_:b69440109 . _:b69440207 . _:b69440110 . _:b637304200 . . _:b69440101 "approaches combining developmental biology and pediatric oncology of the sympathoadrenal system have been published in the past 50\u00A0years, and may still provide novel hints for new molecular targets for diagnosis and treatment of NB [>>15<<\u201320]." . _:b69440135 "of sympathetic and vagal NC has revealed that the emigrating cells are capable to adapt to their new environment, and can produce both cholinergic parasympathetic and adrenergic sympathetic neurons depending on the environment [30, >>31<<, 40]. Thereby, the fate of NC cells is determined by signaling molecules; however, these molecules vary between species [33]." . _:b69440111 . _:b637304196 . _:b69440204 . _:b637304197 . _:b69440204 . _:b637304198 . _:b637304199 . _:b69440104 . _:b637304192 . _:b637304193 . _:b637304194 . _:b637304195 . _:b69440105 . _:b69440091 "tumors with unfavorable prognosis to localized, well-differentiated, Schwann cell stroma-rich tumors with good response to mild chemotherapy or differentiating agents such as retinoic acid, and excellent prognosis (reviewed by [>>4<<\u20136])." . _:b69440106 . _:b69440107 . _:b69440143 _:b69440152 . _:b69440143 _:b69440153 . _:b69440143 _:b69440154 . _:b69440143 _:b69440155 . _:b69440116 . _:b69440111 "However, deregulation of WNT signaling is the cause of various types of cancer (reviewed by [>>48<<, 57, 58]), but also neurodegenerative diseases such as Alzheimer\u2019s and Parkinson\u2019s disease, and WNT pathways are therefore receiving increasing attention in the overlapping fields of oncology and neurosciences [59\u201361]." . _:b69440143 _:b69440156 . _:b69440143 _:b69440157 . _:b69440143 _:b69440158 . _:b69440143 _:b69440159 . _:b69440117 . _:b69440179 . _:b69440143 _:b69440144 . _:b69440143 _:b69440145 . _:b69440202 . _:b69440143 _:b69440146 . _:b69440122 "embryonic development of the sympathoadrenal\u00E2\u0080\u0093paraganglionic system" . _:b69440143 _:b69440147 . _:b69440118 . _:b69440143 _:b69440148 . . _:b69440143 _:b69440149 . _:b69440143 _:b69440150 . _:b69440113 "However, deregulation of WNT signaling is the cause of various types of cancer (reviewed by [48, 57, >>58<<]), but also neurodegenerative diseases such as Alzheimer\u2019s and Parkinson\u2019s disease, and WNT pathways are therefore receiving increasing attention in the overlapping fields of oncology and neurosciences [59\u201361]." . _:b69440210 . _:b69440143 _:b69440151 . _:b69440119 . _:b69440149 . _:b69440193 "Other groups, using RNA-seq, found FZD4 readily expressed in NB cell-lines [85, >>105<<]. This discrepancy is puzzling, and further careful studies have to reveal the status of FZD4 expression at RNA and protein levels." . _:b69440112 . . _:b69440113 . . _:b69440103 "In the human, 19 WNT ligands are known so far, which are secreted in a distinct temporal and spatial order, thereby regulating cell proliferation, survival, migration, polarity, and the fate of stem cells [>>47<<, 48]. The large numbers of membrane-bound receptors and co-receptors, as well as soluble receptors, which have been identified by now, generate\u00A0 high\u00A0complexity of the signaling pathway (reviewed by [49])." . _:b69440114 . _:b69440115 . _:b69440195 . . _:b69440124 . . . _:b69440125 . . _:b69440100 . _:b69440126 . _:b69440165 "in human primary NB was published in 2005, when Blanc and co-workers observed that local xenografts of human IGR-N-91 NB cells in mice exhibited higher WNT5A expression than bone marrow and cardiac metastases of the grafted cells [>>83<<]. They also found increased WNT5A mRNA levels in primary human NB samples with favorable outcome." . _:b69440127 . _:b69440160 . . _:b69440120 . _:b69440206 . . _:b69440121 . _:b69440143 _:b69440160 . _:b69440180 . _:b69440143 _:b69440161 . . _:b69440122 . _:b69440214 "An overview considering targets, signaling molecules and risk factors of the WNT pathways is provided by recent reviews [>>57<<, 59, 121]." . _:b69440092 . . _:b69440194 . _:b69440172 "There is evidence that FZD1, a WNT receptor dedicated to the \u03B2-catenin pathway, mediates the expression of the multidrug-resistance-protein 1 (MDR1) efflux-transporter that confers drug resistance to tumor cells [>>89<<]. Knockdown of FZD1 decreases MDR1 expression and restores chemo-sensitivity in resistant cell lines. Also in these experiments, TCF/LEF-mediated activation of target transcription could not be detected, and suggests the existence of an" . _:b69440123 . . _:b69440132 . . _:b69440181 _:b69440182 . _:b69440181 _:b69440183 . _:b69440133 . _:b69440181 _:b69440184 . _:b69440181 _:b69440185 . _:b69440181 _:b69440186 . _:b69440181 _:b69440187 . _:b69440134 . _:b69440181 _:b69440188 . . _:b69440110 "share key switches, thereby influencing each other and building a dense meshwork of signaling routes that allow spatial and temporal specification of cell fate by variable interactions between the three main pathways (reviewed by [47, >>56<<])." . _:b69440181 _:b69440189 . _:b69440121 "N notochord (chorda dorsalis). Bar\u00A0=\u00A0100\u00A0\u00B5m. Republished from [>>123<<] with permission; license no.:" . _:b69440181 _:b69440190 . . _:b69440181 _:b69440191 . _:b69440135 . _:b69440106 "However, WNT ligands were also shown to act via interconnected intracellular networks, depending on the cellular context [>>50<<\u201352]. In addition, the cellular repertoire of Frizzled (FZD1-10) receptor-family members with divers co-receptors seems to determine, which of the WNT signaling branches are activated. Roughly, interaction of WNTs with FZD members and LRP5" . _:b69440128 . _:b69440100 "Despite initially successful therapy, these patients frequently suffer from relapse, and die because of metastasis formation and resistance to chemotherapy (reviewed by [>>14<<]). However, although MYCN amplification is a potent predictor of disease outcome, it affects only about 25% of the patients, illustrating the urgent need for new diagnostic markers and therapeutic targets in NB. Thereby, interdisciplinary" . _:b69440129 . _:b69440171 . _:b69440192 "Other groups, using RNA-seq, found FZD4 readily expressed in NB cell-lines [>>85<<, 105]. This discrepancy is puzzling, and further careful studies have to reveal the status of FZD4 expression at RNA and protein levels." . _:b69440130 . . _:b69440134 . _:b69440131 . _:b69440162 . _:b69440165 . _:b69440140 . _:b69440141 . _:b69440181 . _:b69440120 . _:b69440142 . . _:b69440197 . _:b69440182 "The functional homologues LGR4 and LGR5 are G-protein-coupled receptors that bind R-spondins, and thereby amplify \u03B2-catenin-dependent WNT signaling [>>99<<] (Fig.