Tumorigenicity of RTK/RAS in urothelium

Although bladder cancer (BC) was the cancer from which the first human oncogene, RAS, was identified, questions persisted over the past 35 years as to whether RAS activation in urothelium was tumorigenic [1]. This was due in large part to the relatively low frequency (~15%) and lack of grade and stage association of RAS mutations in human BC [2]. However, the tide is turning recently in favor of a role for RAS in urothelial tumorigenesis, because of the sheer abundance of the mutations in proteins that act up-and downstream of RAS. For instance, activating mutations of fibroblast growth factor receptor 3 (FGFR3) occur in 45-75% of human BC; those of PI3K and RAF in ~25% and ~8% of human BC, respectively; and those inactivating PTEN in ~8% of human BC [1, 2]. Since most of these mutations are non-overlapping in a given BC, it is not difficult to come to the conclusion that the RTK/RAS signaling pathway is activated in an overwhelming majority of human BC. So, is RTK/RAS pathway activation tumorigenic and, if so, in what context? The recent paper by He et al. [3] and several earlier reports that targeted specific mutations of RTK/ RAS pathway components into urothelia of transgenic mice are starting to offer useful clues. First, the tumorigenicity of activated RTK/RAS components by themselves in urothelium is in general very limited and gene-specific. For instance, expression of a constitutively active kinase mutant of FGFR3 (K644E) in urothelium resulted in normal-appearing epithelia even in aged (18-month old) mice [4]. Expression of a G12V HRAS mutant from its endogenous promoter did not lead to any urothelial abnormality within a year span [5]. Deletion of both but not one allele of PTEN led to urothelial hyperplasia, with only 10% of the mice eventually developing low-grade papillary BC during between 10-20 months [6]. Thus, the growth-promoting potential of activated RTK/RAS pathway varies from component to component, although none seems overly strong. Second, the tumorigenicity of activated RTK/RAS pathway is dosage-dependent. This was best illustrated in transgenic mice expressing an HRAS mutant under the control of a heterologous, Upk2 promoter [7]. While the heterozygous mice consistently developed urothelial hyperplasia before 10 months of age, 100% of the homozygous littermates developed low-grade, papillary BC as early as 3 months and succumbed to obstructive renal failure by 6 months. It appears, therefore, that the magnitude of RAS activation contributes in a major …