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Study of urothelial tumorigenesis using a transgenic approach has become possible through development of a mouse model using a urothelium-specific gene promoter. We used magnetic resonance (MR) imaging to evaluate the development of superficial bladder cancers in transgenic mice harboring an activated Ha-ras gene (Ha-ras-M) driven by the uroplakin II (UPII) gene promoter. This model, which develops non-invasive papillary transitional cell carcinomas similar to superficial bladder cancers diagnosed in humans, may be useful to test new chemopreventive agents for bladder cancer. MR imaging techniques were developed at M. D. Anderson Cancer Center’s Small Animal Cancer Imaging Research Facility using a Signa 1.5 T MR scanner. The mice were anesthetized using isoflurane inhalation anesthesia and contrast was injected via the tail vein. In order to validate the MR imaging method of in vivo tumor detection in this mouse model, we scanned and subsequently sacrificed UPII-Ha-ras-M mice at 3, 4, 6, 8 and 12 months of age, and compared image and histopathologic assessment of the genitourinary tract. T2-weighted and T1-weighted plus contrast images were obtained for each mouse. We found a close correlation between MR image and histologic detection of intravesical abnormalities in the mice in all age groups. Axial T1-weighted post-contrast MR images of the urinary bladders of the 3 and 4 month old mice showed diffuse irregular thickening of the urinary bladder mucosa which corresponded to histological findings of diffuse marked hyperplasia of the transitional epithelium. At 6-8 months of age, MR images identified the bladder lumen lined with numerous papillary masses and thick layers of neoplastic transitional epithelium (papillary transitional cell carcinoma), some with squamous metaplasia, surrounding branching narrow fibrovascular stalks. MR images of 12-month-old mice showed diffuse irregular contrast-enhancing masses lining the bladder lumen, with thick branching pedunculated papillary masses of neoplastic transitional epithelium on histology. Bladder weights increased in correlation with age and tumor mass. Preliminary evaluation of a COX-2 inhibitor used as a chemopreventive agent in this model demonstrates a decrease in tumor formation, as we have previously shown in another mouse model. In conclusion, MR imaging is a non-invasive modality that can accurately detect and monitor in vivo tumor development in this UPII-Ha-ras-M mouse model, which appears promising for evaluation of bladder cancer chemoprevention agents.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]