Interleukin 8 expression regulates tumorigenicity and metastasis in human bladder cancer.
Interleukin 8 (IL-8) is mitogenic and chemotactic for endothelial cells. Within 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 nometastatic 253J-P cell line. To determine whether IL-8 expression regulates tumorigenicity and metastasis in human TCC, 253J B-V cells were transfected 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 cells for each were transfected with the neomycin resistance (Neo) gene. In vitro, sense-transfected 253J-P cells overexpressed IL-8-specific mRNA and protein, whereas both of these were markedly reduced in AS-IL-8-transfected 253J 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 implantation into the bladders of athymic nude mice, the sense-transfected 253J-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 expression and microvessel density. These studies demonstrate that IL-8 expression enhances angiogenic activity through the induction of matrix metalloproteinase type 9 and subsequently regulates the tumorigenesis and production of spontaneous metastases of human TCC.
Inoue
K
K
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA.
Slaton
J W
JW
Kim
S J
SJ
Perrotte
P
P
Eve
B Y
BY
Bar-Eli
M
M
Radinsky
R
R
Dinney
C P
CP
D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000098:blood supply / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism; D004338:Drug Combinations; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D008207:Lymphatic Metastasis; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011509:Proteoglycans / Q000378:metabolism; D020871:RNA Stability; D016372:RNA, Antisense / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004338:Drug Combinations; D016228:Endothelial Growth Factors; D016209:Interleukin-8; D007797:Laminin; D008222:Lymphokines; D011509:Proteoglycans; D016372:RNA, Antisense; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D003094:Collagen; D017364:Collagenases; D020780:Matrix Metalloproteinase 9