Inhibition of lung metastasis by synthetic and recombinant fragments of human fibronectin with functional domains.
We have investigated the antimetastatic effect of synthetic or recombinant peptides containing the functional domains of fibronectin on experimental and spontaneous lung metastases of murine tumor cells. CS1 peptide which is present within type III homology connecting segment (IIICS) as well as C-274 (cell-binding domain) were able to inhibit experimental lung metastasis when co-injected intravenously (iv) with B16-BL6 melanoma cells, while H-271 (heparin-binding domain) could not. In the spontaneous metastasis model, multiple iv administrations of CS1 or C-274 after surgical excision of primary tumors caused a significant reduction of metastatic colonies in the lung. Both CS1 and C-274 significantly inhibited cell adhesion and migration to fibronectin-coated substrates when added freely in solution. CS1 peptide also inhibited the cell adhesion and migration to laminin-coated substrates, but C-274 did not. H-271 did not have any inhibitory effect on cell adhesion or migration to either of the substrates. Similarly, CS1 inhibited tumor invasion to both Matrigel/fibronectin- and Matrigel/laminin-coated filters, whereas C-274 inhibited the invasion to only Matrigel/fibronectin-coated filter. These results indicate that CS1 peptide of fibronectin, lacking the Arg-Gly-Asp-containing domain, actively inhibits tumor metastases in spontaneous and experimental metastasis models. The use of such a peptide might offer a promising therapeutic approach for combatting or preventing cancer metastasis.
Saiki
I
I
Institute of Immunological Sciences, Hokkaido University, Sapporo.
Murata
J
J
Makabe
T
T
Matsumoto
Y
Y
Ohdate
Y
Y
Kawase
Y
Y
Taguchi
Y
Y
Shimojo
T
T
Kimizuka
F
F
Kato
I
I
D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004334:Drug Administration Schedule; D005353:Fibronectins / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000502:physiology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis / Q000473:pathology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology
D005353:Fibronectins; D010446:Peptide Fragments; D011994:Recombinant Proteins