Involvement of the very late antigen 4 integrin on melanoma in interleukin 1-augmented experimental metastases.
We have previously reported that treatment with interleukin 1 (IL-1) induced the augmentation of lung tumor colonies by a human melanoma in nude mice. Here we have investigated the involvement of the alpha 4 beta 1 integrin, the very late antigen 4 (VLA-4) in this augmentation. A375M melanoma cells expressed high levels of VLA-4 and preferentially adhered to a surface coated with vascular cell adhesion molecule 1 (VCAM-1), the ligand for VLA-4 on activated endothelial cells. This adhesion was inhibited by treating tumor cells with saturating concentrations of mAb to VLA-4. The production of lung colonies was significantly enhanced in nude mice given an injection of IL-1 before A375M melanoma cells. Immunoperoxidase staining showed that VCAM-1 could be expressed on lung vascular endothelium of mice in response to IL-1. Pretreatment of melanoma cells with a mAb to VLA-4 completely abrogated the IL-1-induced augmentation of lung colonies. Using two metastatic melanoma clones (clones 2/4 and 2/60) that expressed different levels of VLA-4, we found that only VLA-4-bearing cells adhered to a VCAM-1-coated surface and formed enhanced numbers of lung colonies in IL-1-treated nude mice. This augmentation was inhibited by pretreating the tumor cells with anti-VLA-4 mAb. These results demonstrate, in vivo, the functional involvement of VLA-4 on melanoma cells in IL-1-mediated lung colony augmentation, most probably involving the interaction of tumor cells with VCAM-1 on activated endothelial cells.
Garofalo
A
A
Laboratory of Cancer Metastasis Treatment, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Chirivi
R G
RG
Foglieni
C
C
Pigott
R
R
Mortarini
R
R
Martin-Padura
I
I
Anichini
A
A
Gearing
A J
AJ
Sanchez-Madrid
F
F
Dejana
E
E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000098:blood supply / Q000556:secondary*; D008545:Melanoma / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D016029:Receptors, Very Late Antigen / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured; D019010:Vascular Cell Adhesion Molecule-1
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D007375:Interleukin-1; D016029:Receptors, Very Late Antigen; D019010:Vascular Cell Adhesion Molecule-1