Wnt signaling pathways in urological cancers: past decades and still growing

During embryogenesis, cells often acquire new identities as they migrate to new locations. Many of these morphogenetic changes are induced by extracellular ligands and their receptors [1-3]. Signaling events outside the cell act as positive or negative regulators of signaling pathways. This is particularly true for proteins with key functions in development, such as bone morphogenetic protein (BMPs) Hedgehog and Wnt. Various factors can interact with these proteins outside the cell, modulating their activity or altering their structure [4-10]. Wnt proteins, which are found in animals from hydra to insects, worms and vertebrates, are involved in a wide range of embryonic patterning events and maintenance of homeostasis in adult tissues [8,9,11-13]. One of the most striking effects of Wnt proteins is their ability to induce formation of a new embryonic axis in metazoans ranging from Hydra to Xenopus [14,15]. Defects in this pathway have been shown to cause various embryonic abnormalities in Drosophila and animal models and have been implicated in human cancers. Other signaling pathways important in embryonic pattern formation include the Nothch pathway and the tyrosine kinase receptor/Ras pathways [16] and those headed by members of the transforming growth factor (TGF)-β superfamily [17,18]. Instances of crosstalk between the embryonic signaling pathways notch, wnt, or Hh and other signaling pathways have been reported in a variety of cell types [19-21]. Although aberrant activation of an individual pathway may result in tissue specific carcinogenesis, these pathways rarely operate in isolation. Crosstalk between signaling pathways has the potential to profoundly add to the complexity of cellular responses to external stimuli. Various reports indicate crosstalk between Wnt signaling and other key cancer pathways regulating apoptosis, angiogenesis, proliferation, migration, invasion and metastasis [12,22-25].Wnt-1, the first member of Wnt family protein was initially i