, the level of production of SDF-1alpha by HPMCs was higher than that by various EOC cells. Functionally, SDF-1alpha induced enhanced attachment between ES-2 cells and HPMCs or extracellular matrix components. The enhancement of adhesion potential by SDF-1alpha was inhibited by AMD3100, a CXCR4 antagonist, and by phosphatidylinositol 3 kinase and p44/42 inhibitors. Furthermore, intraperitoneal treatment with AMD3100 resulted in reduced dissemination in nude mice inoculated with ES-2 cells. The present results suggest that there may be a link between the SDF-1alpha/CXCR4 axis and enhanced intraperitoneal dissemination of EOC and that CXCR4 may be a novel target for the treatment of EOC.
Kajiyama
Hiroaki
H
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya 466-8550, Japan. kajiyama@med.nagoya-u.ac.jp
Shibata
Kiyosumi
K
Terauchi
Mikio
M
Ino
Kazuhiko
K
Nawa
Akihiro
A
Kikkawa
Fumitaka
F
D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D002288:Adenocarcinoma, Mucinous / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D000328:Adult; D000368:Aged; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D001596:Benzylamines; D015153:Blotting, Western; D018269:Carcinoma, Endometrioid / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D018920:Coculture Techniques; D000080027:Cyclams; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D010537:Peritoneum / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D019380:Anti-HIV Agents; D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019718:Receptors, CXCR4; C515255:CXCL12 protein, human; C088327:plerixafor