\u00A04). In HEK293 (human embryonic kidney cell-line), LGR5 is co-internalized with FZD5 upon stimulation with WNT3A [100]." . _:b637304198 . _:b69440143 . . _:b69440136 . _:b69440143 . . . _:b69440149 "Sympathetic neuron development and formation of ganglia is, as mentioned above, rather induced by BMPs from the dorsal aorta (reviewed by [>>30<<, 71]). In mice, BMP induces the expression of transcription factors such as MASH1 and PHOX2A, and thereby converts sympathetic neuroblasts into mature sympathetic neurons. There is, however, evidence that the Fzd3 receptor may be involved" . _:b69440137 . _:b69440127 "For the cranial NC a role for WNT signaling has clearly been shown, however, the developmental potential of the cranial NC differs significantly from the other areas by forming connective and skeletal tissues [28, 29, >>32<<].Fig." . _:b69440138 . . . _:b69440139 . _:b69440162 _:b69440168 . _:b69440148 . _:b69440162 _:b69440169 . _:b69440148 "Trunk NC cells that form the dorsal root ganglia express neurotrophin and WNT receptors, and respond to NT3 and WNT from the dorsal neural tube [41, >>42<<]. There is evidence that WNT signaling is also involved in NC cell migration into more ventral regions of the embryo. However, development of the sympathetic trunk ganglia seems not to be driven by WNT signals in the first instance." . _:b69440162 _:b69440170 . . _:b69440162 _:b69440164 . _:b69440149 . . _:b69440162 _:b69440165 . . _:b69440162 _:b69440166 . _:b69440162 _:b69440167 . _:b69440156 "Only recently, a similar function of Wnt5a has been shown for the dendritic branching of Purkinje cells in the cerebellum of mice [>>78<<]. The induction of target innervation by WNT5A has been shown to depend strongly on the presence of ROR tyrosine-kinase receptors, as ROR1/2 neutralizing antibodies inhibit target innervation in mice [79]. Application of WNT5A to cultured" . _:b69440150 . . _:b69440162 _:b69440163 . _:b69440151 . _:b69440214 . _:b69440144 . _:b69440213 "Recently, a group demonstrated that WNT inhibitory factor 1 (WIF1) is silenced by hyper-methylation in NB cell lines [>>120<<]. Restoration of WIF1 expression inhibited proliferation and caused down-regulation of\u00A0\u03B2-catenin and its\u00A0transcriptional targets. So far, WNT signaling can be targeted by several drugs, such as porcupine inhibitors that prevent WNT" . _:b69440145 . _:b69440102 . _:b69440146 . _:b69440091 . _:b69440147 . _:b69440171 _:b69440172 . _:b69440204 . _:b69440156 . _:b69440171 _:b69440173 . _:b69440171 _:b69440174 . _:b69440171 _:b69440175 . . _:b69440122 . . _:b69440157 . _:b69440195 "Thereby, loss of genetic material can be observed at chromosomes 1p and 11q, whereas gain of genes can be found at chromosomes 11p and 17q [>>4<<, 14]. A recent study revealed that loss in 1p and 11q is more frequently found in metastases and relapsed tumors than in primary tumors, underlining the importance of the two chromosomal locations for NB [106]. They and others found" . _:b69440208 "Inhibition of TNKS1 with XAV939 stabilizes this complex and increases \u03B2-catenin destruction, which prevents WNT/\u03B2-catenin-signaling [>>115<<, 116]. The loss of \u03B2-catenin reduces NB growth and increases apoptosis (Fig.\u00A04). Another group very recently found increased sensitivity to doxorubicin in SH-SY5Y cells after treatment with XAV939 [117]. Doxorubicin is a standard drug in" . _:b69440117 . _:b69440158 . _:b69440181 _:b69440192 . _:b69440159 . _:b69440162 "wnt signaling in neuroblastoma" . _:b69440115 . _:b69440132 "Repulsive proteins such as ephrinB1/EphB2 and semaphorin-3F are expressed in the posterior (caudal) sclerotome halves preventing NC cells with appropriate Eph- or neuropilin-2-receptors on their surface from entering [35, 36, >>37<<]. In the anterior sclerotome, thrombospondin is expressed, which allows and promotes NC cells to enter this compartment [38]. Some of the immigrating cells differentiate within the sclerotome and become sensory neurons and glial cells of" . _:b69440181 _:b69440193 . _:b69440119 . _:b69440152 . _:b69440079 . _:b69440171 _:b69440176 . _:b69440153 . _:b69440171 _:b69440177 . _:b69440171 _:b69440178 . _:b69440171 _:b69440179 . _:b69440171 _:b69440180 . _:b69440118 "Interestingly, this is the location where the majority of primary NBs develop [>>3<<]." . _:b69440154 . _:b69440217 . . _:b69440098 . _:b69440171 "wnt signaling and neuroblastoma therapy resistance" . _:b69440206 _:b69440220 . _:b69440146 . _:b69440155 . . _:b69440206 _:b69440216 . _:b69440164 . _:b69440206 _:b69440217 . _:b69440206 _:b69440218 . _:b69440206 _:b69440219 . _:b69440206 _:b69440212 . _:b69440165 . _:b69440206 _:b69440213 . _:b69440084 . _:b69440206 _:b69440214 . _:b69440206 _:b69440215 . _:b69440206 _:b69440208 . _:b69440166 . _:b69440206 _:b69440209 . _:b69440206 _:b69440210 . _:b69440206 _:b69440211 . _:b69440086 . _:b69440167 . _:b69440170 "They observed that NB cells depend on a strictly balanced WNT signaling to direct their behavior towards proliferation, anti-apoptosis and metastasis, or differentiation [>>85<<]. Imbalance induced by both massive inhibition and massive activation of WNT signaling will induce abnormal cell behavior. This angle of view seems to explain many puzzling findings on NB-WNT signaling provided so far." . _:b69440206 _:b69440207 . _:b69440160 . . _:b69440161 . _:b69440190 "Moreover, a BMP gradient seems to attract sympathetic precursors to the adrenal medulla [30, 44, >>45<<]. Norrin, an antagonist of BMP-signaling, has been shown to act via LGR4 and FZD4 [104]. Binding of Norrin to LGR5 has also been shown; however, no activation of \u03B2-catenin-dependent signaling could be detected. Even though we could not" . _:b69440162 . _:b69440194 _:b69440204 . _:b69440163 . _:b69440194 _:b69440205 . _:b69440194 _:b69440200 . _:b69440172 . _:b69440194 _:b69440201 . _:b69440194 _:b69440202 . _:b69440194 _:b69440203 . _:b69440194 _:b69440196 . _:b69440173 . _:b69440194 _:b69440197 . _:b69440117 . _:b69440194 _:b69440198 . _:b69440194 _:b69440199 . _:b69440174 . _:b69440146 "Both promote actin rearrangement, leading to lamellipodia and growth cone formation (Rac1), or induce stress fibres and stabilization of focal adhesion contacts needed for migration [>>66<<\u201370]. Trunk NC cells that form the dorsal root ganglia express neurotrophin and WNT receptors, and respond to NT3 and WNT from the dorsal neural tube [41, 42]. There is evidence that WNT signaling is also involved in NC cell migration into" . _:b69440145 . _:b69440194 _:b69440195 . _:b69440175 . _:b69440168 . . _:b69440169 . _:b69440170 . . _:b69440210 "Another group very