This proposal is in response to a request for application for a network of collaborating laboratories to develop and test quantified markers for bladder cancers. The goals are to improve treatment of bladder tumors and decrease the physical and financial burden of management of this disease. More specifically, recognizing the limitations of classical histopathology, cytology and flow cytometry (FCM), methods must be developed to better predict tumor recurrence, local and/or distant progression and treatment response, as well as to detect highly recurrent superficial tumors by more sensitive and non-invasive means. The basic approach of the programme is to combine hybridoma technology and tumor biology to generate reagents able to discriminate between normal cells and well-differentiated tumor cells or to reflect with more precision the aggressive potential of tumors. As a result of our previous work, a panel of monoclonal antibodies (mABs) is already available which can stratify bladder tumors into different phenotypes which correlate with distinct biological potentials. A method has also been developed to simultaneously study mAb reactivity and DNA content of cells from bladder irrigation and tumors by FCM. Results of a limited prospective study using the technique suggest that mAbs may improve the sensitivity of the test to detect diploid tumors and to predict tumor progression and patient survival. It is proposed that these mAbs be tested in FCM and in urine immunocytology by the members of the network to assess more definitively their clinical value. To advance the capabilities of the network, new mAbs will be produced against purified bladder cancer antigens found to be associated with tumor progression, as well as against a subset of well-differentiated bladder tumors not detected by the existing panel of mAbs. Moreover, immuno-modulation strategies for immunization will be combined with the use of immortalized and transformed uroepithelial cells and a model of lymphatic adhesion of human bladder cancer cells to generate mAbs against molecules functionally important in tumor progression. Evaluative research including immunopathology and FCM studies will assess the potential value of new mAbs as clinical markers. Finally, methodological developments will include dual-laser studies to evaluate the advantages of analyzing simultaneously two mAbs and DNA content, with the aim of designing ultimate DNA and antigen phenotype studies on urine samples.
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