Cyclooxygenase (COX) play a critical role in cellular metabolism, mediating the conversion of arachidonate to a family of bioactive prostaglandins. The discovery of COX2, a second, mitogen inducible isoform, occurred almost simultaneously with realization that patients taking cyclooxygenase inhibitors including aspirin and other non-steroid anti-inflammatory drug (NSAIDs) had nearly a 40% risk reduction of clon and other cancers. Recent studies confirm that COX2 is aberrantly increased in specific epithelium cancer cell sub-populations including colonic prostate, aberrantly increased in specific epithelial cancer cell sub-populations including colonic, prostate, bladder. COX2 inhibitors significantly slow growth of these tumors in a variety of experimental models. Additionally, the observation that COX2 knockout mice and mice exposed to COX2 selective NSAIDs in utero exhibit sever renal dysgenesis suggests a specific and critical role for COX2 in the development and maintenance of normal renal development and genitourinary function. Expression of COX2 in the genitourinary tract is among the highest of any normal tissue. Expression of COX2 in the genitourinary tract is among the highest of any normal tissue. The factors contributing to the particular importance of COX2 in the normal genitourinary tract and in the growth and progression of epithelial cancers are uncharacterized.
The aim of the proposed studies is to 1) develop a mouse expressing a GFP reporter driven by the COX2 promoter to facilitate the isolation of viable COX2 expressing cells from developing mouse and mice with genitourinary cancers.
Specific Aim #2 is to develop cell lines from the developing genitourinary tract and murine neoplastic tissue which will allow genetic and functional distinction of COX2 positive and OX2 negative cells. The is9olation of these cells should provide a means of identifying those factors responsible for aberrant up-regulation of COX2 in cancers, and normal programmed expression of COX2 along the GU tract. Isolation of these cells will allow characterization of the prostanoid profile synthesized by COX2 over- expressing cells which should clarify how COX2 inhibitors progression of cancer in the bladder prostate, and other tissues.