recently found increased sensitivity to doxorubicin in SH-SY5Y cells after treatment with XAV939 [>>117<<]. Doxorubicin is a standard drug in NB treatment, and resistance a major problem. DKK1 knockdown in cell lines led to increased sensitivity to doxorubicin [118]. In patients with metastatic NB, high DKK1 serum levels correlate with poor" . _:b69440171 . _:b69440131 "Repulsive proteins such as ephrinB1/EphB2 and semaphorin-3F are expressed in the posterior (caudal) sclerotome halves preventing NC cells with appropriate Eph- or neuropilin-2-receptors on their surface from entering [35, >>36<<, 37]. In the anterior sclerotome, thrombospondin is expressed, which allows and promotes NC cells to enter this compartment [38]. Some of the immigrating cells differentiate within the sclerotome and become sensory neurons and glial cells" . _:b69440180 . . _:b69440203 "DKK1 and DKK3 were shown to correlate with NB maturation by acting as inhibitors of NB cell differentiation [109, >>110<<]. Both are down-regulated by MYCN, most likely via miRNA-mediated mRNA degradation [109\u2013112]. Expression profiling reveals that the homeobox-domain protein MSX1, which is involved in NC development, induces DKK1-3 and SFRP1 in NB, and its" . _:b69440181 . _:b69440126 "For the cranial NC a role for WNT signaling has clearly been shown, however, the developmental potential of the cranial NC differs significantly from the other areas by forming connective and skeletal tissues [>>28<<, 29, 32].Fig." . _:b69440152 "Notably, TRK-A, the receptor for NGF, is a favorable prognostic marker in NB ([>>73<<, 74]. However, these neurons still lack the key sympatho-adrenergic enzymes tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH), which are induced when the axons reach their target organs. NGF, released from the target tissues," . _:b69440174 . _:b69440182 . _:b69440101 . _:b69440183 . _:b69440121 . _:b69440219 "High-throughput methods will help identify new targets [93, 106, 107, >>120<<, 122]." . _:b69440176 . _:b69440087 "from highly migratory, sympathoadrenal progenitor cells from the neural crest that migrate long distances and form the adrenal medulla, paraganglia, as well as paravertebral and prevertebral sympathetic ganglia (for review see: [2, >>3<<]). It is commonly accepted to refer to NB as an embryonic tumor [1, 3], which becomes evident when looking at the patient\u2019s age." . _:b69440108 . _:b69440099 . _:b69440177 . _:b69440173 "of target transcription could not be detected, and suggests the existence of an alternative pathway to the transcriptional activation through nuclear \u03B2-catenin, probably via \u2018developmental\u2019 transcription factors such as SOX and FOXO [>>89<<]." . _:b69440178 . . _:b69440179 . . . _:b69440132 . _:b69440188 . _:b69440159 "However, in vertebrates, Wnt5a/Ror1/2 signaling widely overlaps with the PCP pathway, while Wnt5a/Ryk can be involved in both PCP and WNT\u2013Ca2+ signaling (reviewed in [>>49<<]). Our expression analyses of 25 NB cell lines show that either ROR1 or ROR2 is found in virtually every cell line, and RYK in fact is expressed in every cell line tested, strengthening the hypothesis of an involvement of ROR1/2 and RYK" . _:b69440189 . _:b69440207 "Very recently, FZD2 has been shown to interact with WNT5A and WNT3A, thereby activating \u2018canonical\u2019 and \u2018non-canonical\u2019 WNT signaling in NB cells [>>114<<]. Knockdown of FZD2 was shown to suppress the growth of mouse xenograft NB and reduce tumor angiogenesis." . _:b69440190 . _:b69440191 . . _:b69440184 . _:b69440185 "In NB cell lines, co-stimulation with WNT3A and R-spondins strongly activated TCF/LEF reporter-gene constructs, and LGR5 knock-down by siRNA inhibited this reaction [>>102<<]. Additionally, the same authors observed induction of apoptosis upon LGR5 knock-down in NB cell lines. Meta-analyses of micro-array data from primary NB revealed increased expression of LGR5 in MYCN-amplified tumors, and positive" . _:b69440185 . _:b69440144 "This initiation requires FGF, retinoic acid and WNT signals (for review see [>>62<<]). The second major event is the maintenance of NC cells during neurulation of the embryo by BMP and WNT signaling. Transcription factors such as Snail2, FoxD3, Sox9/10, Twist, cMYC, and AP2 are highly constant markers for NC cells from" . . _:b69440186 . _:b69440102 "wnt signaling" . . _:b69440130 . . _:b69440187 . . . _:b69440196 . _:b69440176 "High HIF expression in neuroblastoma cells promotes an undifferentiated state with stem-like phenotype [>>88<<, 95], and correlates with poor prognosis [96]." . _:b637304193 . _:b69440197 . _:b69440198 . _:b69440185 . _:b69440199 . _:b69440192 . _:b69440193 . _:b69440168 "low-risk NB, but found higher \u03B2-catenin levels and more nuclear \u03B2-catenin in MYCN non-amplified cell lines [>>86<<]. In our expression analyses, WNT5A was detectable in 16 out of 25 cell lines and there was no difference between MYCN-amplified and MYCN-non-amplified cell lines (Table\u00A01). However, the cell lines are commonly derived from progressed NB" . . _:b69440194 . . _:b69440195 . _:b69440197 "A recent study revealed that loss in 1p and 11q is more frequently found in metastases and relapsed tumors than in primary tumors, underlining the importance of the two chromosomal locations for NB [>>106<<]. They and others found mutations accumulating in ALK, and especially in the RAS/MAPK-signaling pathway [107]. However, this does not exclude that the complete loss of WNT pathway genes in 1p or 11q may also be of relevance for NB" . _:b69440204 . _:b69440205 . _:b69440178 . _:b69440133 . _:b69440147 "Trunk NC cells that form the dorsal root ganglia express neurotrophin and WNT receptors, and respond to NT3 and WNT from the dorsal neural tube [>>41<<, 42]. There is evidence that WNT signaling is also involved in NC cell migration into more ventral regions of the embryo. However, development of the sympathetic trunk ganglia seems not to be driven by WNT signals in the first instance." . _:b69440206 . _:b69440153 "Notably, TRK-A, the receptor for NGF, is a favorable prognostic marker in NB ([73, >>74<<]. However, these neurons still lack the key sympatho-adrenergic enzymes tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH), which are induced when the axons reach their target organs. NGF, released from the target tissues," . . _:b69440207 . . _:b69440155 . _:b69440200 . _:b69440206 "wnt pathways as a therapeutic target" . _:b69440201 . _:b69440081 "Our expression data (Table\u00A01) support the possibility of \u03B2-catenin-independent WNT signaling in NB cell lines, as shown earlier [83, >>84<<, 113, 114]." . . _:b69440202 . _:b69440128 "Some of them may already be pre-determined when they leave the neural tube, however, differentiation is also regulated by environmental signals the cells receive during their migratory route (recently reviewed by [>>33<<]). There are two major pathways NC cells can take (Fig.