Embryonal neural tumours and cell death

Johnsen, John Inge; Kogner, Per; Albihn, Ami; Henriksson, Marie Arsenian

doi:10.1007/s10495-009-0325-y

Cited by 58 publications

(49 citation statements)

References 145 publications

(193 reference statements)

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“…High-risk metastatic tumors frequently show amplified MYCN proto-oncogene, and overall patient survival is less than 50% (1,2). Progression of neuroblastoma is associated with expression of inflammatory factors (3), and intratumoral myeloid cells predict poor clinical outcome (4,5).…”

Section: Introductionmentioning

confidence: 99%

Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

Mao

Eißler

Blanc

et al. 2016

Clinical Cancer Research

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128

105

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Purpose: Neuroblastoma is the most common extracranial solid cancer type in childhood, and high-risk patients have poor prognosis despite aggressive multimodal treatment. Neuroblastoma-driven inflammation contributes to the induction of suppressive myeloid cells that hamper efficient antitumor immune responses. Therefore, we sought to enhance antitumor immunity by removing immunosuppression mediated by myeloid cells.Experimental

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Section: Introductionmentioning

confidence: 99%

Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

Mao

Eißler

Blanc

et al. 2016

Clinical Cancer Research

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128

105

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“…N euroblastoma is a childhood tumor of the peripheral sympathetic nervous system, causing 6% of all childhood cancers but 9% of deaths from malignant tumors in children (1,2). Approximately half of patients present with high-risk disease characterized by unresectable primary lesions and multiple metastases (2,3).…”

mentioning

confidence: 99%

Rho-associated kinase is a therapeutic target in neuroblastoma

Dyberg

Fransson

Andonova

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Neuroblastoma is a peripheral neural system tumor that originates from the neural crest and is the most common and deadly tumor of infancy. Here we show that neuroblastoma harbors frequent mutations of genes controlling the Rac/Rho signaling cascade important for proper migration and differentiation of neural crest cells during neuritogenesis. RhoA is activated in tumors from neuroblastoma patients, and elevated expression of Rho-associated kinase (ROCK)2 is associated with poor patient survival. Pharmacological or genetic inhibition of ROCK1 and 2, key molecules in Rho signaling, resulted in neuroblastoma cell differentiation and inhibition of neuroblastoma cell growth, migration, and invasion. Molecularly, ROCK inhibition induced glycogen synthase kinase 3β-dependent phosphorylation and degradation of MYCN protein. Small-molecule inhibition of ROCK suppressed MYCN-driven neuroblastoma growth in TH-MYCN homozygous transgenic mice and MYCN gene-amplified neuroblastoma xenograft growth in nude mice. Interference with Rho/Rac signaling might offer therapeutic perspectives for high-risk neuroblastoma.N euroblastoma is a childhood tumor of the peripheral sympathetic nervous system, causing 6% of all childhood cancers but 9% of deaths from malignant tumors in children (1, 2). Approximately half of patients present with high-risk disease characterized by unresectable primary lesions and multiple metastases (2, 3). Although survival in this group has improved, the majority of the tumors show resistance to therapy with poor patient survival despite intensive multimodal therapy, necessitating the search for new therapeutic options (2).Compared with adult tumors, pediatric cancers exhibit significantly fewer genomic aberrations and mutations. In neuroblastoma, somatically acquired amplification of MYCN, hemizygous deletions of 1p and 11q, and gain of 17q are the most common chromosomal aberrations associated with a poor prognosis (3). Exome-and whole-genome sequencing analysis of neuroblastoma has reported an overall low somatic mutation count (12 to 18, median 15), with ALK being the most frequently mutated gene (7 to 10%) (4-6). In addition, chromothripsis, PHOX2B, and ATRX mutations have also been detected in a subset of highrisk tumors (4,5).Neuritogenesis is initiated during embryogenesis by a transient population of cells called the neural crest. During embryonic development, neural crest cells migrate throughout the embryo and eventually differentiate into multiple cell types, such as neurons and glial cells of the peripheral nervous system, pigment cells, fibroblasts, smooth muscle cells, and odontoblasts. The failure of neural crest cells to differentiate can result in development of cancers such as neuroblastoma and melanoma (7). A combination of Wingless (Wnt), bone morphogenetic protein, and fibroblast growth factor (FGF) signals is required to induce the formation of the neural crest and to initiate migration of neural crest cells by acquiring cell motility through epithelialmesenchymal transition (8). The no...

