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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 -
Lung Cancer (Amsterdam, Netherlands) Apr 2020Increased expression of REarranged during Transfection (RET) kinase is reported in 10-20 % of lung adenocarcinomas (LUAD) and is associated with metastasis and reduced...
OBJECTIVES
Increased expression of REarranged during Transfection (RET) kinase is reported in 10-20 % of lung adenocarcinomas (LUAD) and is associated with metastasis and reduced survival. Ezrin is a scaffold protein that promotes protein interactions with the actin cytoskeleton to regulate cell migration and is also associated with invasion and metastasis in cancers. RET isoforms interact with unique combinations of scaffold proteins to promote distinct signaling pathways. We hypothesized that RET isoforms associate distinctly with Ezrin for cytoskeletal reorganization and LUAD cell migration processes.
METHODS
HCC1833 and A549 LUAD, SH-SY5Y neuroblastoma or HEK-293 cells expressing RET and Ezrin were stimulated with the RET ligand glial cell line-derived neurotrophic factor (GDNF) and treated with RET, Ezrin or Src inhibitors. Co-immunoprecipitation or pull-down assays coupled to immunoblotting were used to investigate protein activation and interactions. Immunofluorescence confocal microscopy assessed LUAD cytoskeletal reorganization and colocalization of RET and Ezrin. Live-cell fluorescence imaging was used to measure cell migration and chemotaxis.
RESULTS
GDNF promoted activation, interaction and colocalization of RET51 isoform and Ezrin. Inhibition of RET or Src impaired Ezrin interactions with RET and Src. GDNF stimulation enhanced the formation of actin-rich filopodia, in which both RET and Ezrin were enriched, and promoted chemotaxis in LUAD cells. However, inhibition of RET, Src or Ezrin suppressed filopodia formation, reduced colocalization of Ezrin with RET, and impaired cell migration and/ or chemotaxis. We further showed that GDNF-mediated activation of RET and Ezrin promoted RhoA-GTPase activity and signaling of ROCK1 and ROCK2 in LUAD cells.
CONCLUSIONS
Expression and activation of RET51 mediates unique protein interactions with Ezrin to promote LUAD cell chemotaxis for cancer cell dissemination, which may have implications in LUAD metastatic progression.
Topics: Adenocarcinoma of Lung; Apoptosis; Cell Movement; Cell Proliferation; Chemotaxis; Cytoskeletal Proteins; HEK293 Cells; Humans; Lung Neoplasms; Neuroblastoma; Phosphorylation; Protein Interaction Domains and Motifs; Protein Isoforms; Proto-Oncogene Proteins c-ret; Tumor Cells, Cultured
PubMed: 32146264
DOI: 10.1016/j.lungcan.2020.02.004 -
Open Medicine (Warsaw, Poland) 2019Neural cell adhesion molecules like close homolog of L1 protein (CHL1) and neuronal glia related cell adhesion molecule (NrCAM) play an important role in development and...
BACKGROUND
Neural cell adhesion molecules like close homolog of L1 protein (CHL1) and neuronal glia related cell adhesion molecule (NrCAM) play an important role in development and regeneration of the central nervous system. However, they are also associated with cancerogenesis and progression in adult malignancies, thus gain increasing importance in cancer research. We therefore studied the expression of CHL1 and NrCAM according to the course of disease in children with neuroblastoma.
METHODS
CHL1 and NrCAM expression levels were histologically assessed by tissue microarrays from surgically resected neuroblastoma specimens of 56 children. Expression of both markers was correlated to demographics as well as clinical data including metastatic dissemination and survival.
RESULTS
CHL1 was expressed in 9% and NrCAM in 51% of neuroblastoma tissue samples. Expression of CHL1 was higher in patients with low Hughes grade 1a/b (p=0.01). NrCAM was more often detected in patients with a low International Staging System (INSS) score 1/2 (p=0.04).
CONCLUSION
CHL1 and NrCAM expression was associated with low-grade pediatric neuroblastoma. These adhesion molecules may play a role in early tumor development of neuroblastoma.
PubMed: 31989042
DOI: 10.1515/med-2019-0109 -
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 -
Pediatric Blood & Cancer Apr 2020Esthesioneuroblastoma (ENB) is a rare neuroectodermal tumor that seldom occurs during childhood. Multimodal treatments are currently proposed, but the place of each...