\u00A03). The first, called the dorsolateral pathway, enables cells to migrate between epidermis and dermal mesenchyme. Cells following this route will finally invade the epidermis and" . _:b69440203 . _:b69440144 . . _:b69440212 . _:b69440140 . . _:b69440213 . . . . _:b69440214 . _:b637304196 . _:b69440090 "Even more strikingly, at the age of 10\u00A0years, more than 98% of NBs have been presented clinically [>>1<<]. Histologically and clinically, NBs present heterogeneously, spanning from poorly differentiated, highly proliferative, metastasizing and chemotherapy-resistant tumors with unfavorable prognosis to localized, well-differentiated, Schwann" . _:b69440215 . . _:b69440208 . _:b69440209 . _:b69440189 "Moreover, a BMP gradient seems to attract sympathetic precursors to the adrenal medulla [>>30<<, 44, 45]. Norrin, an antagonist of BMP-signaling, has been shown to act via LGR4 and FZD4 [104]. Binding of Norrin to LGR5 has also been shown; however, no activation of \u03B2-catenin-dependent signaling could be detected. Even though we" . _:b69440210 . _:b69440216 . _:b69440202 "DKK1 and DKK3 were shown to correlate with NB maturation by acting as inhibitors of NB cell differentiation [>>109<<, 110]. Both are down-regulated by MYCN, most likely via miRNA-mediated mRNA degradation [109\u2013112]. Expression profiling reveals that the homeobox-domain protein MSX1, which is involved in NC development, induces DKK1-3 and SFRP1 in NB," . _:b69440211 . _:b69440140 "Upon arrival, their differentiation into sympathetic neurons is blocked by the exposure to glucocorticoids (cortisol) from the adrenal cortex, and they form (nor)adrenalin-producing chromaffin cells [31, >>39<<, 43]. When adrenal cortex is ectopically induced in the embryo by the over-expression of SF1/ZFM 162 (splicing factor 1/zinc finger protein 162), adrenomedullary precursors are attracted to this site [44, 45]." . _:b69440220 . _:b69440155 "Failure of target innervation due to loss of NGF, TRK-A, or WNT5A leads to increased apoptosis and loss of sympathetic neurons [>>75<<\u201377]. Only recently, a similar function of Wnt5a has been shown for the dendritic branching of Purkinje cells in the cerebellum of mice [78]. The induction of target innervation by WNT5A has been shown to depend strongly on the presence of" . _:b69440161 . . _:b69440187 . _:b69440080 . _:b69440216 . . _:b69440204 . _:b69440188 "As mentioned above, migrating sympathetic neuroblasts require BMP from the dorsal aorta to differentiate into postganglionic neurons during formation of sympathetic ganglia [39, >>43<<]. Moreover, a BMP gradient seems to attract sympathetic precursors to the adrenal medulla [30, 44, 45]. Norrin, an antagonist of BMP-signaling, has been shown to act via LGR4 and FZD4 [104]. Binding of Norrin to LGR5 has also been shown;" . _:b69440217 . . _:b69440218 . _:b69440129 . _:b69440153 . _:b69440160 "The functions of ROR and RYK were recently reviewed in detail by Green and coworkers [>>80<<].Table" . _:b69440142 "When adrenal cortex is ectopically induced in the embryo by the over-expression of SF1/ZFM 162 (splicing factor 1/zinc finger protein 162), adrenomedullary precursors are attracted to this site [44, >>45<<]." . . _:b69440219 . _:b69440139 "Upon arrival, their differentiation into sympathetic neurons is blocked by the exposure to glucocorticoids (cortisol) from the adrenal cortex, and they form (nor)adrenalin-producing chromaffin cells [>>31<<, 39, 43]. When adrenal cortex is ectopically induced in the embryo by the over-expression of SF1/ZFM 162 (splicing factor 1/zinc finger protein 162), adrenomedullary precursors are attracted to this site [44, 45]." . . _:b69440157 . _:b69440101 . _:b69440175 . _:b69440096 "taking into account that despite metastases to skin, liver, and to a low extend, also to bone marrow, these tumors are in most cases well curable by mild chemotherapy and application of differentiating agents such as retinoids [>>4<<, 10]. In general, localized tumors in young patients are highly prone to spontaneous differentiation and regression." . _:b69440088 . _:b69440175 "Very recent expression analyses show that DKK1 and FZD7 are inversely regulated by MYCN and RA, and may be part of the RA-induced differentiation signaling cascade [>>93<<]. Failure of differentiation therapy with retinoids may also be due to increased levels of HIF1/2\u03B1, which activate \u03B2-catenin-dependent WNT signaling, and thereby promote proliferation and metastasis formation [94]. High HIF expression in" . _:b69440114 . . _:b69440090 . _:b69440203 . _:b69440113 . _:b69440085 . . . _:b69440131 . _:b69440101 . _:b69440092 "Classically, NB are staged into five groups (1\u20134, and 4S) according to localization, lymph node involvement, and metastasis formation [>>7<<, 8]. Currently, classification is about to change into a system considering a variety of risk factors, with the\u00A0aim to facilitate the comparison of different national studies." . . . _:b69440079 "conclusions" . _:b69440125 . _:b69440123 "postganglionic sympathetic neurons and chromaffin cells emigrate from the neural crest (NC). Along the craniocaudal axis, the NC can be subdivided into different areas: cranial, cardiac, vagal, sympathetic, adrenal and sacral (Fig.\u00A02) [>>28<<, 29]. Sympathoadrenal progenitors develop in specific trunk regions, and are often referred to as trunk NC." . . _:b69440091 . _:b69440182 . _:b69440156 . _:b637304197 "2"^^ . _:b69440158 . _:b637304196 "2"^^ . _:b637304199 "2"^^ . . _:b69440186 "Meta-analyses of micro-array data from primary NB revealed increased expression of LGR5 in MYCN-amplified tumors, and positive correlation with adverse outcome [>>103<<]. Our expression analyses confirm LGR5 expression only in some NB cell lines, whereas in the majority of cells it is completely absent. However, its functional homologue LGR4 could be detected in all cell lines to variable extend (Table" . _:b637304198 "2"^^ . _:b69440205 . _:b69440125 "Of note, the trunk NC cells not only form sympathetic neurons and chromaffin cells, but also glial cells, as well as sensory neurons of the dorsal root ganglia, and melanocytes [30, >>31<<]. For the cranial NC a role for WNT signaling has clearly been shown, however, the developmental potential of the cranial NC differs significantly from the other areas by