Enhanced metastatic ability of TNF-alpha-treated malignant melanoma cells is reduced by intercellular adhesion molecule-1 (ICAM-1, CD54) antisense oligonucleotides.
Treating human malignant melanoma cells with tumor necrosis factor-alpha (TNF-alpha) or interferon-gamma (IFN-gamma) causes a dose- and time-dependent increase in surface expression of ICAM-1. Increased ICAM-1 expression corresponds to greater binding of human leukocyte functional antigen-1 (CD11a/CD18)-expressing peripheral blood mononuclear cells (PBMC) to C8161 monolayers, suggesting that cytokine-treated melanoma cells would be more metastatic due to PBMC-tumor cell emboli. The purpose of this study was: (1) to test whether TNF-alpha-treated human melanoma cells are indeed more metastatic than untreated C8161 and (2) to determine whether ICAM-1 plays a role in metastasis of C8161. When surface ICAM-1 expression is upregulated, formation of lung metastases in nude mice increases 1.5- to 4-fold (P < 0.05) for human melanoma cell lines C8161, MeWo, and A375. Treatment of C8161 with ICAM-1 phosphorothioate antisense oligonucleotides using cationic lipids results in > 90% inhibition of ICAM-1 surface expression as determined by ELISA and flow cytometry. Antisense ICAM-1-treated cells form 41-64% fewer metastases than sham-treated cells. Metastasis does not increase when antisense-treated melanoma cells are exposed to TNF-alpha. However, treatment of C8161 with antisense 5-lipoxygenase (5-LO) oligonucleotides inhibits metastases 39% in Lipofectin-treated cells, but does not inhibit TNF-alpha-induced upregulation of experimental metastases. Similar experiments were performed to measure PBMC adhesion to antisense oligonucleotide-treated C8161 cells; however, TNF-alpha-inducible increase in adhesion was unaffected by ICAM-1 or 5-LO antisense oligonucleotides. These results demonstrate that ICAM-1 is involved in melanoma metastasis, but probably not at the step of PBMC adhesion to C8161 cells.
Miele
M E
ME
Department of Pathology, Pennsylvania State University College of Medicine, Hershey 17033.
Bennett
C F
CF
Miller
B E
BE
Welch
D R
DR
D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000235:genetics*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008546:Melanoma, Experimental / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D013873:Thionucleotides / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma