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Cell Oct 2022Neural migration is a critical step during brain development that requires the interactions of cell-surface guidance receptors. Cancer cells often hijack these...
Neural migration is a critical step during brain development that requires the interactions of cell-surface guidance receptors. Cancer cells often hijack these mechanisms to disseminate. Here, we reveal crystal structures of Uncoordinated-5 receptor D (Unc5D) in complex with morphogen receptor glypican-3 (GPC3), forming an octameric glycoprotein complex. In the complex, four Unc5D molecules pack into an antiparallel bundle, flanked by four GPC3 molecules. Central glycan-glycan interactions are formed by N-linked glycans emanating from GPC3 (N241 in human) and C-mannosylated tryptophans of the Unc5D thrombospondin-like domains. MD simulations, mass spectrometry and structure-based mutants validate the crystallographic data. Anti-GPC3 nanobodies enhance or weaken Unc5-GPC3 binding and, together with mutant proteins, show that Unc5/GPC3 guide migrating pyramidal neurons in the mouse cortex, and cancer cells in an embryonic xenograft neuroblastoma model. The results demonstrate a conserved structural mechanism of cell guidance, where finely balanced Unc5-GPC3 interactions regulate cell migration.
Topics: Animals; Cell Movement; Glypicans; Humans; Mice; Mutant Proteins; Netrin Receptors; Receptors, Cell Surface; Single-Domain Antibodies; Thrombospondins
PubMed: 36240740
DOI: 10.1016/j.cell.2022.09.025 -
Pediatric Radiology Apr 2023Neuroblastoma is the most common extracranial solid malignancy of childhood. The prognosis is highly variable ranging from spontaneous involution in infants to fatal... (Review)
Review
Neuroblastoma is the most common extracranial solid malignancy of childhood. The prognosis is highly variable ranging from spontaneous involution in infants to fatal outcome, despite aggressive treatment, in disseminated high-risk neuroblastoma. This paper provides a comprehensive review of the crucial role of imaging during the extensive treatment course.
Topics: Infant; Humans; Diagnostic Imaging; Neuroblastoma; Prognosis
PubMed: 36063183
DOI: 10.1007/s00247-022-05489-2 -
Molecular and Clinical Oncology Sep 2022Neuroblastoma is a highly malignant disease with a poor prognosis and few treatment options. Despite conventional chemotherapy for neuroblastoma, resistance,...
Neuroblastoma is a highly malignant disease with a poor prognosis and few treatment options. Despite conventional chemotherapy for neuroblastoma, resistance, invasiveness, and metastatic mobility limit the treatment efficacy. Therefore, it is necessary to develop new strategies for treating neuroblastoma. The present study aimed to evaluate the anticancer effects of nafamostat mesylate, a previously known serine protease inhibitor, on neuroblastoma cells. Effects of nafamostat mesylate on neuroblastoma cell migration and proliferation were analyzed by wound healing assay and WST-8 assay, respectively. To elucidate the mechanisms underlying the effects of nafamostat mesylate on neuroblastoma, the expression levels of NF-κB were measured via western blotting, and the production of the cytokine vascular endothelial growth factor (VEGF) in the cell culture supernatants was determined via ELISA. In addition, a mouse model of hematogenous metastasis was used to investigate the effects of nafamostat mesylate on neuroblastoma. It was determined that nafamostat mesylate significantly inhibited migration and invasion of Neuro-2a cells, but it had no effect on cell proliferation at 24 h after treatment. Exposure of Neuro-2a cells to nafamostat mesylate resulted in decreased vascular endothelial growth factor production, which could be a pivotal mechanism underlying the inhibitory effects of neuroblastoma metastasis. The results of the present study suggest that nafamostat mesylate may be an effective treatment against neuroblastoma invasion and metastasis.
PubMed: 35949892
DOI: 10.3892/mco.2022.2571 -
Cancer Medicine Jan 2023Neuroblastoma is the most common extracranial solid tumor in children, accounting for 10% to 20% of deaths of pediatric malignancies. Due to the poor prognosis and... (Review)
Review
Neuroblastoma is the most common extracranial solid tumor in children, accounting for 10% to 20% of deaths of pediatric malignancies. Due to the poor prognosis and significant biological heterogeneity of neuroblastoma, it is essential to develop personalized therapeutics and monitor treatment response. Circulating tumor cells (CTCs), as one of the important analytes for liquid biopsy, could facilitate response assessment and outcome prediction for patients in a non-invasive way. Several methods and platforms have been used for the enrichment and detection of CTCs. The enumeration of CTCs counts and evaluation of tumor-specific mRNA transcript levels could provide prognostic information at diagnosis, during or after chemotherapy, and during the process of disease progression. So far, studies into neuroblastoma CTCs are only in the preliminary stages. The quality-controlled large prospective cohort studies are needed to evaluate the clinical significance and statistical rigor of CTC detection methods. Moreover, there remains a lot to be explored and investigated in genotyping characterization of neuroblastoma (NB) CTCs and construction of in-vitro or in-vivo functional models. CTCs and circulating tumor DNA (ctDNA) analysis will be complementary in understanding tumor heterogeneity and evolution over the course of therapy for patients with NB in the future.
Topics: Child; Humans; Neoplastic Cells, Circulating; Prospective Studies; Prognosis; Neuroblastoma; Circulating Tumor DNA; Biomarkers, Tumor
PubMed: 35632981
DOI: 10.1002/cam4.4893 -
Cancer Metastasis Reviews Sep 2020Tumor metastasis comprises a series of coordinated events that culminate in dissemination of cancer cells to distant sites within the body representing the greatest... (Review)
Review
Tumor metastasis comprises a series of coordinated events that culminate in dissemination of cancer cells to distant sites within the body representing the greatest challenge impeding effective therapy of cancer and the leading cause of cancer-associated morbidity. Cancer cells exploit multiple genes and pathways to colonize to distant organs. These pathways are integrated and regulated at different levels by cellular- and extracellular-associated factors. Defining the genes and pathways that govern metastasis can provide new targets for therapeutic intervention. Melanoma differentiation associated gene-9 (mda-9) (also known as Syntenin-1 and SDCBP (Syndecan binding protein)) was identified by subtraction hybridization as a novel gene displaying differential temporal expression during differentiation of melanoma. MDA-9/Syntenin is an established Syndecan binding protein that functions as an adaptor protein. Expression of MDA-9/Syntenin is elevated at an RNA and protein level in a wide-range of cancers including melanoma, glioblastoma, neuroblastoma, and prostate, breast and liver cancer. Expression is increased significantly in metastatic cancer cells as compared with non-metastatic cancer cells or normal cells, which make it an attractive target in treating cancer metastasis. In this review, we focus on the role and regulation of mda-9 in cancer progression and metastasis.
Topics: Animals; Humans; Neoplasm Metastasis; Neoplasms; Syntenins
PubMed: 32410111
DOI: 10.1007/s10555-020-09886-7 -
Frontiers in Oncology 2019Neuroblastoma is a common extracranial solid tumor of neural crest (NC) origin that accounts for up to 15% of all pediatric cancer deaths. The disease arises from a... (Review)
Review
Neuroblastoma is a common extracranial solid tumor of neural crest (NC) origin that accounts for up to 15% of all pediatric cancer deaths. The disease arises from a transient population of NC cells that undergo an epithelial-mesenchymal transition (EMT) and generate diverse cell-types and tissues. Patients with neuroblastoma are characterized by their extreme heterogeneity ranging from spontaneous regression to malignant progression. More than half of newly diagnosed patients present highly metastatic tumors and are stratified into a high-risk group with dismal outcome. As many as 20% of high-risk patients have residual disease that is refractory or progressive during induction chemotherapy. Although a majority of high-risk patients achieve remission, larger part of those patients has minimal residual disease (MRD) that causes relapse even after additional consolidation therapy. MRD is composed of drug-resistant tumor cells and dynamically presented as cancer stem cells (CSCs) in residual tumors, circulating tumor cells (CTCs) in peripheral blood (PB), and disseminated tumor cells (DTCs) in bone marrow (BM) and other metastatic sites. EMT appears to be a key mechanism for cancer cells to acquire MRD phenotypes and malignant aggressiveness. Due to the restricted availability of residual tumors, PB and BM have been used to isolate and analyze CTCs and DTCs to evaluate MRD in cancer patients. In addition, recent technical advances make it possible to use circulating tumor DNA (ctDNA) shed from tumor cells into PB for MRD evaluation. Because MRD can be detected by tumor-specific antigens, genetic or epigenetic changes, and mRNAs, numerous assays using different methods and samples have been reported to detect MRD in cancer patients. In contrast to the tumor-specific gene-rearrangement-positive acute lymphoblastic leukemia (ALL) and the oncogenic fusion-gene-positive chronic myelogenous leukemia (CML) and several solid tumors, the clinical significance of MRD remains to be established in neuroblastoma. Given the extreme heterogeneity of neuroblastoma, dynamics of MRD in neuroblastoma patients will hold a key to the clinical validation. In this review, we summarize the biology and detection methods of cancer MRD in general and evaluate the available assays and clinical significance of neuroblastoma MRD to clarify its dynamics in neuroblastoma patients.
