Pathways of metastasis suppression in bladder cancer Neveen Said & Dan Theodorescu Published online: 16 December 2009 # Springer Science+Business Media, LLC 2009 Abstract Despite the recent advances in the diagnosis of bladder cancer, recurrence after surgical intervention for muscle invasive disease is still problematic as nearly half of the patients harbor occult distant metastases and this, in turn, is associated with poor 5-year survival rate. We have recently identified Rho family GDP dissociation inhibitor 2 (RhoGDI2) protein as functional metastasis suppressor and a prognostic marker in patients after cystectomy. In identifying the mechanisms underlying metastasis suppres- sion by RhoGDI2, we found this protein to be associated with the c-Src kinase in human tumors, where the expression of both is diminished as a function of stage. Interestingly, c-Src bound to and phosphorylated RhoGDI2 resulting in enhanced metastasis suppressive potency. In this review, we will discuss the established roles of c-Src and RhoGDI2 in bladder cancer and speculate on their therapeutic relevance. Keywords Bladder neoplasms . Metastasis . Src . RhoGDI2 1 Introduction Bladder cancer is a common malignancy affecting the genitourinary system. In the United States, 70,980 estimat- ed new cases, and approximately 14,330 deaths are expected in 2009 [1]. Most cases are of urothelial (formerly named “transitional”) histology and, of these, 75% of patients present with non-muscle invasive and 20–30% present with muscle invasive disease [2]. Despite good prognosis for patients with non-muscle invasive disease, recurrence is common and associated with development of muscle invasive disease in up to 30% [2]. Nearly half of the patients presenting with muscle invasive disease or pro- gressing to this state from non-muscle invasive cancer already harbor occult distant metastases and a poor 5-year survival rate [3]. Numerous factors, including chromosomal markers, genetic polymorphisms, and genetic and epigenet- ic alterations are involved in tumorigenesis, progression, and metastasis of bladder cancer [4]. Our laboratory has identified the Rho family GDP dissociation inhibitor 2 (RhoGDI2) protein as functional metastasis suppressor in human bladder cancer models and a prognostic marker in patients after cystectomy where diminished tumor expression is associated with decreased patient survival [4–8]. Further examination of these find- ings revealed that a subset of patients with tumors having RhoGDI2 expression levels similar to those found in non- muscle invasive disease still developed metastasis. This led us to investigate whether mechanisms, other than the expression level, regulate RhoGDI2 function. We have recently identified the c-Src kinase as a novel binding partner of RhoGDI2, phosphorylating it at a specific tyrosine residue and thus mediating its metastasis suppres- sor function. Surprisingly, decreased c-Src and RhoGDI2 expression levels appeared mutually exclusive in individual tumors, indicating shared signaling pathways leading to metastasis suppression [9]. These findings broaden the possible roles of c-Src in cancer and raise the possibility that some of these are mediated in a tissue specific manner. In this review, we will focus on the roles of c-Src and RhoGDI2 in bladder carcinogenesis and metastasis. N. Said : D. Theodorescu (*) Department of Urology, University of Virginia, Box 800422, Charlottesville, VA 22908, USA e-mail: dt9d@virginia.edu D. Theodorescu Departments of Molecular Physiology and Biological Physics, University of Virginia, Box 800422, Charlottesville, VA 22908, USA D. Theodorescu Paul Mellon Urologic Cancer Institute, University of Virginia, Box 800422, Charlottesville, VA 22908, USA Cancer Metastasis Rev (2009) 28:327–333 DOI 10.1007/s10555-009-9197-4