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Cureus May 2023Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant tumor of neuroectodermal origin that arises from the olfactory epithelium. We...
Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant tumor of neuroectodermal origin that arises from the olfactory epithelium. We present a case of ENB metastasizing through the leptomeningeal route to the spinal dura, which was treated with CyberKnife (CK) stereotactic radiosurgery (SRS), and aim to assess the safety and effectiveness of SRS in such cases. To the best of our knowledge, this is the first case report in the literature that discusses ENB spinal leptomeningeal metastases treated with CK radiosurgery. We retrospectively review the clinical and radiological outcomes in a 70-year-old female with ENB metastasis to the spine. Progression-free survival (PFS), overall survival (OS), and local tumor control (LTC) are investigated. In our patient, ENB had been diagnosed at the age of 58 years and spinal metastases had been first noted at the age of 65 years. A total of six spinal lesions received CK SRS. Lesions were present at the level of C1, C2, C3, C6-C7, T5, and T10-11. The median target volume was 0.72 cc (range: 0.32-2.54). A median marginal dose of 24 Gy was delivered to the tumors with a median of three fractions to a median isodose line of 80% (range: 78-81). LTC at the 24-month follow-up was 100%. PFS and OS were 27 months and 40 months, respectively. No adverse radiation effects were reported. Even though the treated spinal lesions remained stable, the number of new metastatic lesions had increased with progressive osseous and dural metastatic lesions within the cervical, thoracic, and lumbar spine at the last follow-up. SRS provides relatively good LTC for patients with ENB metastasizing to the spine, with no radiation-induced adverse events.
PubMed: 37398775
DOI: 10.7759/cureus.39791 -
Cell & Bioscience May 2023Tumor hypoxia stimulates release of extracellular vesicles (EVs) that facilitate short- and long-range intercellular communication and metastatization. Albeit hypoxia...
BACKGROUND
Tumor hypoxia stimulates release of extracellular vesicles (EVs) that facilitate short- and long-range intercellular communication and metastatization. Albeit hypoxia and EVs release are known features of Neuroblastoma (NB), a metastasis-prone childhood malignancy of the sympathetic nervous system, whether hypoxic EVs can facilitate NB dissemination is unclear.
METHODS
Here we isolated and characterized EVs from normoxic and hypoxic NB cell culture supernatants and performed microRNA (miRNA) cargo analysis to identify key mediators of EVs biological effects. We then validated if EVs promote pro-metastatic features both in vitro and in an in vivo zebrafish model.
RESULTS
EVs from NB cells cultured at different oxygen tensions did not differ for type and abundance of surface markers nor for biophysical properties. However, EVs derived from hypoxic NB cells (hEVs) were more potent than their normoxic counterpart in inducing NB cells migration and colony formation. miR-210-3p was the most abundant miRNA in the cargo of hEVs; mechanistically, overexpression of miR-210-3p in normoxic EVs conferred them pro-metastatic features, whereas miR-210-3p silencing suppressed the metastatic ability of hypoxic EVs both in vitro and in vivo.
CONCLUSION
Our data identify a role for hypoxic EVs and their miR-210-3p cargo enrichment in the cellular and microenvironmental changes favoring NB dissemination.
PubMed: 37202777
DOI: 10.1186/s13578-023-01045-z -
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 -
Cirugia Pediatrica : Organo Oficial de... Jan 2023Disseminated intravascular coagulation (DIC) is a rare oncological emergency. We report a pediatric neuroblastoma complicated with DIC which required...
BACKGROUND
Disseminated intravascular coagulation (DIC) is a rare oncological emergency. We report a pediatric neuroblastoma complicated with DIC which required thromboelastometry-guided surgery.
OBSERVATION
A 6-year-old female diagnosed with intermediate risk adrenal neuroblastoma developed tumor-related DIC after chemotherapy first cycle. She remained stable without clinical bleeding and emergent tumor resection guided by intraoperative-thromboelastometry was decided. DIC resolved early after surgery and complete remission was achieved.
CONCLUSION
Treatment of the underlying condition is critical to manage DIC. Thromboelastometry can guide goal-directed therapy, including surgery in pediatric patients. However, larger studies are needed to examine its applicability in different clinical settings, such as cancer related DIC.
Topics: Female; Humans; Child; Thrombelastography; Disseminated Intravascular Coagulation; Neuroblastoma
PubMed: 36629349
DOI: 10.54847/cp.2023.01.20 -
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 -
Cellular and Molecular Life Sciences :... Oct 2022The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis....