PubMed: 31214500
DOI: 10.3389/fonc.2019.00455 -
Journal of AAPOS : the Official... Jun 1998The purpose of this study was to define the etiologies of Horner syndrome in the pediatric population.
INTRODUCTION
The purpose of this study was to define the etiologies of Horner syndrome in the pediatric population.
METHODS
A retrospective review was performed of the medical records of all pediatric Horner syndrome patients (< 18 years old) examined by the pediatric ophthalmology services at two large referral centers.
RESULTS
Seventy-three pediatric Horner syndrome patients were identified. Of these, 31 (42%) were congenital, 11 (15%) were acquired without surgical intervention, and 31 (42%) were acquired after a surgical procedure of the thorax, neck, or central nervous system. Of the congenital Horner syndrome patients, a history of delivery with the use of forceps, vacuum extraction, shoulder dystocia, fetal rotation, or postterm delivery was elicited in 16 patients (53%). Concomitant brachial plexus injury was identified in only 3 patients. Two patients had congenital varicella syndrome and 1 patient was diagnosed with neuroblastoma. This patient had a palpable supraclavicular mass and stridor. Diagnosis of the patients with acquired Horner syndrome included neuroblastoma (2), trauma (1), rhabdomyosarcoma (1), brainstem vascular malformation (1), disseminated sclerosis (1), and not determined (5).
CONCLUSION
In children with congenital Horner syndrome, a history of forceful manipulation of the infant during birth may reduce the need for extensive systemic evaluation. Without such history, a decision to proceed with further evaluation is made with consideration of the relative incidence of neuroblastoma by age and the physical findings. All acquired pediatric Horner syndrome patients without a known etiology require thorough evaluation because of the frequent association of serious underlying disease.
Topics: Birth Injuries; Child; Child, Preschool; Communicable Diseases; Horner Syndrome; Humans; Infant; Neoplasms; Neuroblastoma; Practice Guidelines as Topic; Retrospective Studies
PubMed: 10532753
DOI: 10.1016/s1091-8531(98)90008-8 -
Neoplasia (New York, N.Y.) Apr 2020Neuroblastoma is an aggressive pediatric malignancy of the neural crest with suboptimal cure rates and a striking predilection for widespread metastases, underscoring...
Neuroblastoma is an aggressive pediatric malignancy of the neural crest with suboptimal cure rates and a striking predilection for widespread metastases, underscoring the need to identify novel therapeutic vulnerabilities. We recently identified the RNA binding protein LIN28B as a driver in high-risk neuroblastoma and demonstrated it promotes oncogenic cell proliferation by coordinating a RAN-Aurora kinase A network. Here, we demonstrate that LIN28B influences another key hallmark of cancer, metastatic dissemination. Using a murine xenograft model of neuroblastoma dissemination, we show that LIN28B promotes metastasis. We demonstrate that this is in part due to the effects of LIN28B on self-renewal and migration, providing an understanding of how LIN28B shapes the metastatic phenotype. Our studies reveal that the let-7 family, which LIN28B inhibits, decreases self-renewal and migration. Next, we identify PDZ Binding Kinase (PBK) as a novel LIN28B target. PBK is a serine/threonine kinase that promotes the proliferation and self-renewal of neural stem cells and serves as an oncogenic driver in multiple aggressive malignancies. We demonstrate that PBK is both a novel direct target of let-7i and that MYCN regulates PBK expression, thus elucidating two oncogenic drivers that converge on PBK. Functionally, PBK promotes self-renewal and migration, phenocopying LIN28B. Taken together, our findings define a role for LIN28B in neuroblastoma metastasis and define the targetable kinase PBK as a potential novel vulnerability in metastatic neuroblastoma.
