A model for 3-dimensional growth of bladder cancers to investigate cell-matrix interactions.

Elucidating the mechanisms by which the phenotype of cancer cells is modulated by the extracellular matrix (ECM) potentially identifies mechanisms that could be exploited for cancer control. Three readily available bladder cancer cell lines of different aggressiveness were grown on a bioscaffold material (Small Intestine Submucosa: SIS) under a variety of media and nutrient schedules to determine the influence of epigenetic factors on phenotype. The aggressive TCCSUP and J82 lines displayed an invasive phenotype when fed twice weekly with medium containing 10% fetal calf serum (FCS), but grew as a layered, noninvasive structure when fed daily with the same nutrient. The papillary RT4 cells grew as a nearly normal appearing layered phenotype when fed with medium containing 10% FCS, regardless of the feeding schedule. The papillary phenotype appeared only when the fetal calf serum concentration was reduced to 1% and the cells were fed twice weekly. Immunohistochemical staining showed E-cadherin was detected in the nucleus of the TCCSUP line rather than on the cell periphery, thus, demonstrating that normalization of the TCCSUP line into a layered phenotype did not alter the fundamental dysregulation of the cadherin-B-catenin-cytoskeleton complex. In contrast, in the RT4 cells the biomarker was distributed discretely around the cell periphery in 10% fetal calf serum but in the nucleus in 1% fetal calf serum and twice weekly feeding. Modulating the phenotype of cancer cells from invasive to noninvasive through manipulation of matrix and nutrient components presents a model system for identifying the key factors involved in invasiveness and may identify new therapeutic targets and markers.