Functional role of sialyl Lewis X and fibronectin-derived RGDS peptide analogue on tumor-cell arrest in lungs followed by extravasation.
Our study demonstrates that synthetic sialyl Lewis X (SLex) as a ligand for selectins and fibronectin-derived RGDS peptide analogue [Ar(DRGDS)3] inhibits lung metastases produced by i.v. co-injection of B16-BL6 melanoma cells. To investigate the inhibitory mechanisms in a living animal, we performed positron-emission tomography (PET) analysis after i.v. injection of [2-18F]2-fluoro-2v-deoxy-D-glucose-labeled tumor cells with or without liposomal SLex or Ar(DRGDS)3. The real-time PET measurement for the first 120 min, started immediately after injection, showed that tumor-cell arrest, i.e., accumulation in the target organ (lung) was remarkably inhibited by liposomal SLex, but not inhibited by Ar(DRGDS)3 or liposomal Me-SLex, which is not recognized by selectins. In contrast, Ar(DRGDS)3 inhibited the invasion of B16-BL6 cells into reconstituted basement membrane (Matrigel) following tumor arrest, whereas SLex- or Me-SLex-entrapped liposomes did not affect tumor invasion. In the metastatic processes containing tumor-cell lodgement and arrest in the target organ followed by extravasation (invasion), SLex resulted in the inhibition of initial arrest of tumor cells, presumably tumor-endothelium interaction, while Ar(DRGDS)3 achieved inhibition of tumor invasion into basement membrane at later steps of the cascade, consequently leading to inhibition of metastasis. Thus, tumor-cell arrest in lungs in the metastatic processes must be precisely and properly controlled by different adhesion molecules at different stages, which are similar to those observed in leukocyte-endothelium interaction.
Saiki
I
I
Research Institute for Wakan-yaku, Toyama Medical and Pharmaceutical University, Japan.
Koike
C
C
Obata
A
A
Fujii
H
H
Murata
J
J
Kiso
M
M
Hasegawa
A
A
Komazawa
H
H
Tsukada
H
H
Azuma
I
I
Okada
S
S
Oku
N
N
D000595:Amino Acid Sequence; D000818:Animals; D001485:Basement Membrane / Q000502:physiology; D002240:Carbohydrate Sequence; D002448:Cell Adhesion / Q000502:physiology; D005260:Female; D005353:Fibronectins / Q000494:pharmacology* / Q000502:physiology; D016023:Integrins / Q000378:metabolism; D008081:Liposomes; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D009842:Oligopeptides / Q000494:pharmacology* / Q000502:physiology; D009844:Oligosaccharides / Q000494:pharmacology*; D019087:Selectins / Q000378:metabolism; D000080506:Sialyl Lewis X Antigen; D014055:Tomography, Emission-Computed
D005353:Fibronectins; D016023:Integrins; D008081:Liposomes; D009842:Oligopeptides; D009844:Oligosaccharides; D019087:Selectins; D000080506:Sialyl Lewis X Antigen; C046617:arginyl-glycyl-aspartyl-serine