Abstract 2280: Endothelin axis in bladder cancer metastasis

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Abstract In bladder cancer, recurrence after surgical intervention for muscle invasive disease is problematic as nearly half of patients harbor occult distant metastases, mainly in the lungs, with poor 5-year survival rate. Our prior work has indicated that RhoGDI2 reduces tumor Endothelin 1 (ET-1) secretion and this may contribute to its metastasis suppressor function, however how the endothelin axis acts to promote lung metastasis is unclear. We have found from gene expression profiling of human bladder tumors that high ET-1 expression was correlated with poor survival. Here we also identify ET-1 as a novel mediator of bidirectional cross talk between tumor cells and inflammatory macrophages. Tumor-derived endothelin, through its cognate endothelin receptor A (ETAR) exerts autocrine and paracrine effects on tumor cells and macrophages, significantly inducing its own production, by both cell types, concomitant with triggering an early inflammatory response in the lungs, which progressively increases till development of lung metastases. Abrogation of ET-1/ETAR axis by knock down tumor cell ET-1 by short hairpin RNA (shRNA) or systemic administration of ETAR blocker (ZD4054) significantly suppressed the development and the progression of this lung inflammatory response, and decreased the development of microscopic and macroscopic lung metastases, together with improvement of animal survival. In vitro, genetic manipulation of ET-1, ETAR and ETBR in bladder cancer cell lines co-cultured with macrophages revealed that ET-1 augments the inflammatory response through activation of transcriptional factors NFκB and AP-1, key orchestrators of inflammation, in both cancer cells and macrophages. The reciprocal activation of both transcriptional factors was mediated by ET-1/ETAR axis in cancer cells, whereas in macrophages it was mediated by ET-1/ETAR and ETBR axis. These findings highlight a molecular mechanism that can be pharmacologically manipulated to enhance the efficacy of current adjuvant approaches to muscle invasive bladder cancer. 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 2280.