An improved mouse orthotopic bladder cancer model exhibiting progression and treatment response characteristics of human recurrent bladder cancer.

Abstract

Nonmuscle-invasive (superficial) bladder cancer is generally treated via surgical removal, followed by adjuvant therapy (bacillus Calmette-Guerin). However, bladder cancer can often recur, and in a substantial number of recurrent cases, the cancer progresses and metastasizes. Furthermore, residual microtumors following excision may lead to an increased risk of recurrence. An in vivo model mimicking the pattern of urinary bladder microtumor regrowth may provide an effective experimental system for improving postsurgical treatment outcomes. A mouse bladder cancer model established using orthotopic transplant of UM-UC-3 human urinary bladder carcinoma cells has been established, however, to the best of our knowledge, no report has investigated sequential histological changes, including early-phase changes and treatment responses in bladder cancer. In the present study, the efficiency of the model was optimized and the sequential changes were examined using histopathology and in situ imaging. The therapeutic effects of cisplatin (CDDP) and gemcitabine (GEM) were also examined, which are drugs that are often used for follow-up chemotherapy. Tumor-seeding efficiency reached 90–100%, with muscle layer and bladder lumen invasion occurring in ~21 days, using the following modifications: i) Shallow catheter insertion to mitigate bladder wall damage; ii) bladder pretreatment using prewarmed trypsin, followed by light urethral clamping and body temperature maintenance for more efficient removal of transitional epithelium; and iii) seeding with UM-UC-3 cells (rather than HT1376, 5637 or T24 tumor cells) in a medium supplemented with Matrigel. Transplant with UM-UC-3 cells resulted in isolated microlesions that progressed into tumors, invading the bladder lumen and muscle layer to the serosal surface. Tumor growth was markedly reduced by weekly intravenous injections of CDDP and partially suppressed by GEM. Therefore, this model is reliable, and pathological progression and treatment responses recapitulate the features of recurrent human bladder cancer.