Abstract 3082: A paradoxical suppressive role for Src in urothelial carcinoma

Abstract

Abstract The most prevalent type of bladder cancer in western nations is urothelial carcinoma (UC). A significant number of patients with UC present with the muscle invasive form of the disease that is treated by radical cystectomy. Even with these treatments approximately 50% of these patients will develop metastases, resulting in essentially incurable disease. Thus, understanding the molecular basis of metastases in UC may prove useful in providing new therapeutic insights and targets. Src (v-Src sarcoma viral oncogene homolog) has been found to play pivotal oncogenic roles in a variety of in vitro and in vivo cancer models. Interestingly, when Src expression and activity was evaluated in a panel of bladder cancer cell lines and human bladder cancer tissue, it was shown that there was an inverse correlation between Src expression/activity and bladder tumor grade, suggesting that the Src oncogene might play a paradoxical suppressive role in UCs. Herein, we show that that stable expression of constitutively active Src in a high grade bladder cancer cell line (UMUC3) corresponds to a decrease in in vitro monolayer growth (p = 0.05), Boyden Chamber migration (over a period of time where growth effects are inconsequential) (p < 0.01) and a reduction of experimental lung metastases in nude mice (p < 0.036). Supportive of this surprising finding that Src is a suppressor of various malignant phenotypes, we demonstrate that pharmacological inhibition of Src tyrosine kinase activity in the KU7 non invasive UC cells that have high Src expression and tyrosine kinase activity increases cellular proliferation and anchorage independent growth, compared to carrier treated controls. Interestingly, we show that stimulation of FGFR3, a tyrosine kinase receptor that has been associated with low grade and stage non- invasive bladder cancers with favorable prognoses, leads to induction of Src kinase activity in the KU7 cell line. Taken together, these data suggest direct evidence that Src acts paradoxically as a suppressor or aggressive urothelial cancer phenotypes and provide a possible explanation how FGFR3 activity may maintain a non aggressive tumor phenotype. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3082.