The Ral GTPase pathway in metastatic bladder cancer: key mediator and therapeutic target

Bladder cancer is a relatively common and strikingly costly malignancy. Here, we will focus on recent advances in our understanding of the molecular pathogenesis of metastatic bladder cancer, a stage of this disease curable in only a minority of patients. Our group has recently investigated the role of a class of small G-proteins known as the Ras-like or Ral GTPases and their role in this disease. These signaling proteins, regulated by the Ras pathway and other mechanisms, have been shown to be necessary for key cellular phenotypes associated with transformation or cancer progression in diverse cancer systems. In bladder cancer we have observed that these GTPases are overexpressed, are necessary for key phenotypes in models of bladder cancer progression, and finally, are essential for the regulation of expression of key molecules, including the prognostic marker and cell surface GPI-linked glycoprotein, CD24. These findings are reviewed here and suggest that Ral GTPases and their downstream pathways constitute key mediators of bladder cancer progression and may include targets for future therapeutic strategies.