Dominant role of E-cadherin in the progression of bladder cancer.

Abstract

To elucidate factors with a role in the progression of bladder cancer. One invasive (T24) and two superficial (RT4 and KK47) human bladder cancer cell lines, which express metastasis-related genes, were used. Cells were intravenously inoculated into chick embryos to evaluate metastatic potential to the liver. An orthotopic model with severe combined immunodeficiency mice was also used to investigate both histological appearance and changes in metastasis-related gene expression. Finally, gene expression patterns in a clinical setting were compared between superficial and invasive bladder cancers. In culture condition metastasis-related genes, including matrix metalloproteinases, urokinase-type plasminogen activator, and integrins alpha2 and alpha3 were continually expressed in T24 but only slightly or not at all in RT4 and KK47, respectively. The expression pattern of the metastasis-related genes in vitro reflected the characteristics of the original tumors. Liver metastasis in chick embryos was demonstrated not only with T24 cells, but also with RT4 cells in which enhanced expression of metastasis-related genes was induced. In the orthotopic model, histological appearances were in accordance with the characteristics of the original tumors, although enhanced gene expression was notable with RT4. Expression of E-cadherin by Western blotting was demonstrated only with RT4 under these experimental conditions. Furthermore, predominant E-cadherin mRNA expression was found in superficial and not in invasive human primary bladder cancers; expression of other genes was similar in the two groups. Dominant expression of E-cadherin in superficial tumors was confirmed by immunohistochemical analysis. These results implicate loss of E-cadherin expression as a critical factor in facilitating the progression of bladder cancer.