Studies in various types of cancer have revealed key functions of exosomes in facilitating tumor survival and progression. Such activities include stimulating tumor growth and angiogenesis, suppressing immune response, remodeling extracellular matrix, assisting the formation of the premetastatic niche and directly promoting metastasis

[3, 9, 19•• and 20]. The biological and pathological roles of exosomes in cell Doramapimod manufacturer signaling have been extensively reviewed elsewhere [3, 7 and 9]. In this review, we focus on recent studies that have identified key roles of exosomes in regulating Wnt signaling, which has important implications in development and cancer. Wnt proteins constitute a major family of morphogens that is conserved across all metazoan species. After binding to its receptors, Wnt triggers a number of signaling pathways that regulate essential biological processes including body axis patterning, cell proliferation, cell polarity and migration, stem

cell renewal, cell fate specification and apoptosis, etc. [21, 22 and 23]. These pathways include the canonical Wnt/β-catenin pathway, BIBF 1120 the noncanonical Wnt/planar cell polarity (PCP) pathway and the noncanonical Wnt/Ca2+ pathway [22 and 23]. Deregulation in Wnt signaling often results in catastrophic disorders including cancer. Overall, the downstream signaling events in Wnt recipient cells have been extensively studied and comprehensively reviewed in the last three decades [24]. However, it was not until recently that our knowledge began to accumulate about the complex upstream events that occur within Wnt producing cells that include biosynthesis, modifications, secretion and trafficking of Wnt

proteins (Figure 1) [23]. Before secretion, Wnt proteins undergo a complex series of posttranslational modifications Ketotifen including palmitoylation and glycosylation, which are important for Wnt functions [23 and 25]. Exit of Wnt from the endoplasmic reticulum (ER) is dependent on palmitoylation by Porcupine, a membrane-bound O-acyl-transferase [23 and 25] and the family of p24 proteins that subsequently help transport Wnts from the ER to the Golgi network [26 and 27]. In the Golgi, the multispan transmembrane protein Eveness interrupted (Evi)/Wntless (Wls) binds Wnt through the palmitate modification and facilitates the sorting of Wnts to the plasma membrane [28, 29, 30 and 31]. In addition, the activity of V-ATPase, a proton pump essential for vacuolar acidification, is required for the secretion of Wnt from producing cells [32]. Many questions remain outstanding with regards to the molecular and cellular mechanisms that regulate the extracellular transport and gradient formation of Wnt proteins [23].