Human bladder cancer invasion model using rat bladder in vitro and its useto test mechanisms and therapeutic inhibitors of invasion

As well as being a passive support, the extracellular matrix also regulates key biological processes such as invasion, differentiation and angiogenesi s. We have therefore developed an in vitro model of bladder cancer invasion using de-epithelialized rat bladder to allow for tumour cell-extracellular matrix interactions. Onto this we have seeded a panel of human bladder can cer cell lines (RT4, RT112, 253J and EJ28 (T24)) representing progression f rom well to poorly differentiated phenotypes and used as models of superfic ial to invasive bladder cancer. The better differentiated cell lines RT4 an d RT112 reproducibly grew as stratified epithelium, whereas poorly differen tiated EJ28 cells invaded across a broad front. Invasion was not simply rel ated to proliferation rate, measured either as doubling time on plastic (no n-invasive 253J and invasive EJ28 having the same doubling time) or by Ki-6 7 proliferation index within the model, We used the model to test the abili ty of 4 compounds that interfere with tumour cell-extracellular matrix inte ractions (suramin, N-acetylcysteine and the urokinase plasminogen activator pathway antagonists A5 compound and monoclonal antibody Mab 3936) to inhib it invasion. At non-toxic concentrations, all significantly inhibited invas ion (P < 0.05), although to varying degrees, suramin and A5 almost complete ly and N-acetylcysteine the least. In conclusion, this model shows the urok inase system is important for bladder invasion and can be used to investiga te other mechanisms of bladder cancer invasion and also for the testing of intravesical drugs. (C) 2001 Cancer Research Campaign.