Xue-Ru Wu, MD

Diseases involving the urinary bladder are of major clinical and social concerns. Bladder cancer is the fifth most common neoplasm and the twelfth leading cause of cancer deaths in the United States. Urinary tract infections are one of most common infectious diseases, accounting for 8-10 million physician''s visits annually. Together, these two diseases cost over 5 billion health care dollars in the clinical management. Despite extensive studies, little is known about the pathogenesis of these bladder disorders.

Our approach to better understand the molecular pathogenesis of bladder diseases is to utilize a group of bladder-specific markers?the uroplakins?that we have recently identified. These proteins, naturally forming two-dimensional crystals, are synthesized by all mammalian bladders studied, represent the major differentiation products of the normal bladder epithelium and are retained by a majority of the human bladder cancers. They are therefore excellent lineage-specific markers for bladder epithelium and for differentiating bladder cancers from cancers from other tissue origins. In addition, we have found that two of the uroplakins, uroplakins Ia and Ib, can serve as the major urothelial receptors for type 1-fimbriated E. coli, which cause more than 85% of the urinary tract infections. The preferential binding between a sub-population of E. coli that are predominant in urinary tract infection and uroplakins provides a molecular explanation for the recently recognized tissue tropism of uropathogenic E. coli. To study the bladder tumorigenesis, we have developed transgenic mouse models by specifically expressing activated oncogenes and mutated tumor suppressor genes in bladder epithelium. Mice harboring simian virus 40 large T oncogene, whose protein product inactivates p53 and retinoblastoma tumor suppressor protein, induced carcinoma in situ which progresses to invasive and metastatic transitional cell carcinomas. Mice harboring an activated H-ras induced bladder epithelial hyperplasia which progresses to superficial papillary tumors. These transgenic models provide strong experimental evidence that bladder cancers develop and progress via two distinctive pathways each of which is caused by unique genetic defects. Ongoing research efforts include the development of novel transgenic and knockout models, and the identification of molecular signatures of cancer progression through high-throughput screening, biochemical and cell biologic approaches.