forming connective and skeletal tissues [28, 29, 32].Fig." . _:b69440105 . _:b69440155 . _:b637304193 "2"^^ . _:b69440154 . . _:b637304192 "3"^^ . _:b637304195 "2"^^ . _:b637304194 "2"^^ . . _:b69440211 . . _:b69440158 "WNT5A to cultured mouse sympathetic chain ganglia neither affected \u03B2-catenin-dependent WNT signaling nor JNK- and c-Jun-dependent PCP signaling, but induced strong phosphorylation of PKC, a key player in the Ca2+-dependent WNT pathway [>>75<<]. These findings imply that WNT5A may signal via ROR1/2 co-receptors and finally affects the WNT\u2013calcium pathway." . _:b69440088 "It is commonly accepted to refer to NB as an embryonic tumor [>>1<<, 3], which becomes evident when looking at the patient\u2019s age." . _:b69440083 . _:b69440080 "Our expression data (Table\u00A01) support the possibility of \u03B2-catenin-independent WNT signaling in NB cell lines, as shown earlier [>>83<<, 84, 113, 114]." . _:b637304200 "2"^^ . _:b69440201 "This may be enhanced by increased expression of LGR4 as discussed above [>>99<<] (Fig.\u00A04). Decreasing expression of \u03B2-catenin-independent signaling molecules ROR1 and VANGL1, which are located in loss-prone regions, may also contribute to this shift. However, DKK3, which is also located in a gain location and is an" . . _:b69440141 "Upon arrival, their differentiation into sympathetic neurons is blocked by the exposure to glucocorticoids (cortisol) from the adrenal cortex, and they form (nor)adrenalin-producing chromaffin cells [31, 39, >>43<<]. When adrenal cortex is ectopically induced in the embryo by the over-expression of SF1/ZFM 162 (splicing factor 1/zinc finger protein 162), adrenomedullary precursors are attracted to this site [44, 45]." . _:b69440142 . _:b69440114 . "10.1007%2Fs00018-017-2685-8" . _:b69440137 "Sympathoadrenal precursor cells that continue their way through the sclerotomes to form sympathetic ganglia and the adrenal medulla do not express receptors for WNTs, NT3, Delta or Notch [>>41<<, 42]. Therefore, the transient absence rather than the presence of WNT signaling seems to correlate with their normal development. Their differentiation is dependent on the exposure to bone morphogenetic protein (BMP) from the dorsal" . _:b69440115 "the sympathoadrenal\u00E2\u0080\u0093paraganglionic system" . _:b69440124 . _:b69440180 "Inhibition of HIF was shown to shift cells into a more differentiated expression profile, and enhance differentiation of NB cells by retinoids [97, >>98<<]. This effect seems to be associated with inhibition of the WNT/\u03B2-catenin signaling pathway, or a significant disturbance of the WNT balance in malignant cells." . . _:b69440199 "As mentioned above, this seems to be in conflict with recently published RNAseq data, and further studies should pay special attention to this discrepancy [>>85<<, 105]. However, we speculate that loss of functional FZD4, either by mutation or chromosomal loss could be a common feature of NB cells and a key event in NB genesis.Table" . _:b69440143 "wnt signaling and the neural crest" . _:b69440152 . _:b69440200 . _:b69440190 . _:b69440108 . _:b69440101 . _:b69440209 . . _:b69440181 "unorthodox wnt signaling in neuroblastoma" . _:b69440146 . _:b69440112 "However, deregulation of WNT signaling is the cause of various types of cancer (reviewed by [48, >>57<<, 58]), but also neurodegenerative diseases such as Alzheimer\u2019s and Parkinson\u2019s disease, and WNT pathways are therefore receiving increasing attention in the overlapping fields of oncology and neurosciences [59\u201361]." . _:b69440146 . . _:b69440151 "that the Fzd3 receptor may be involved in the expansion of neuroblasts and keeps them in a premature proliferative state, but ligands and signaling cascades have not been identified yet, except that \u03B2-catenin seems not to be involved [>>72<<]." . _:b69440196 "Thereby, loss of genetic material can be observed at chromosomes 1p and 11q, whereas gain of genes can be found at chromosomes 11p and 17q [4, >>14<<]. A recent study revealed that loss in 1p and 11q is more frequently found in metastases and relapsed tumors than in primary tumors, underlining the importance of the two chromosomal locations for NB [106]. They and others found mutations" . _:b69440196 . _:b69440177 . _:b69440146 . _:b69440155 . _:b69440096 . _:b69440193 . _:b69440147 . . _:b69440167 "interaction studies in NB, melanoma and colorectal carcinoma, and provided data that correlate high WNT3A, WNT5A, APC, or FZD10 expression with longer event-free survival, while high WNT3 or FZD1 indicates less favorable outcome [>>85<<]. This group also pointed out to interactions between WNT signaling and MYCN activity at various levels, and provided a gene signature based on the WNT pathway, which may improve risk stratification for NB patients." . . _:b69440123 . . _:b69440166 . _:b69440112 . _:b69440108 "Even though the division into three distinct pathways initially suggested independence of each pathway, it is becoming increasingly evident that WNT signaling is not linear and does not fit in this \u2018simple\u2019 scheme [>>53<<\u201355]. Instead, some WNT ligands can bind to more than one receptor, and several receptors bind more than one WNT ligand. Additionally, downstream signaling cascades share key switches, thereby influencing each other and building a dense" . _:b69440183 "In HEK293 (human embryonic kidney cell-line), LGR5 is co-internalized with FZD5 upon stimulation with WNT3A [>>100<<]. LGR5 is regarded as a marker for tumor stem cells and has been shown to be up-regulated in highly tumorigenic primary NB cells, which are able to form tumor spheres in nude mice [101]. In NB cell lines, co-stimulation with WNT3A and" . _:b637304200 . _:b69440177 "High HIF expression in neuroblastoma cells promotes an undifferentiated state with stem-like phenotype [88, >>95<<], and correlates with poor prognosis [96]." . _:b69440219 . _:b69440127 . _:b69440126 . _:b69440114 "cancer (reviewed by [48, 57, 58]), but also neurodegenerative diseases such as Alzheimer\u2019s and Parkinson\u2019s disease, and WNT pathways are therefore receiving increasing attention in the overlapping fields of oncology and neurosciences [>>59<<\u201361]." . . _:b69440137 . _:b69440138 . . _:b637304197 . _:b69440085 "In Germany, NB accounts for 7% of childhood cancer cases, but is responsible for approx. 