Inhibition of tumor cell-induced platelet aggregation and experimental tumor metastasis by the synthetic Gly-Arg-Gly-Asp-Ser peptide.
The mechanism by which the murine fibrosarcoma clone PAK 17.15 induces platelet aggregation [tumor cell-induced platelet aggregation (TCIPA)] was studied because platelet activation by this clone is necessary for metastasis to the lungs. PAK 17.15 TCIPA was completely inhibited by ADP-clearing enzymes, such as apyrase, or a mixture of creatine phosphate and creatine phosphokinase. Thrombin and collagen were not involved in PAK 17.15 TCIPA. Further studies showed that ADP is most likely secreted from activated platelets and that membrane protein(s) on PAK 17.15 cells are responsible for platelet activation. Inasmuch as ADP-dependent platelet aggregation requires fibrinogen and can be inhibited by the Gly-Arg-Gly-Asp-Ser (GRGDS) synthetic peptide, the effect of this peptide on PAK 17.15 TCIPA was studied. PAK 17.15 TCIPA was completely inhibited by the GRGDS peptide (0.4 mM) but not by a control peptide, Gly-Arg-Gly-Glu-Ser (0.8 mM). In addition, the GRGDS peptide inhibited adhesion of PAK 17.15 cells to immobilized fibronectin. As expected, the GRGDS peptide almost completely inhibited lung colonization by iv injected PAK 17.15 cells in C57BL/6 mice. Our results indicate that GRGDS may inhibit pulmonary metastases by interfering with TCIPA as well as with tumor cell adhesion to extra-cellular matrix components in the host.
Ugen
K E
KE
Department of Pathology, College of Medicine, University of Florida, Gainesville 32610.
Mahalingam
M
M
Klein
P A
PA
Kao
K J
KJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002999:Clone Cells; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009842:Oligopeptides / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*
D000970:Antineoplastic Agents; D005353:Fibronectins; D009842:Oligopeptides; C049554:glycyl-arginyl-glycyl-aspartyl-serine