Interleukin-6 functions as an autocrine growth factor in human bladder carcinoma cell linesin vitro

Abstract

Interleukin (IL)-6 is reported to function as a growth factor for renal and prostatic carcinomas. We conducted the present study to define the role of IL-6 in the growth of normal and neoplastic urothelial cells. Human bladder carcinoma cell lines (253J, RT4 and T24) and primary cultured human urothelial cells derived from normal ureters were used. Recombinant human IL-6 stimulated the growth of bladder carcinoma cell lines far better than that of normal urothelial cells (p F 0.001). All carcinoma cell lines tested produced and released IL-6, whereas normal urothelial cells did so only at marginal levels. Furthermore, treatment with lipopolysaccharide derived from Escherichia coli, tumor necrosis factor-a or IL-1 increased IL-6 secretion by bladder carcinoma cell lines but not by normal urothelial cells. Growth of bladder carcinoma cells was significantly inhibited by anti-IL-6 neutralizing antibody or the anti-sense oligonucleotide for IL-6 cDNA. We conclude that IL-6 functions as an autocrine growth factor for bladder carcinoma cells but not for normal urothelial cells and that it may be a factor accounting for the marked enhancement of inflammation-associated bladder carcinogenesis and tumor growth. Interleukin (IL)-6, originally identified as a T cell-derived cytokine that induces final maturation of B cells into antibodyproducing cells , exhibits multiple biologic activities that differ widely among various types of tissue and cell. IL-6 can enhance or inhibit the proliferation of carcinoma cells (Eustace et al., 1993;Miki et al., 1989;Tam et al., 1989). A variety of malignant tumors, including squamous-cell carcinomas and adenocarcinomas, have been shown to contain or synthesize IL-6, and autocrine growth stimulation has been suggested as the mechanism for IL-6 action (Eustace et al., 1993;Lu and Kerbel, 1993). In the genito-urinary system, IL-6 functions as an autocrine growth factor for renal-cell and prostatic carcinomas (Miki et al., 1989;Takenawa et al., 1991;Borsellino et al., 1995;Okamoto et al., 1997).We have shown that a continuous inflammatory stimulus strikingly accelerates N-methyl-N-nitrosourea-initiated rat urinary bladder carcinogenesis (Yamamoto et al., 1992;Kawai et al., 1993Kawai et al., , 1994 and that transformation in vitro can be enhanced significantly by IL-6 treatment (Okamoto et al., 1995). Furthermore, we observed that IL-6 released by inflammatory cells and bladder stromal cells could greatly stimulate the growth of non-tumorigenic and tumorigenic rat urothelial cell lines that did not secrete IL-6 and that transfected IL-6 markedly accelerated the growth rate of low-tumorigenicity rat urothelial cells ; data not shown). These findings suggest that IL-6 functions as a paracrine growth factor for bladder epithelial cells in vitro.Several reports, however, suggest that IL-6 is an autocrine growth factor in bladder cancer. Meyers et al. (1991) reported that specific mRNAs for both IL-6 and IL-6 receptor were expressed in de novo bladder carcinomas and bladder carcinoma cell lines. S...

Blockage of IGF-1R signaling sensitizes urinary bladder cancer cells to mitomycin-mediated cytotoxicity

“…Furthermore, criss-cross experiments showed that supernatants of the autologous cell line of bladder cancer not only stimulated the proliferation of its own cells, but also the growth of other bladder cancer cell lines, which suggested the production of common autocrine growth factors for bladder cancer cells [28]. Some factors or their receptors involved in autocrine loop mechanism of bladder cancer cells have been confirmed, such as IL-6, EGFR, IFN-β, transferrins-like substance etc [34], [35]. But more other unknown factors which may play key roles in autocrine mechanisms of TCCs need to be further characterized.…”

The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1

“…Literature reports about either growth-promoting or -inhibiting activities of IL-6 in androgen-sensitive LNCaP cells are available (Okamoto et al, 1997;Lou et al, 2000;Lin et al, 2001). In our previous studies, proliferation of LNCaP cells was consistently decreased after exposure to IL-6, whereas LNCaP-IL-6 þ cells were not affected by the exogenous cytokine .…”

The relationship between the systemic inflammatory response and survival in patients with transitional cell carcinoma of the urinary bladder

“…However, it is known that as part of the systemic inflammatory response to the tumour there is a release of proinflammatory cytokines and growth factors, which not only stimulate tumour growth (Abramovitch et al, 1999;Coussens and Werb, 2002) but also produce profound catabolic effects on host metabolism (Kotler, 2000). For example, interleukin-6, produced by the tumour or infiltrating inflammatory cells, is recognised as a growth promoter in bladder cancer (Okamoto et al, 1997;Andrews et al, 2002). Interleukin-6 also stimulates liver production of acute-phase proteins, such as Creactive protein, which increases the demand for certain amino acids, which, if limited in the diet, must be obtained from the breakdown of skeletal muscle Preston et al, 1998).…”