Resistance to IL-1 anti-proliferative effect, accompanied by characteristics of advanced melanoma, permits invasion of human melanoma cells in vitro, but not metastasis in the nude mouse.
We reported earlier that IL-1 inhibits the growth of human melanoma cells (A375-6), and that these cells become resistant to IL-1 after prolonged periods of culture. The resistant cells constitutively produce IL-alpha and IL-6 with IL-6 production was induced by endogenous IL-1 in an autocrine manner. The cells are also resistant to IL-6 anti-proliferative effects. In the present study, we show that the resistant clones exhibited up-regulated expression of intercellular-adhesion molecule 1 (ICAM-1) and vitronectin receptor (integrin alpha(v)beta3) when compared with the IL-1-sensitive clone, A375-6. Moreover, these IL-1-resistant clones exhibited many other metastatic characteristics, such as expression of IL-8 mRNA, production of matrix metalloproteinases (MMP-2 and MMP-9), and augmented invasion activity. However, contrary to our expectations, the IL-1-resistant cells did not exhibit experimental metastasis in a nude-mouse model, similarly to the IL-1-sensitive parental A375-6 cell line. In contrast, the highly metastatic clone A375-SM exhibited alpha(v)beta3 expression at a level comparable to that of the IL-1-resistant cells, but expressed low or no ICAM-1, metalloproteinase and displayed little in vitro invasion activity. These results show that the metastatic characteristics of IL-1-resistant cells are not sufficient to produce metastasis in vivo and suggest that these resistant clones may provide a good model system for characterizing the molecular mechanisms of metastasis.
Hayashi
H
H
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Nagoya City University, Mizuho, Nagoya, Japan.
Shimizu
R
R
Fujii
K
K
Itoh
S
S
Yang
D
D
Onozaki
K
K
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D017364:Collagenases / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D018093:Gelatinases / Q000096:biosynthesis; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000633:toxicity*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000633:toxicity; D016209:Interleukin-8 / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008545:Melanoma / Q000276:immunology / Q000473:pathology*; D008666:Metalloendopeptidases / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D012333:RNA, Messenger / Q000096:biosynthesis; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology*; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9