Involvement of very late activation antigen 4 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) in tumor necrosis factor alpha enhancement of experimental metastasis.
In this study, we examined the effect of tumor necrosis factor alpha (TNF-alpha) on pulmonary metastasis of murine melanoma B16-BL6 by focusing on the intercellular adhesion molecules involved in the metastatic process. TNF-alpha administration before B16-BL6 inoculation significantly enhanced the experimental pulmonary metastasis. The enhancement was seen when TNF-alpha was administered 4 h, but not 24 h, before B16-BL6 inoculation. Administration of 50-5000 units of TNF-alpha increased the number of metastatic lung colonies in a dose-dependent manner. Flow cytometric analysis demonstrated a high expression of very late activation antigen 4 (VLA-4) on the surface of B16-BL6 cells. Immunoperoxidase staining demonstrated that a ligand for VLA-4, vascular cell adhesion molecule 1, was expressed on lung vascular endothelium 4 h after administration of TNF-alpha. Pretreatment of B16-BL6 cells with an anti-VLA-4 monoclonal antibody abolished the TNF-alpha-enhanced pulmonary lung colonies. Administration of an anti-vascular cell adhesion molecule 1 monoclonal antibody also abolished the enhancement. These results indicate that the interaction between VLA-4 on tumor cells and vascular cell adhesion molecule 1 on activated endothelial cells is critically involved in TNF-alpha enhancement of metastasis.
Okahara
H
H
First Department of Surgery, School of Medicine, Juntendo University, Tokyo, Japan.
Yagita
H
H
Miyake
K
K
Okumura
K
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D008175:Lung Neoplasms / Q000139:chemically induced / Q000556:secondary*; D008546:Melanoma, Experimental / Q000139:chemically induced / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D016029:Receptors, Very Late Antigen / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D016029:Receptors, Very Late Antigen; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1