Interleukin 8 expression regulates tumorigenicity and metastases in androgen-independent prostate cancer

Interleukin 8 (IL-8) is mitogenic and chemotactic for endothelial cells. Wi thin a neoplasm, IL-8 is secreted by inflammatory and neoplastic cells. The highly metastatic PC-3M-LN4 cell line overexpresses IL-8 relative to the p oorly metastatic PC-3P cell line. We evaluated whether IL-8 expression by h uman prostate cancer growing within the prostate of athymic nude mice regul ates tumor angiogenesis, growth, and metastasis, PC-SP cells were transfect ed with the full-length sense IL-8 cDNA, whereas PC-3M-LN4 cells were trans fected with the full-sequence antisense IL-8 cDNA, Control cells were trans fected with the neomycin resistance gene (Neo), In vitro, sense-transfected PC-JP cells overexpressed IL-g-specific mRNA and protein, which resulted i n up-regulation of matrix metalloproteinase 9 (MMP-9) mRNA, and collagenase activity, resulting in increased invasion through Matrigel. After antisens e transfection of the PC-3M-LN4 cells, IL-8 and MMP-9 expression, collagena se activity, and invasion were markedly reduced relative to controls. After orthotopic implantation, the sense-transfected PC-3P cells were highly tum origenic and metastatic, with significantly increased neovascularity and IL -8 expression compared with either PC-3P cells or controls. Antisense trans fection significantly reduced the expression of IL-8 and MMP-9 and tumor-in duced neovascularity, resulting in inhibition of tumorigenicity and metasta sis. These results demonstrate that IL-8 expression regulates angiogenesis in prostate cancer, in part by induction of MMP-9 expression, and subsequen tly regulates the growth and metastasis of human prostate cancer.