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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 -
Clinics in Perinatology Mar 2021Neuroblastoma accounts for approximately 8% of all pediatric cancers, with 5% diagnosed during the neonatal period. Despite the disproportionate contribution of... (Review)
Review
Neuroblastoma accounts for approximately 8% of all pediatric cancers, with 5% diagnosed during the neonatal period. Despite the disproportionate contribution of neuroblastoma to childhood cancer deaths, neonatal neuroblastoma has a favorable prognosis, often with little or no therapy required. Therefore, minimizing therapy and mitigating complications/toxicities are emphasized, including using a watch-and-wait approach for patients at low risk for disease progression/relapse. However, stage MS neuroblastoma exhibits a unique pattern of disseminated disease, can be challenging to manage, and may require early intervention with systemic chemotherapy. In this review, the epidemiology, treatment options, and anticipated outcomes for neonatal neuroblastoma are discussed.
Topics: Child; Humans; Infant; Neoplasm Staging; Neuroblastoma; Prognosis
PubMed: 33583499
DOI: 10.1016/j.clp.2020.11.006 -
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 -
Seminars in Pediatric Surgery Dec 2019Neuroblastoma is a heterogenous disease, with solid tumors arising in the adrenal gland or paraspinal regions in young children. Neuroblastoma is unique, with varied... (Review)
Review
Neuroblastoma is a heterogenous disease, with solid tumors arising in the adrenal gland or paraspinal regions in young children. Neuroblastoma is unique, with varied presentation and prognosis based on primary location and tumor stage. Tumor behavior and response to treatment ranges from spontaneous regression to disseminated, lethal disease depending on the individual biology of a patient's tumor. Stratification of the disease has changed, with patients now placed in low, intermediate, and high-risk categories depending on age, stage, and tumor biology. Long-term survival for the high-risk subset of patients with metastatic disease is <40% despite aggressive multimodal therapy. Derived from sympathoadrenal cells of the adrenal medulla and sympathetic nervous system, both malignant neuroblastoma and differentiated tumors have specialized norepinephrine transporter (NET) receptors which are naturally occurring in the sympathetic nervous system throughout the body. Metaiodobenzylguanidine (MIBG) is a norepinephrine analog that undergoes active uptake by NET receptors resulting in accumulation in neuroblastoma as well as tissues normally expressing the NET receptor. When radioiodine labeled, MIBG can be used for both diagnosis and treatment. This article describes the history of MIBG use in neuroblastoma, including its utility as an imaging modality for diagnosis as well as the varied ways in which is it included in the multimodal treatment algorithm.
Topics: 3-Iodobenzylguanidine; Adrenal Gland Neoplasms; Antineoplastic Agents; Child; Humans; Neuroblastoma; Norepinephrine; Radiopharmaceuticals
PubMed: 31931960
DOI: 10.1016/j.sempedsurg.2019.150859 -
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 -
Clinical Cancer Research : An Official... Jan 2020Circulating tumor cells (CTCs) serve as noninvasive tumor biomarkers in many types of cancer. Our aim was to detect CTCs from patients with neuroblastoma for use as...
PURPOSE
Circulating tumor cells (CTCs) serve as noninvasive tumor biomarkers in many types of cancer. Our aim was to detect CTCs from patients with neuroblastoma for use as predictive and pharmacodynamic biomarkers.
EXPERIMENTAL DESIGN
We collected matched blood and bone marrow samples from 40 patients with neuroblastoma to detect GD /CD45 neuroblastoma CTCs from blood and disseminated tumor cells (DTCs) from bone marrow using the Imagestream Imaging flow cytometer (ISx). In six cases, circulating free DNA (cfDNA) extracted from plasma isolated from the CTC sample was analyzed by high-density single-nucleotide polymorphism (SNP) arrays.
RESULTS
CTCs were detected in 26 of 42 blood samples (1-264/mL) and DTCs in 25 of 35 bone marrow samples (57-291,544/mL). Higher numbers of CTCs in patients with newly diagnosed, high-risk neuroblastoma correlated with failure to obtain a complete bone marrow (BM) metastatic response after induction chemotherapy ( < 0.01). Nutlin-3 (MDM2 inhibitor) treatment of blood and BM increased p53 and p21 expression in CTCs and DTCs compared with DMSO controls. In five of six cases, cfDNA analyzed by SNP arrays revealed copy number abnormalities associated with neuroblastoma.
CONCLUSIONS
This is the first study to show that CTCs and DTCs are detectable in neuroblastoma using the ISx, with concurrently extracted cfDNA used for copy number profiling, and may be useful as pharmacodynamic biomarkers in early-phase clinical trials. Further investigation is required to determine whether CTC numbers are predictive biomarkers of BM response to first-line induction chemotherapy.
Topics: Biomarkers, Tumor; Bone Marrow; DNA Copy Number Variations; Flow Cytometry; Humans; Image Processing, Computer-Assisted; Imidazoles; Neoplastic Cells, Circulating; Neuroblastoma; Piperazines; Predictive Value of Tests; Proto-Oncogene Proteins c-mdm2
PubMed: 31767563
DOI: 10.1158/1078-0432.CCR-19-0656 -
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 -
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 -
Research (Washington, D.C.) 2023The recurrence and metastasis of children with mediastinal neuroblastoma (NB) are also occurred after surgery, chemotherapy, or radiotherapy. Strategies targeting the...
The recurrence and metastasis of children with mediastinal neuroblastoma (NB) are also occurred after surgery, chemotherapy, or radiotherapy. Strategies targeting the tumor microenvironment have been reported to improve survival; however, thorough investigations of monocytes and tumor-associated macrophages (Mϕs) with specialized functions in NB are still lacking. Our data first demonstrated polypyrimidine tract binding protein 2 (PTBP2) as a possible identifier in patients with mediastinal NB screened by proteomic profiling and that PTBP2 predicted good outcomes. Functional studies revealed that PTBP2 in NB cells induced the chemotactic activity and repolarization of tumor-associated monocytes and Mϕs, which, in turn, inhibited NB growth and dissemination. Mechanistically, PTBP2 prevents interferon regulatory factor 9 alternative splicing and upregulates signal transducers and activators of transcription 1 to stimulate C-C motif chemokine ligand 5 (CCL5) and interferon-stimulated gene factor-dependent type I interferon secretion, to induce monocyte/Mϕs chemotaxis, and to sustain monocytes in a proinflammatory phenotype. Our study defined a critical event of PTBP2-induced monocytes/Mϕs in NB progression and revealed that RNA splicing occurred by PTBP2 benefits immune compartmentalization between NB cells and monocytes. This work revealed the pathological and biological role of PTBP2 in NB development and indicates that PTBP2-induced RNA splicing benefits immune compartmentalization and predicted a favorable prognosis in mediastinal NB.
PubMed: 37040518
DOI: 10.34133/research.0033