Abstract 2407: Decreased inflammation and tumor stage in COX-2 knockout mice in the BBN model of bladder cancer

Abstract

Abstract Introduction and Objective: Prostaglandins (PG) play a critical role in the development of solid tumors. Inhibition of cyclooxygenase-2 (COX-2), the committed step in PG synthesis, has been shown to impair tumor development in the BBN mouse model of bladder cancer. Because inhibitors of COX-2 have been reported to have anti-tumorigenic properties independent of COX-2, we evaluated the impact of gene disruption of COX-2 in the BBN mouse model. Methods: We used 2 mo old male COX-2 knockout (KO) and wild type (WT) mice in an outbred CD-1 background. Mice were treated with (n=13-14 / group) and without (n=6/group) BBN in drinking water and euthanized after 25-27 wks. Bladders were harvested, weighed, bisected and step sectioned after formalin fixation. H&E stained sections were evaluated for pathologic stage/grade, percent involvement by invasive disease and degree of inflammatory infiltrate(grade 1-3). Results: All animals receiving BBN had inflammatory changes at the time of euthanasia, with the grade being higher in WT (grade 2-3) than KO mice (grade 1-2). Six WT mice and 3 KO mice receiving BBN died, all within the first 18 wks of study, without gross evidence of tumor. Compared to previous studies with C57Bl/6 mice, tumor development was slower and burden was lower at 25-27 wks. All 7 BBN-treated WT mice had high grade invasive cancer at euthanasia: 6 pT1 and 1 pT3. Out of 11 BBN-treated KO mice at euthanasia, 10 had high grade cancer and 2 had invasive disease: 1 pT0, 6 CIS, 2 pTa (non-invasive) and 2 pT1. Mean bladder weight at euthanasia was elevated only in BBN-treated WT mice. There was a strong correlation between WT genotype and tumor stage by Pearson's R (0.74, p=0.03). The percent of tumor representing invasive disease was 0.31 in COX-2 WT mice vs 0.01 in KO mice (t-test, p=0.002). Conclusions: Genetic disruption of COX-2 resulted in lower tumor stage and percent invasiveness in the BBN mouse model of bladder cancer. However, most COX-2 KO mice developed high grade disease, indicating disruption of COX-2 was not sufficient to prevent tumorigenesis. Reduced inflammation in the COX-2 KO mice may account for the decreased invasiveness. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2407. doi:10.1158/1538-7445.AM2011-2407