11% of cancer deaths in children [>>1<<]. It originates from highly migratory, sympathoadrenal progenitor cells from the neural crest that migrate long distances and form the adrenal medulla, paraganglia, as well as paravertebral and prevertebral sympathetic ganglia (for review" . _:b69440213 . _:b69440215 "An overview considering targets, signaling molecules and risk factors of the WNT pathways is provided by recent reviews [57, >>59<<, 121]. Clinical trials of WNT-targeting therapies\u00A0are underway for different solid tumor entities, and successful passing of these trials will probably make them interesting for NB therapy. Interactions between the MYCN and WNT pathways" . _:b637304196 . _:b69440166 "Notably, Dyberg et al. reported that high expression of VANGL2 and PRICKLE1 correlates with low-risk NB and reduced levels of active \u03B2-catenin [>>84<<]. Both VANGL2 and PRICKLE1 are key players of the (non-canonical) PCP-pathway. Inhibition of ROCK1/2, central molecules of PCP, increases PRICKLE1 expression and inhibits \u03B2-catenin pathway activity. This suggests a direct inhibition of" . _:b69440208 . _:b637304199 . _:b69440191 "Norrin, an antagonist of BMP-signaling, has been shown to act via LGR4 and FZD4 [>>104<<]. Binding of Norrin to LGR5 has also been shown; however, no activation of \u03B2-catenin-dependent signaling could be detected. Even though we could not detect FZD4 expression in any of our 25 NB cell-lines, it cannot be ruled out that a" . _:b69440129 "This pathway has been shown to depend on WNT signals [>>34<<]. The second route is called the ventral pathway." . _:b69440119 "The only exception are\u00A0the sympathetic axons that supply the dermal sweat glands, which are cholinergic [>>26<<]. Homovanillic acid and vanillylmandelic acid are degradation products of catecholamines, and they are commonly found enriched in the urine of NB patients [27]." . _:b637304198 . _:b69440089 . _:b69440083 "Our expression data (Table\u00A01) support the possibility of \u03B2-catenin-independent WNT signaling in NB cell lines, as shown earlier [83, 84, 113, >>114<<]. All cell lines we examined express WNT5A, 5B, or WNT11, but expression levels vary dramatically. Also, transcripts for receptors such as FZD5, ROR1, RYK, VANGL2, and PTK7 are present in almost all cell-lines, but in varying amounts." . _:b69440093 . _:b69440107 "However, WNT ligands were also shown to act via interconnected intracellular networks, depending on the cellular context [50\u2013>>52<<]. In addition, the cellular repertoire of Frizzled (FZD1-10) receptor-family members with divers co-receptors seems to determine, which of the WNT signaling branches are activated. Roughly, interaction of WNTs with FZD members and LRP5 or" . _:b637304193 . _:b637304192 . _:b69440094 "Here, the risk groups are divided into L1, L2, M and MS [>>5<<, 9]. However, both systems emphasize the special significance of tumors in children up to 18\u00A0months of age." . _:b637304195 . _:b637304194 . . . _:b69440179 "Inhibition of HIF was shown to shift cells into a more differentiated expression profile, and enhance differentiation of NB cells by retinoids [>>97<<, 98]. This effect seems to be associated with inhibition of the WNT/\u03B2-catenin signaling pathway, or a significant disturbance of the WNT balance in malignant cells." . _:b69440184 . _:b69440211 "DKK1 knockdown in cell lines led to increased sensitivity to doxorubicin [>>118<<]. In patients with metastatic NB, high DKK1 serum levels correlate with poor outcome, however, there was no difference between all NB patients and healthy controls, or between patients with or without metastases." . _:b69440141 . _:b69440087 . _:b69440209 "Inhibition of TNKS1 with XAV939 stabilizes this complex and increases \u03B2-catenin destruction, which prevents WNT/\u03B2-catenin-signaling [115, >>116<<]. The loss of \u03B2-catenin reduces NB growth and increases apoptosis (Fig.\u00A04). Another group very recently found increased sensitivity to doxorubicin in SH-SY5Y cells after treatment with XAV939 [117]. Doxorubicin is a standard drug in NB" . . _:b69440108 . _:b69440145 "Inhibition of either Snail or Rho expression disturbs the development of the NC [>>63<<\u201365]. Most likely, Wnt11 non-canonical signaling induces small GTPases such as Rac1 and RhoB. Both promote actin rearrangement, leading to lamellipodia and growth cone formation (Rac1), or induce stress fibres and stabilization of focal" . _:b69440150 "Sympathetic neuron development and formation of ganglia is, as mentioned above, rather induced by BMPs from the dorsal aorta (reviewed by [30, >>71<<]). In mice, BMP induces the expression of transcription factors such as MASH1 and PHOX2A, and thereby converts sympathetic neuroblasts into mature sympathetic neurons. There is, however, evidence that the Fzd3 receptor may be involved in" . _:b69440218 "High-throughput methods will help identify new targets [93, 106, >>107<<, 120, 122]." . _:b69440114 . . _:b69440082 "Our expression data (Table\u00A01) support the possibility of \u03B2-catenin-independent WNT signaling in NB cell lines, as shown earlier [83, 84, >>113<<, 114]. All cell lines we examined express WNT5A, 5B, or WNT11, but expression levels vary dramatically. Also, transcripts for receptors such as FZD5, ROR1, RYK, VANGL2, and PTK7 are present in almost all cell-lines, but in varying amounts." . _:b69440168 . _:b69440148 . _:b637304200 . . . _:b69440217 "High-throughput methods will help identify new targets [93, >>106<<, 107, 120, 122]." . _:b69440103 . _:b69440146 . _:b69440097 "taking into account that despite metastases to skin, liver, and to a low extend, also to bone marrow, these tumors are in most cases well curable by mild chemotherapy and application of differentiating agents such as retinoids [4, >>10<<]. In general, localized tumors in young patients are highly prone to spontaneous differentiation and regression." . . . . . _:b69440104 "In the human, 19 WNT ligands are known so far, which are secreted in a distinct temporal and spatial order, thereby regulating cell proliferation, survival, migration, polarity, and the fate of stem cells [47, >>48<<]. The large numbers of membrane-bound receptors and co-receptors, as well as soluble receptors, which have been identified by now, generate\u00A0 high\u00A0complexity of the signaling pathway (reviewed by [49])." . "PMC0" . . _:b69440109 . _:b69440139 . _:b69440161 "Expression of indicated transcripts was measured by real-time RT-PCR and calculated as relative expression values according to the \u0394\u0394CT method as described previously [>>124<<]. CHLA-20 was chosen as reference cell line (=\u00A01, bold) for all transcripts, except for ROR2 where IMR32 was chosen." . . _:b69440201 . _:b69440188 . _:b69440134 "Exchange of sympathetic and vagal NC has revealed that the emigrating cells are capable to adapt to their new environment, and can produce both