[Bladder carcinoma cell lines as models of the pathobiology of bladder cancer. Review of the literature and establishment of a new progression series]. / Harnblasenkarzinomzelllinien als Modellsysteme zur Pathobiologie des Harnblasenkarzinoms. Uberblick und Etablierung einer neuen Progressionsserie.

ABSTRACT

BACKGROUND: Tumour cell lines represent valuable preclinical models to decipher underlying biology and identify potential therapy targets and pharmacologically useful compounds. Approximately 50 human bladder cancer cell lines have been established to date, mainly from invasive and metastatic tumours. Two of these, namely T24 and 253J, were experimentally further developed into progression series. These models have provided important insights into later tumour progression events and metastatic dissemination. Only a few cell lines are available as models of non-invasive papillary bladder cancer and no progression series have yet been established. MATERIAL AND METHODS: During the course of establishing a doxorubicin-resistant variant cell line of the human papillary bladder carcinoma cell line BFTC-905, a unique cell colony was identified, apparently involving cells with divergent growth patterns. Subsequent subculturing yielded three daughter cell lines, BFTC-905-compact, BFTC-905-diffuse und BFTC-905-diffuse M. Their fundamental characterization included basic cell morphology, cell membrane expression of E-Cadherin, karyotype analysis, invasion and colony forming capacity in soft agar. The clonal origin of the newly established daughter cell lines was assessed by means of molecular genetic methods. RESULTS: We could identify important differences in multiple transformation related traits among the cell lines of the BFTC-905 progression series. Both diffuse cell lines (BFTC-905-diffuse und BFTC-905-diffuse M) differed from the BFTC-905-compact cell line by growing in a less organized,"diffuse" manner, which involved colonies of cells exhibiting apparently normal cell-to-cell adhesion as well as individual cells outside of them. This diminution of the cell-to-cell adhesion was accompanied by a corresponding decrease of membranous E-Cadherin. The BFTC-905-diffuse M cell line displayed a dramatic increase in the overall chromosome number, resulting in a hypertetraploid karyotype. At the same time, this cell line, as the only one in the progression series, acquired the ability to grow independent of anchorage in soft agar. All three cell lines remained noninvasive. Allelic distribution of highly polymorphic DNA-markers in the cell lines of the BFTC-905 progression series provided unequivocal evidence of their common origin. CONCLUSION: The newly established BFTC-905 progression series manifests two aspects of the early progression of non-invasive bladder carcinoma, not exhibited by any other progression series published so far, namely dynamic changes in the expression of E-Cadherin and a complex karyotypic evolution. It may thus contribute important insights into further understanding of the pathobiology of bladder cancer.