PubMed: 32339949
DOI: 10.1016/j.neo.2020.04.001 -
Frontiers in Oncology 2018Application of the CAR targeting strategy in solid tumors is challenged by the need for adequate target antigens. As a consequence of their tissue origin, embryonal... (Review)
Review
Application of the CAR targeting strategy in solid tumors is challenged by the need for adequate target antigens. As a consequence of their tissue origin, embryonal cancers can aberrantly express membrane-anchored gangliosides. These are carbohydrate molecules consisting of a glycosphingolipid linked to sialic acids residues. The best-known example is the abundant expression of ganglioside G on the cell surface of neuroblastomas which derive from G-positive neuroectoderm. Gangliosides are involved in various cellular functions, including signal transduction, cell proliferation, differentiation, adhesion and cell death. In addition, transformation of human cells to cancer cells can be associated with distinct glycosylation profiles which provide advantages for tumor growth and dissemination and can serve as immune targets. Both gangliosides and aberrant glycosylation of proteins escape the direct molecular and proteomic screening strategies currently applied to identify further immune targets in cancers. Due to their highly restricted expression and their functional roles in the malignant behavior, they are attractive targets for immune engineering strategies. G-redirected CAR T cells have shown activity in clinical phase I/II trials in neuroblastoma and next-generation studies are ongoing. Further carbohydrate targets for CAR T cells in preclinical development are O-acetyl-G, NeuGc-GM3 (N-glycolyl GM3), G, SSEA-4, and oncofetal glycosylation variants. This review summarizes knowledge on the role and function of some membrane-expressed non-protein antigens, including gangliosides and abnormal protein glycosylation patterns, and discusses their potential to serve as a CAR targets in pediatric solid cancers.
PubMed: 30483473
DOI: 10.3389/fonc.2018.00513 -
Oncotarget Jun 2017Neuroblastoma (NB), ganglioneuroblastoma intermixed (GNBi) and ganglioneuroblastoma nodular (GNBn) are neuroblastic tumors that present with a wide range of symptoms and...
Neuroblastoma (NB), ganglioneuroblastoma intermixed (GNBi) and ganglioneuroblastoma nodular (GNBn) are neuroblastic tumors that present with a wide range of symptoms and variable prognoses. We retrospectively reviewed the pretreatment clinical (age, sex and tumor stage) and biological (MYCN amplification; and levels of lactate dehydrogenase, ferritin and neuron-specific enolase) characteristics of 279 patients who were diagnosed with pathologically confirmed NB and GNB from January 2005 to December 2015. The median age at diagnosis increased with grade of differentiation (NB: 28.9 months; GNBn: 38.4 months; GNBi: 47.5 months; p < 0.01). NB patients were more frequently diagnosed with adrenal tumors and had a higher prevalence of abnormal serum ferritin at the time of diagnosis (60.0% vs. 40.0% vs. 12.0%, P<0.001), NSE (96.0% vs. 93.0% vs. 81.0%, P=0.013) when compared with GNBn and GNBi patients. The prevalence rates of disseminated tumors and MYCN amplified tumors were lower in the GNBi group than in the GNBn and NB groups (13.0% vs. 25.0% vs. 44.0%, P=0.002; 0 vs. 14.0% vs. 26.0%, P=0.032, respectively). The overall survival (OS) of patients with GNB was significantly better than that of patients with NB (GNBi: 100%, GNBn: 74.5±11.4%, NB: 50.8±4.5%, respectively; P<0.01). Our study revealed that both NB and GNB have a wide range of presentations, and clinicians should be aware of both typical and atypical symptoms and signs. Children with GNB (especially GNBi) were more likely to present favorable prognostic factors than their NB counterparts, which consequently lead to better outcomes and longer survival for these patients.
Topics: Adult; Female; Ganglioneuroblastoma; Humans; Male; Neuroblastoma; Retrospective Studies; Survival Analysis
PubMed: 28465480
DOI: 10.18632/oncotarget.17146