Systemic inflammation increases cancer cell adhesion to hepatic sinusoids by neutrophil mediated mechanisms.
Interactions between endothelial selectins and selectin ligands expressed on tumor cells have been implicated in the binding of circulating metastatic cancer cells to the vascular endothelium during extravasation. Moreover, there is mounting evidence that inflammatory environments can accelerate the progression of metastasis by neutrophil mediated mechanisms. In this study, a physiologically relevant in vivo model of early metastasis coupled with intravital microscopy was used to visualize the trafficking of tumor cells within the liver vasculature in real time. Using GFP-labeled Lewis lung carcinoma subline H-59 cells, we show here that disrupting the interactions between endothelial selectins and tumor cell selectin ligands diminished tumor cell recruitment to the liver. Furthermore, systemic inflammation induced by intravenous injection of lipopolysaccharide significantly enhanced the metastatic potential of these lung carcinoma cells by increasing their propensity to adhere to the liver sinusoidal endothelium. Confocal microscopy revealed frequent colocalization of cancer cells with neutrophils and neutrophil depletion in vivo significantly attenuated the lipopolysaccharide-induced increase in H-59 cell adhesion. Although direct selectin-selectin ligand interactions contributed significantly to tumor cell adhesion to sinusoidal endothelial cells, we show here that in addition, interactions between adherent neutrophils within the inflamed sinusoids and circulating tumor cells may further increase tumor cell arrest in the liver.
LD McLean Surgical Research Laboratories, Department of Surgery, McGill University, Montreal, Quebec, Canada.
Braedon
B
McDonald
Jonathan
J
Spicer
Betty
B
Giannais
Lucia
L
Fallavollita
Pnina
P
Brodt
Lorenzo E
LE
Ferri
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000378:metabolism* / Q000556:secondary; D002448:Cell Adhesion; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000098:blood supply*; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology*; D009844:Oligosaccharides / Q000378:metabolism*; D019087:Selectins / Q000378:metabolism*; D000080506:Sialyl Lewis X Antigen; D014407:Tumor Cells, Cultured
D008024:Ligands; D008070:Lipopolysaccharides; D009844:Oligosaccharides; D019087:Selectins; D000080506:Sialyl Lewis X Antigen