The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis. This is a paradox, since more than 90% of cancer deaths are attributable to metastatic progression. Integrin alpha9 (ITGA9) has been previously described as playing an essential role in metastasis; however, little is known about the mechanism that links this protein to this process, being one of the less studied integrins. We have now deciphered the importance of ITGA9 in metastasis and provide evidence demonstrating its essentiality for metastatic dissemination in rhabdomyosarcoma and neuroblastoma. However, the most translational advance of this study is to reveal, for the first time, the possibility of reducing metastasis by pharmacological inhibition of ITGA9 with a synthetic peptide simulating a key interaction domain of ADAM proteins, in experimental metastasis models, not only in childhood cancers but also in a breast cancer model.
Topics: ADAM Proteins; Humans; Integrin alpha Chains; Integrins; Neoplasm Metastasis; Neuroblastoma; Rhabdomyosarcoma
PubMed: 36221013
DOI: 10.1007/s00018-022-04557-y -
Cell Reports Oct 2022Peripheral neuroblastic tumors (PNTs) represent a spectrum of neural-crest-derived tumors, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Malignant...
Peripheral neuroblastic tumors (PNTs) represent a spectrum of neural-crest-derived tumors, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Malignant cells in PNTs are theorized to interconvert between adrenergic/noradrenergic and mesenchymal/neural crest cell states. Here, single-cell RNA-sequencing analysis of 10 PNTs demonstrates extensive transcriptomic heterogeneity. Trajectory modeling suggests that malignant neuroblasts move between adrenergic and mesenchymal cell states via an intermediate state that we term "transitional." Transitional cells express programs linked to a sympathoadrenal development and aggressive tumor phenotypes such as rapid proliferation and tumor dissemination. Among primary bulk tumor patient cohorts, high expression of the transitional gene signature is predictive of poor prognosis compared with adrenergic and mesenchymal expression patterns. High transitional gene expression in neuroblastoma cell lines identifies a similar transitional H3K27-acetylation super-enhancer landscape. Collectively, our study supports the concept that PNTs have phenotypic plasticity and uncovers potential biomarkers and therapeutic targets.
Topics: Adrenergic Agents; Ganglioneuroblastoma; Ganglioneuroma; Humans; Neuroblastoma; RNA
PubMed: 36198269
DOI: 10.1016/j.celrep.2022.111455 -
Frontiers in Oncology 2022Existing marker-based methods of minimal residual disease (MRD) determination in neuroblastoma do not effectively enrich for the circulating disease cell population....
Existing marker-based methods of minimal residual disease (MRD) determination in neuroblastoma do not effectively enrich for the circulating disease cell population. Given the relative size differential of neuroblastoma tumor cells over normal hematogenous cells, we hypothesized that cell size-based separation could enrich circulating tumor cells (CTCs) from blood samples and disseminated tumor cells (DTCs) from bone marrow aspirates (BMA) of neuroblastoma patients, and that their gene expression profiles could vary dynamically with various disease states over the course of treatment. Using a spiral microfluidic chip, peripheral blood of 17 neuroblastoma patients at 3 serial treatment timepoints (diagnosis, n=17; post-chemotherapy, n=11; and relapse, n=3), and bone marrow samples at diagnosis were enriched for large intact circulating cells. Profiling the resulting enriched samples with immunohistochemistry and mRNA expression of 1490 cancer-related genes NanoString, 13 of 17 samples contained CTCs displaying cytologic atypia, TH and PHOX2B expression and/or upregulation of cancer-associated genes. Gene signatures reflecting pro-metastatic processes and the neuroblastoma mesenchymal super-enhancer state were consistently upregulated in 7 of 13 samples, 6 of which also had metastatic high-risk disease. Expression of 8 genes associated with PI3K and GCPR signaling were significantly upregulated in CTCs of patients with bone marrow metastases versus patients without. Correspondingly, in patients with marrow metastases, differentially-expressed gene signatures reflected upregulation of immune regulation in bone marrow DTCs versus paired CTCs samples. In patients who later developed disease relapse, 5 genes involved in immune cell regulation, JAK/STAT signaling and the neuroblastoma mesenchymal super-enhancer state (OLFML2B, STAT1, ARHGDIB, STAB1, TLR2) were upregulated in serial CTC samples over their disease course, despite urinary catecholamines and bone marrow aspirates not indicating the disease recurrences. In summary, using a label-free cell size-based separation method, we enriched and characterized intact circulating cells in peripheral blood indicative of neuroblastoma CTCs, as well as their DTC counterparts in the bone marrow. Expression profiles of pro-metastatic genes in CTCs correlated with the presence of bone marrow metastases at diagnosis, while longitudinal profiling identified persistently elevated expression of genes in CTCs that may serve as novel predictive markers of hematogenous MRD in neuroblastoma patients that subsequently relapse.
PubMed: 36176417
DOI: 10.3389/fonc.2022.939460 -
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