Suppression and activation of the malignant phenotype by extracellular matrix in xenograft models of bladder cancer: a model for tumor cell "dormancy".

A major problem in cancer research is the lack of a tractable model for delayed metastasis. Herein we show that cancer cells suppressed by SISgel, a gel-forming normal ECM material derived from Small Intestine Submucosa (SIS), in flank xenografts show properties of suppression and re-activation that are very similar to normal delayed metastasis and suggest these suppressed cells can serve as a novel model for developing therapeutics to target micrometastases or suppressed cancer cells. Co-injection with SISgel suppressed the malignant phenotype of highly invasive J82 bladder cancer cells and highly metastatic JB-V bladder cancer cells in nude mouse flank xenografts.

From microarray to biology: an integrated experimental, statistical and in silico analysis of how the extracellular matrix modulates the phenotype of cancer cells.

A statistically robust and biologically-based approach for analysis of microarray data is described that integrates independent biological knowledge and data with a global F-test for finding genes of interest that minimizes the need for replicates when used for hypothesis generation. First, each microarray is normalized to its noise level around zero. The microarray dataset is then globally adjusted by robust linear regression.

Systems biology approach for mapping the response of human urothelial cells to infection by Enterococcus faecalis.

Background: To better understand the response of urinary epithelial (urothelial) cells to Enterococcus faecalis, a uropathogen that exhibits resistance to multiple antibiotics, a genome-wide scan of gene expression was obtained as a time series from urothelial cells growing as a layered 3-dimensional culture similar to normal urothelium. We herein describe a novel means of analysis that is based on deconvolution of gene variability into technical and biological components.

Results: Analysis of the expression of 21,521 genes from 30 minutes to 10 hours post infection, showed 9553 genes were expressed 3 standard deviations (SD) above the system zero-point noise in at least 1 time point.

Proteome-level display by 2-dimensional chromatography of extracellular matrix-dependent modulation of the phenotype of bladder cancer cells.

Background: The extracellular matrix can have a profound effect upon the phenotype of cancer cells. Previous work has shown that growth of bladder cancer cells on a matrix derived from normal basement membrane suppresses many malignant features that are displayed when the cells are grown on a matrix that has been modified by malignant tumors. This work was undertaken to investigate proteome-level changes as determined by a new commercially available proteome display involving 2-dimensional chromatography for bladder cancer cells grown on different extracellular matrix preparations that modulate the expression of the malignant phenotype.

Analysis of the interaction of extracellular matrix and phenotype of bladder cancer cells.

Background: The extracellular matrix has a major effect upon the malignant properties of bladder cancer cells both in vitro in 3-dimensional culture and in vivo. Comparing gene expression of several bladder cancer cells lines grown under permissive and suppressive conditions in 3-dimensional growth on cancer-derived and normal-derived basement membrane gels respectively and on plastic in conventional tissue culture provides a model system for investigating the interaction of malignancy and extracellular matrix. Understanding how the extracellular matrix affects the phenotype of bladder cancer cells may provide important clues to identify new markers or targets for therapy.

Exogenous glycosaminoglycans coat damaged bladder surfaces in experimentally damaged mouse bladder.

Background: Interstital cystitis is often treated with exogenous glycosaminoglycans such as heparin, chondroitin sulphate (Uracyst), hyaluronate (Cystistat) or the semi-synthetic pentosan polysulphate (Elmiron). The mechanism of action is presumed to be due to a coating of the bladder surface to replace the normally present chondroitin sulphate and heparan sulphate lost as a result of the disease. This study used fluorescent labelled chondroitin sulphate to track the distribution of glycosaminoglycans administered intravesically to mouse bladder that had been damaged on the surface.

Curcumin: a new radio-sensitizer of squamous cell carcinoma cells.

Purpose: Curcumin, a potential chemopreventive agent, was found to inhibit cancer cells in S/G2M phases of the cell cycle, when radiation is more effective. The purpose of the current study was to investigate whether curcumin can sensitize squamous cell carcinoma (SCC) cells to the ionizing effects of irradiation.

Methods: Curcumin (3.

A novel multidrug resistance phenotype of bladder tumor cells grown on Matrigel or SIS gel.

We have previously shown that growth of bladder carcinoma cell lines onto matrices such as Matrigel and small intestinal submucosal (SIS) gel cause distinct changes in cellular morphology and motility. In these studies, we found that bladder cells grown on Matrigel showed increased resistance to either doxorubicin or mitomycin-C whereas growth of cells in SIS gel caused either significant increases or little difference in drug resistance, depending on both the cells and the drug. Finally, it was found that this altered drug sensitivity is reversible with a finite half-life and is likely due to altered drug accumulation and/or cell cycle kinetics.

Abnormal expression of molecular markers for bladder impermeability and differentiation in the urothelium of patients with interstitial cystitis.

Purpose: Despite a lack of consensus concerning the etiology of interstitial cystitis (IC) the loss of impermeability and other abnormalities of the urothelium are features of the disease. In this study the distribution of proteins involved with epithelial adhesion, cellular differentiation and bladder impermeability in urothelial biopsies were explored by the immunohistochemical assessment of E-cadherin, ZO-1, uroplakin and chondroitin sulfate.

Materials And Methods: Biopsies obtained from 27 patients with IC and 7 controls were immediately fixed in formalin, immunohistochemically labeled for the described proteins and scored for protein expression, morphology and differentiation.

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.

Matrix-dependent plasticity of the malignant phenotype of bladder cancer cells.

The purpose of this study was to investigate the effect of cancer- and normal basement membrane-derived extracellular matrix to modulate the phenotype of bladder cancer cell lines. Five lines, varying in malignancy from papilloma to highly undifferentiated and invasive and immortalized human urothelial cells, were grown on two extracellular matrix preparations, Matrigel and SISgel. Matrigel represents matrix remodeled by malignancy while SISgel, obtained from small intestine submucosa (SIS), represents the normal matrix supporting differentiated cell growth.