Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway

A complex equilibrium of biological signals exists within the human body to regulate normal cellular function and growth. Unfortunately, there are various ways in which disruption of these signaling pathways can result in uncontrollable cell growth-an important element in oncogenesis. In particular, the mammalian target of rapamycin (mTOR) pathway appears to play a central role in the development of multiple cancers, including urothelial cell carcinoma (UCC). Although often called 'a master regulator,' mTOR is but one signal in an intricate signaling cascade that controls cell growth and angiogenesis in both normal and cancerous conditions. Other important factors in this pathway include upstream activators such as phosphatidylinositol 3 kinase (PI3K) and Akt, negative regulators such as the tuberous sclerosis complex (TSC) 1/2, and downstream effectors such as p70 S6 kinase and eukaryotic initiation factor eIF4E. On the basis of its important role in tumor growth, efforts have focused on developing means to effectively target the mTOR pathway in hopes of designing new treatments for various tumor types. To address the role of mTOR pathway activity in UCC, we will first review the basic elements of the PI3K/Akt/mTOR pathway and then apply this pathway to bladder cancer oncogenesis. As will be evident, significant progress has been made in defining the role of this pathway in UCC; however, continued research into the nuances of pathway regulation and the usage of targeted inhibition in bladder cancer patients is necessary to define mTOR as a promising target in this disease. Laboratory Investigation (2010) 90, 1406-1414; doi: 10.1038/labinvest.2010.133; published online 26 July 2010