Soluble interleukin 6 receptor (sIL-6R) mediates colonic tumor cell adherence to the vascular endothelium: a mechanism for metastatic initiation?
The mechanisms by which surgery increases metastatic proliferation remain poorly characterized, although endotoxin and immunocytes play a role. Recent evidence suggests that endothelial adherence of tumor cells may be important in the formation of metastases. Soluble receptors of interleukin-6 (sIL-6R) shed by activated neutrophils exert IL-6 effects on endothelial cells, which are unresponsive under normal circumstances. This study examined the hypothesis that sIL-6R released by surgical stress increases tumor cell adherence to the endothelium. Neutrophils (PMN) were stimulated with lipopolysaccharide, C-reactive protein (CRP), and tumor necrosis factor-alpha. Soluble IL-6R release was measured by enzyme-linked immunosorbent assay. Colonic tumor cells transfected with green fluorescent protein and endothelial cells were exposed to sIL-6R, and tumor cell adherence and transmigration were measured by fluorescence microscopy. Basal release of sIL-6R from PMN was 44.7 +/- 8.2 pg/ml at 60 min. This was significantly increased by endotoxin and CRP (131 +/- 16.8 and 84.1 +/- 5.3, respectively; both P < 0.05). However, tumor necrosis factor-alpha did not significantly alter sIL-6R release. Endothelial and tumor cell exposure to sIL-6R increased tumor cell adherence by 71.3% within 2 h but did not significantly increase transmigration, even at 6 h. Mediators of surgical stress induce neutrophil release of a soluble receptor for IL-6 that enhances colon cancer cell endothelial adherence. Since adherence to the endothelium is now considered to be a key event in metastatic genesis, these findings have important implications for colon cancer treatment strategies.
Dowdall
J F
JF
Department of Academic Surgery, Cork University Hospital, Wilton, Ireland.
Winter
D C
DC
Andrews
E
E
Laug
W E
WE
Wang
J H
JH
Redmond
H P
HP
D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000503:physiopathology* / Q000556:secondary; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000503:physiopathology; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D012995:Solubility
D019947:Receptors, Interleukin-6; D018799:Intercellular Adhesion Molecule-1