The progression of primary and metastatic bladder cancer depends upon the establishment of an adequate blood supply. Tumor and host microvascular proliferation is regulated by a diverse group of molecules including basic fibroblast growth factor (bFGF) and interleukin-8 (IL-8). Elevated levels of bFGF have been associated with a number of malignancies, including renal cell carcinoma, breast carcinoma, and lung carcinoma. The major goal of this proposal is to evaluate the effect of the level of expression of these angiogenic factors by human bladder cancer cells on the growth and metastases of human bladder cancer. The expression of these factors by the bladder carcinoma cell lines 253J, and its metastatic variants (253J Lung-IV, 253J B-V, 253J Liver-IV, and 253J LN-IV) will be determined in vitro and following anchorage independent growth in hard agarose. Following orthotopic implantation in the bladder of nude mice, the expression of these factors will be correlated with tumor growth and metastases. Human bladder carcinoma cells which express either high or low levels of bFGF and IL-8 will be selected by cloning. The tumorigenicity, vascular and metastatic potential of these selected carcinoma cells will be compared with that of the cell line from which they were derived. Endothelial cells will be cultured in conditioned media from these cell lines and endothelial cell proliferation will be measured in the presence and absence of specific neutralizing antibodies. In order to provide direct evidence for the role of bFGF and IL-8 in the pathogenesis of human bladder cancer, cells which are either high or low expressors of bFGF or IL-8 will be transfected with either the antisense or sense constructs in order to determine whether downregulation or upregulation of a specific factor will influence the growth and metastases of these tumors. In addition, following orthotopic implantation with 253J B-V cells, mice will be treated systemically with low levels of interferon alpha and beta, in order to inhibit the production of bFGF, and inhibit the vascularization and growth of human bladder cancer growing in the bladder of nude mice. Simultaneously, primary and metastatic human bladder cancer specimens will be collected and evaluated for mRNA and protein expression of these factors. These studies should provide a better understanding of the significance of angiogenic factor expression by bladder cancer and may provide a specific target for the therapy of human bladder carcinoma.
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| Dinney, C P; Bielenberg, D R; Perrotte, P et al. (1998) Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth of human bladder carcinoma in mice by systemic interferon-alpha administration. Cancer Res 58:808-14 |