cholinergic parasympathetic and adrenergic sympathetic neurons depending on the environment [>>30<<, 31, 40]. Thereby, the fate of NC cells is determined by signaling molecules; however, these molecules vary between species [33]." . _:b69440117 . _:b69440159 . _:b69440135 . _:b69440194 "chromosomal aberrations in neuroblastoma affect wnt signaling" . . . . _:b69440215 . _:b69440102 _:b69440112 . _:b69440099 "The basis for this type of tumor behavior seems to reside in a natural regression of sympathoadrenal tissue starting at 18\u00A0months of age [12, >>13<<]." . _:b69440102 _:b69440113 . _:b69440124 "Of note, the trunk NC cells not only form sympathetic neurons and chromaffin cells, but also glial cells, as well as sensory neurons of the dorsal root ganglia, and melanocytes [>>30<<, 31]. For the cranial NC a role for WNT signaling has clearly been shown, however, the developmental potential of the cranial NC differs significantly from the other areas by forming connective and skeletal tissues [28, 29, 32].Fig." . _:b69440095 "Here, the risk groups are divided into L1, L2, M and MS [5, >>9<<]. However, both systems emphasize the special significance of tumors in children up to 18\u00A0months of age." . _:b69440094 . . _:b69440102 _:b69440114 . _:b69440102 _:b69440108 . _:b69440102 _:b69440109 . _:b69440095 . _:b69440102 _:b69440110 . _:b69440102 _:b69440111 . _:b69440102 _:b69440104 . _:b69440138 "Sympathoadrenal precursor cells that continue their way through the sclerotomes to form sympathetic ganglia and the adrenal medulla do not express receptors for WNTs, NT3, Delta or Notch [41, >>42<<]. Therefore, the transient absence rather than the presence of WNT signaling seems to correlate with their normal development. Their differentiation is dependent on the exposure to bone morphogenetic protein (BMP) from the dorsal aorta," . _:b69440102 _:b69440105 . _:b69440102 _:b69440106 . _:b637304195 . _:b69440102 _:b69440107 . _:b69440157 "The induction of target innervation by WNT5A has been shown to depend strongly on the presence of ROR tyrosine-kinase receptors, as ROR1/2 neutralizing antibodies inhibit target innervation in mice [>>79<<]. Application of WNT5A to cultured mouse sympathetic chain ganglia neither affected \u03B2-catenin-dependent WNT signaling nor JNK- and c-Jun-dependent PCP signaling, but induced strong phosphorylation of PKC, a key player in the" . _:b69440091 . _:b69440102 _:b69440103 . . _:b69440174 . _:b69440109 "share key switches, thereby influencing each other and building a dense meshwork of signaling routes that allow spatial and temporal specification of cell fate by variable interactions between the three main pathways (reviewed by [>>47<<, 56])." . _:b69440220 . _:b69440136 "Thereby, the fate of NC cells is determined by signaling molecules; however, these molecules vary between species [>>33<<]. Cells stopping in the sclerotome to develop into glia and neurons of the dorsal root ganglia express WNT and neurotrophin receptors, and may already be pre-determined by WNTs and neurotrophin-3 (NT3) from the dorsal neural tube. Within" . _:b637304192 . _:b69440118 . _:b69440133 "of the aorta, where they give rise to sympathetic neurons and glial cells of the para-vertebral sympathetic trunk ganglia, but also to parasympathetic ganglia and enteric neurons depending on their position along the craniocaudal axis [>>39<<].Fig." . . _:b69440093 "Classically, NB are staged into five groups (1\u20134, and 4S) according to localization, lymph node involvement, and metastasis formation [7, >>8<<]. Currently, classification is about to change into a system considering a variety of risk factors, with the\u00A0aim to facilitate the comparison of different national studies." . _:b69440184 "LGR5 is regarded as a marker for tumor stem cells and has been shown to be up-regulated in highly tumorigenic primary NB cells, which are able to form tumor spheres in nude mice [>>101<<]. In NB cell lines, co-stimulation with WNT3A and R-spondins strongly activated TCF/LEF reporter-gene constructs, and LGR5 knock-down by siRNA inhibited this reaction [102]. Additionally, the same authors observed induction of apoptosis" . . _:b69440117 . . _:b69440198 "They and others found mutations accumulating in ALK, and especially in the RAS/MAPK-signaling pathway [>>107<<]. However, this does not exclude that the complete loss of WNT pathway genes in 1p or 11q may also be of relevance for NB etiology. We used a gene database search to identify prominent members of the WNT signaling pathway [108]." . _:b69440115 _:b69440120 . . _:b69440115 _:b69440121 . _:b69440145 . . . _:b69440136 . . _:b69440089 "It is commonly accepted to refer to NB as an embryonic tumor [1, >>3<<], which becomes evident when looking at the patient\u2019s age." . _:b69440115 _:b69440116 . _:b69440115 _:b69440117 . _:b69440115 _:b69440118 . . _:b69440115 _:b69440119 . _:b69440117 "In addition, the adrenal medulla hosts small groups of post-ganglionic neurons, as well as glia-like cells (sustentacular cells), and may therefore be considered a dual sympathetic ganglion [>>22<<\u201325]. Interestingly, this is the location where the majority of primary NBs develop [3]." . _:b69440176 . _:b69440122 _:b69440124 . _:b69440122 _:b69440125 . _:b69440097 . _:b69440122 _:b69440126 . . _:b69440101 . _:b69440122 _:b69440127 . . . _:b69440122 _:b69440123 . _:b69440128 . _:b69440122 _:b69440140 . . _:b69440122 _:b69440141 . _:b69440122 _:b69440142 . _:b69440106 . _:b69440122 _:b69440136 . _:b69440200 "As mentioned above, this seems to be in conflict with recently published RNAseq data, and further studies should pay special attention to this discrepancy [85, >>105<<]. However, we speculate that loss of functional FZD4, either by mutation or chromosomal loss could be a common feature of NB cells and a key event in NB genesis.Table" . . _:b69440122 _:b69440137 . _:b69440122 _:b69440138 . . _:b69440122 _:b69440139 . _:b69440169 . _:b69440167 . _:b69440122 _:b69440132 . _:b69440079 _:b69440080 . _:b69440079 _:b69440081 . . _:b69440122 _:b69440133 . _:b69440122 _:b69440134 . _:b69440183 . _:b69440079 _:b69440082 . _:b69440122 _:b69440135 . . _:b69440079 _:b69440083 . _:b69440122 _:b69440128 . _:b69440130 "Repulsive proteins such as ephrinB1/EphB2 and semaphorin-3F are expressed in the posterior (caudal) sclerotome halves preventing NC cells with appropriate Eph- or neuropilin-2-receptors on their surface from entering [>>35<<, 36, 37]. In the anterior sclerotome, thrombospondin is expressed, which allows and promotes NC cells to enter this compartment [38]. Some of the immigrating cells differentiate within the sclerotome