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“…oncogene | embryonic development | pediatric tumor | transcription factor | hormone receptor N euroblastoma (NB) represents a remarkably heterogeneous pediatric cancer derived from precursor cells of the sympathetic ganglionic lineage, with clinical behavior ranging from spontaneous regression to rapid progression and death (1,2). Despite the frequent display of multiple genetic defects, including chromosomal gains and losses, aneuploidy, and amplification of chromosomal material, few established molecular genetic markers associate with disease outcome.…”

mentioning

confidence: 99%

“…Transcriptional activation is mediated by binding of the Myc/Max dimer to the consensus E-box sequence CA(C/T)GTG in target gene promoters while the mechanism of Myc-mediated transcriptional repression is not fully understood (5). A direct link between MYCN expression and the transformed phenotype has been established in a range of studies, including a transgenic model in which targeted MYCN overexpression in migrating neural crest cells results in NB (2,6). However, despite considerable progress, NB development linked to MYCN amplification remains to be fully elucidated.…”

mentioning

confidence: 99%

MYCN-regulated microRNAs repress estrogen receptor-α ( ESR1 ) expression and neuronal differentiation in human neuroblastoma

Lovén

Zinin

Wahlström

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

124

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MYCN, a proto-oncogene normally expressed in the migrating neural crest, is in its amplified state a key factor in the genesis of human neuroblastoma (NB). However, the mechanisms underlying MYCN-mediated NB progression are poorly understood. Here, we present a MYCN-induced miRNA signature in human NB involving the activation and transrepression of several miRNA genes from paralogous clusters. Several family members derived from the miR-17∼92 cluster, including miR-18a and miR-19a, were among the up-regulated miRNAs. Expression analysis of these miRNAs in NB tumors confirmed increased levels in MYCN-amplified samples. Specifically, we show that miR-18a and miR-19a target and repress the expression of estrogen receptor-α (ESR1), a ligand-inducible transcription factor implicated in neuronal differentiation. Immunohistochemical staining demonstrated ESR1 expression in human fetal sympathetic ganglia, suggesting a role for ESR1 during sympathetic nervous system development. Concordantly, lentiviral restoration of ESR1 in NB cells resulted in growth arrest and neuronal differentiation. Moreover, lentiviral-mediated inhibition of miR-18a in NB cells led to severe growth retardation, outgrowth of varicosity-containing neurites, and induction of neuronal sympathetic differentiation markers. Bioinformatic analyses of microarray data from NB tumors revealed that high ESR1 expression correlates with increased event-free survival in NB patients and favorable disease outcome. Thus, MYCN amplification may disrupt estrogen signaling sensitivity in primitive sympathetic cells through deregulation of ESR1, thereby preventing the normal induction of neuroblast differentiation. Collectively, our findings demonstrate the molecular consequences of abnormal miRNA transcription in a MYCN-driven tumor and offer unique insights into the pathology underlying MYCN-amplified NB.oncogene | embryonic development | pediatric tumor | transcription factor | hormone receptor N euroblastoma (NB) represents a remarkably heterogeneous pediatric cancer derived from precursor cells of the sympathetic ganglionic lineage, with clinical behavior ranging from spontaneous regression to rapid progression and death (1, 2). Despite the frequent display of multiple genetic defects, including chromosomal gains and losses, aneuploidy, and amplification of chromosomal material, few established molecular genetic markers associate with disease outcome. Amplification of the MYCN locus, present in ≈20 to 30% of all cases, represents the most important genetic aberration, and is strongly related to poor clinical diagnosis (3). MYCN is expressed in the migrating neural crest and encodes a phosphoprotein that belongs to the Myc network of helix-loop-helix leucine zipper transcriptional regulators, which play key roles in governing cell growth, apoptosis, and differentiation (4). Transcriptional activation is mediated by binding of the Myc/Max dimer to the consensus E-box sequence CA(C/T)GTG in target gene promoters while the mechanism of Myc-mediated transcriptional r...

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Embryonal neural tumours and cell death

Cited by 58 publications

References 145 publications

Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

Rho-associated kinase is a therapeutic target in neuroblastoma

MYCN-regulated microRNAs repress estrogen receptor-α ( ESR1 ) expression and neuronal differentiation in human neuroblastoma

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