Interleukin 8 expression regulates tumorigenicity and metastasis in human bladder 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 tumorigenic and highly metastatic human transitional cell carcinoma (TCC) cell line 253J B-V overexpresses IL-8 relative to the nontumorigenic and nonmetastatic 253J-P cell line. To determine whether IL-8 expression r egulates tumorigenicity and metastasis in human TCC, 253J B-V cells were tr ansfected with the full-sequence antisense (AS) cDNA for IL-8, whereas 253J -P cells were transfected with the full-length IL-8 cDNA, and control tells for each were transfected with the neomycin resistance (Neo) gene. In vitr o, sense-transfected 253J-P cells overexpressed IL-8-specific mRNA and prot ein, whereas both of these were markedly reduced in AS-IL-8-transfected 253 J B-V cells relative to controls. Moreover, sense-transfected cells showed up-regulation in matrix metalloproteinase type 9 mRNA, collagenase activity , and increased invasiveness through Matrigel-coated filters, whereas these measures were lower in AS-transfected cells relative to controls. After im plantation into the bladders of athymic nude mice, the sense-transfected 25 3J-P cells acquired increased tumorigenicity and metastasis, whereas the AS -transfected cells significantly inhibited tumorigenicity and metastases in the 253J B-V cell lines. This effect was accompanied by reduced IL-8 expre ssion and microvessel density. These studies demonstrate that IL-8 expressi on enhances angiogenic activity through the induction of matrix metalloprot einase type 9 and subsequently regulates the tumorigenesis and production o f spontaneous metastases of human TCC.