and become sensory neurons and glial" . _:b69440122 _:b69440129 . _:b69440122 _:b69440130 . _:b69440151 . _:b69440122 _:b69440131 . _:b69440081 . _:b69440174 . _:b69440198 . . . _:b69440220 "High-throughput methods will help identify new targets [93, 106, 107, 120, >>122<<]." . . . _:b69440116 . _:b69440174 "Retinoids (RA) are standard drugs used for differentiation therapy in NB [>>90<<\u201392]. However, in MYCN-amplified high-risk tumors, differentiation therapy often fails." . . . _:b69440169 "In several mouse and human NB cell lines, a subpopulation of FZD6 expressing cells was shown to exhibit a highly tumorigenic \u2018stem-like\u2019 phenotype that disappears in FZD6-siRNA knock-down experiments [>>88<<]. Thereby, FZD6 expression correlates with activation of non-canonical WNT signaling, as shown by phosphorylation of JNK (jun kinase)." . _:b69440150 . _:b69440191 . . _:b69440098 "As only a small percentage of these tumors progresses to metastatic stages, medical intervention is no longer regarded as the first choice, instead observation and waiting (\u201Cwait and see\u201D) may be sufficient [>>11<<]. The basis for this type of tumor behavior seems to reside in a natural regression of sympathoadrenal tissue starting at 18\u00A0months of age [12, 13]." . . _:b69440145 . _:b69440079 . _:b69440189 . _:b69440186 . . _:b69440170 . _:b69440187 "As mentioned above, migrating sympathetic neuroblasts require BMP from the dorsal aorta to differentiate into postganglionic neurons during formation of sympathetic ganglia [>>39<<, 43]. Moreover, a BMP gradient seems to attract sympathetic precursors to the adrenal medulla [30, 44, 45]. Norrin, an antagonist of BMP-signaling, has been shown to act via LGR4 and FZD4 [104]. Binding of Norrin to LGR5 has also been" . _:b69440218 . _:b69440084 . _:b69440085 . _:b69440086 . _:b69440173 . _:b69440087 . _:b69440084 _:b69440100 . _:b69440084 _:b69440101 . . _:b69440172 . _:b69440080 . _:b69440084 _:b69440096 . _:b69440084 _:b69440097 . _:b69440084 _:b69440098 . _:b637304197 . _:b69440084 _:b69440099 . _:b69440081 . _:b637304194 . _:b69440082 . _:b69440105 "The large numbers of membrane-bound receptors and co-receptors, as well as soluble receptors, which have been identified by now, generate\u00A0 high\u00A0complexity of the signaling pathway (reviewed by [>>49<<])." . _:b69440101 . _:b69440163 "WNT pathway studies in NB were first conducted in the mouse cell line Neuro2a in the context of neurite outgrowth and differentiation [>>81<<, 82]. Although the studies added new and valuable information on WNT pathway mechanisms, they regarded NB cells as a neuronal model system, and not as a malignancy model. However, they provided evidence for WNT signaling in NB. The first" . _:b69440154 "NGF, released from the target tissues, binds to TRK-A on the axonal membrane and induces DBH, TH, and WNT5A transcription in ganglionic neurons [>>75<<]. NT3, also known as a TRK-A ligand, cannot substitute for NGF in this case. Endogenous WNT5A then promotes axon branching and subsequent innervation of multiple target cells in an autocrine manner (Fig.\u00A04). Failure of target innervation" . _:b69440083 . _:b69440084 _:b69440085 . _:b69440084 _:b69440086 . _:b637304199 . _:b69440084 _:b69440087 . _:b69440092 . . _:b69440093 . _:b69440084 _:b69440092 . _:b69440120 "Homovanillic acid and vanillylmandelic acid are degradation products of catecholamines, and they are commonly found enriched in the urine of NB patients [>>27<<]." . _:b69440084 _:b69440093 . _:b69440205 "Expression profiling reveals that the homeobox-domain protein MSX1, which is involved in NC development, induces DKK1-3 and SFRP1 in NB, and its expression correlates with good prognosis [>>113<<]. However, WNT5A and WNT3 signaling via DVL3 remained active, indicating the puzzling roles for soluble WNT inhibitors in NB." . _:b69440084 _:b69440094 . . . _:b69440084 _:b69440095 . _:b69440094 . _:b69440084 _:b69440088 . _:b69440084 _:b69440089 . _:b69440212 . . _:b69440084 _:b69440090 . _:b69440084 _:b69440091 . _:b69440095 . _:b69440204 "Both are down-regulated by MYCN, most likely via miRNA-mediated mRNA degradation [>>109<<\u2013112]. Expression profiling reveals that the homeobox-domain protein MSX1, which is involved in NC development, induces DKK1-3 and SFRP1 in NB, and its expression correlates with good prognosis [113]. However, WNT5A and WNT3 signaling via" . _:b69440088 . _:b69440089 . _:b69440090 . _:b69440091 . _:b69440100 . _:b69440116 "25%) cells are innervated by pre-ganglionic cholinergic neurons [>>16<<]. In addition, the adrenal medulla hosts small groups of post-ganglionic neurons, as well as glia-like cells (sustentacular cells), and may therefore be considered a dual sympathetic ganglion [22\u201325]." . _:b69440199 . _:b69440163 . _:b69440101 . _:b69440212 "Cytotoxic therapy might also be improved by combining chemotherapy with LiCl, an activator of the WNT/\u03B2-catenin pathway, as shown in cell culture experiments [>>119<<]. Recently, a group demonstrated that WNT inhibitory factor 1 (WIF1) is silenced by hyper-methylation in NB cell lines [120]." . _:b69440107 . _:b69440102 . _:b69440086 "from highly migratory, sympathoadrenal progenitor cells from the neural crest that migrate long distances and form the adrenal medulla, paraganglia, as well as paravertebral and prevertebral sympathetic ganglia (for review see: [>>2<<, 3]). It is commonly accepted to refer to NB as an embryonic tumor [1, 3], which becomes evident when looking at the patient\u2019s age." . _:b69440103 . _:b69440104 . . _:b69440110 . _:b69440164 "WNT pathway studies in NB were first conducted in the mouse cell line Neuro2a in the context of neurite outgrowth and differentiation [81, >>82<<]. Although the studies added new and valuable information on WNT pathway mechanisms, they regarded NB cells as a neuronal model system, and not as a malignancy model. However, they provided evidence for WNT signaling in NB. The first" . _:b69440192 . _:b69440096 . _:b69440216 "High-throughput methods will help identify new targets [>>93<<, 106, 107, 120, 122]." . _:b69440097 . _:b69440084 "neuroblastoma" . . _:b69440178 "High HIF expression in neuroblastoma cells promotes an undifferentiated state with stem-like phenotype [88, 95], and correlates with poor prognosis [>>96<<]. Inhibition of HIF was shown to shift cells into a more differentiated expression profile, and enhance differentiation of NB cells by retinoids [97, 98]. This effect seems to be associated with inhibition of the WNT/\u03B2-catenin signaling" . _:b69440111 . _:b69440098 . _:b69440082 . _:b69440099 . _:b69440164 . _:b69440108 .