Figure 1. Signaling networks and treatment targets in muscle-invasive and metastatic urothelial carcinomas.

Growth factor signaling is increased in urothelial carcinoma [60]. This results in triggering of growth factor receptors (ERBB-2, ERBB-3, EGFR, FGFR1, FGFR3) leading to Ras activation. Hyperactivation of Ras is a key transition from a non-invasive to an invasive phenotype in urothelial carcinomas [18]. Ras hyperactivation results in phosphotidylinositol-3-kinase (PI3K) signaling, that leads to Akt and mTOR activation downstream. Ras hyperactivation also increases activity of MAP kinases, which activate key regulators of the epithelial-mesenchymal transition [81]. This ultimately leads to an inhibition of E-cadherin expression, promoting local invasion of the tumor through a loss of appropriate cell-cell adhesion [189]. Ras also induces RAF-MEK-ERK signaling, which impacts cytoskeletal dynamics as well as induces a heat shock factor response with increased activity of Hsp27 and Hsp90, as well as other components [155]. Ras is negatively regulated by NF1, which is deficient in some urothelial carcinomas, allowing for uninhibited Ras activation. PI3K activity is inhibited by PTEN, which is also deficient in some urothelial carcinomas due to mutation, leading to increased activation of Akt by PI3K [60, 190]. Akt inhibits the tuberous sclerosis complex (TSC) that acts as a negative regulator of mTORC1 activity. PI3K-Akt activation, as well as mutation within a TSC component (TSC1 or TSC2), leads to inappropriate mTORC1 activation by Rheb GTPase [191]. mTORC1 promotes numerous anabolic processes, including cell growth, metabolism, protein translation, and hypoxic signaling through increased production of hypoxia-inducible factor-1 (HIF-1) [192]. HIF-1 and vascular endothelial growth factor (VEGF) promote angiogenesis and support an intratumor vasculature. Akt also stimulates the mechanistic target of rapamycin (mTOR) complex 2 to activate NF-kB and promote cytoskeletal growth [193]. NF-kB in turn inhibits p53, which promotes apoptotic resistance [194]. Loss of p53 expression leads to uninhibited cell cycle progression, as does loss of the retinoblastoma (RB1) tumor suppressor gene [195]. Reduced RB1 expression results from mutation of its locus as well as through reduced accessibility of chromatin to transcribe its locus from inactivation of the SWI-SNF chromatin remodeling complex [84]. Increased cell cycle progression, paired with an increase in anabolic processes, promotes survival and growth of the tumor. *Molecules in red are upregulated in urothelial carcinomas, while those in green are downregulated. Molecular targeted therapies to disrupt these key processes implicated in urothelial carcinomas growth and progression are highlighted in boxes.