Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: Possible involvement of TNFα and IL-1α

Abstract

We examined whether macrophage infiltration is associ- ated with angiogenesis in cutaneous melanoma. The numbers of macrophages and microvessels increased significantly with increasing depth of tumor and with tumor angiogenesis. Macrophage infiltration thus appeared to provide a useful diagnostic marker for the progression of cutaneous mela- noma.Wefurther examined whether human melanoma cells produce angiogenic factors in response to macrophage- derived cytokines, tumor necrosis factor alpha (TNF?) and interleukin-1 alpha (IL-1?). Treatment of melanoma cells with TNF? and IL-1? in vitro enhanced the production of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF), and of basic fibroblast growth factor (bFGF) to a lesser degree, in human melanoma cells. Lipopolysaccharide (LPS)-activated human monocytes enhanced production of IL-8, VEGF,TNF?, as well as IL-1?, but not bFGF. Co-culture of human monocytes and human melanoma cells was also found to significantly enhance production of IL-8 and VEGF in the absence and presence of LPS, compared with either monocytes or melanoma cells alone. The production of IL-8 and VEGF from co-cultured melanoma cells and LPS- activated monocytes was blocked when anti-TNF-? antibody or anti-IL-1? antibody was co-administrated. This is direct evidence that production of the potent angiogenic factors IL-8 and VEGF from melanoma cells is up-regulated through TNF? and/or IL-1? secreted by activated monocytes/macro- phages, influencing both tumor growth and angiogenesis in melanomas.