Molecular Tumorigenesis of Bladder Cancer

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Summary Bladder cancer is comprised of two major variants: low-grade papillary tumors and high-grade muscle-invasive tumors. Although the majority of the low-grade papillary tumors are slow-growing, approximately 1 in 5 of these tumors progresses to the stage of muscle invasion in a presently unpredictable manner. This is the principal reason of why low-grade papillary bladder tumors require lifelong, vigilant follow-up with repeated cystoscopy and biopsy and why bladder cancer is the most expensive cancer to treat. The genetic causes underlying the transition from low-grade papillary bladder tumors to high-grade invasive bladder tumors have not been delineated. Under the auspices of our parent P01 grant, we recently found that ablation of tumor suppressors residing on human chromosome 9p21, which occurs frequently in human muscle-invasive bladder tumors, in mice accelerates the formation of HRas-induced low-grade papillary bladder tumors, but failed to trigger invasion. Our results suggest that loss of additional genetic components on 9p21 is necessary in order for the invasion to take place. The objective of this administrative supplement is to request funds to support the development of a novel transgenic line that lacks gene components additional to what we initially proposed to investigate. The requested research supplement is well within the general scope of our parent P01 grant, and the new mouse line will serve to accelerate the research contained in all the component projects of the parent P01 grant. Additionally, the mouse line has the potential to facilitate the investigation of other cancer types in which 9p21 is frequently deleted.