BACKGROUND
Esthesioneuroblastoma (ENB) is a rare neuroectodermal tumor that seldom occurs during childhood. Multimodal treatments are currently proposed, but the place of each therapy is still in debate. Our objective is to describe clinical evolution, especially the pattern of relapses and determine contributors to tumor progression.
PROCEDURE
Medical charts of all children (≤18 years) affected by ENB treated in France from January 1990 to December 2015 were retrospectively analyzed.
RESULTS
Eighteen patients were selected (10 males). Median age at diagnosis was 12.2 years (0.9-18). Tumor extension was Kadish stage A (n = 1), B (n = 3), C (n = 10), and D (n = 4). Hyams histological grades were I (n = 1), II (n = 3), III (n = 6), and IV (n = 6) (in two cases not defined). Initial cervical nodal spread was assessed by magnetic resonance imaging (n = 15), computed tomography scan (n = 16), fluorodeoxyglucose-positron emission tomography-computed tomography (n = 7), and cytological/histological analysis (n = 2). N1 stage was confirmed by imaging in two of 18 cases and one of two cases had cervical node dissection with neck irradiation (58 Gy). After a median follow-up of survivors of 7.6 years (3.8-17.9), 10 patients developed neuromeningeal progression, whereas no cervical nodal relapse occurred and only eight survived. Both 5-year overall and event-free survival rates were 44.4% (±11.7%).
CONCLUSIONS
The poor prognosis is mainly related to neuromeningeal dissemination that should be considered during treatment strategy. However, cervical lymph node relapse is rare.
Topics: Adolescent; Child; Child, Preschool; Combined Modality Therapy; Esthesioneuroblastoma, Olfactory; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Male; Nasal Cavity; Neoplasm Recurrence, Local; Nose Neoplasms; Prognosis; Rare Diseases; Retrospective Studies; Survival Rate
PubMed: 31930719
DOI: 10.1002/pbc.28154 -
Frontiers in Molecular Neuroscience 2019Long non-coding RNAs (lncRNAs) have emerged as an important regulatory control in biological systems. Though the field of lncRNA has been progressing rapidly, a complete...
Long non-coding RNAs (lncRNAs) have emerged as an important regulatory control in biological systems. Though the field of lncRNA has been progressing rapidly, a complete understanding of the role of lncRNAs in neuroblastoma pathogenesis is still lacking. To identify the abrogated lncRNAs in primary neuroblastoma and in the metastasized as well as the relapsed form of neuroblastoma, we analyzed an RNA-seq dataset on neuroblastoma that is available online to identify the lncRNAs that could potentially be contributing to the biology of neuroblastoma. The identified lncRNAs were further scrutinized using a publicly available epigenetic dataset of neuroblastoma and a cancer database. After this cross-sectional study, we were able to identify three significant lncRNAs, , , and , which could serve as potential biomarkers in clinical studies of neuroblastoma pathogenesis.
PubMed: 31920530
DOI: 10.3389/fnmol.2019.00293 -
Medical Hypotheses Mar 2020Although frequently disseminated to other anatomical sites, neuroblastoma (NB) is rarely reported as involving the central nervous system (CNS), which may reflect...
Although frequently disseminated to other anatomical sites, neuroblastoma (NB) is rarely reported as involving the central nervous system (CNS), which may reflect insufficient research in poorly controlled systemic disease. Here we demonstrate the involvement of the CNS in patients with NB over 18 months of age at diagnosis of extensive systemic disease. Meningeal metastases were observed even in the presence of complete systemic control. Although no improvement in patient's survival was observed, radiotherapy was effective in preventing CNS recurrence after observation of actual or previous dural disease. In conclusion, this study uncovered the uncommon pathologic involvement of the CNS in children with advanced NB and underscores the meningeal surface as a potential pathway for this to occur.
Topics: Central Nervous System; Child, Preschool; Humans; Infant; Meningeal Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neuroblastoma; Prospective Studies; Radiotherapy; Skull Neoplasms; Treatment Outcome
PubMed: 31778890
DOI: 10.1016/j.mehy.2019.109479 -
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 -
World Neurosurgery Feb 2020Olfactory neuroblastoma (ON) is a highly aggressive and locally recurrent neoplasm. Distant systemic metastases are not uncommon, but remote leptomeningeal dissemination...
BACKGROUND
Olfactory neuroblastoma (ON) is a highly aggressive and locally recurrent neoplasm. Distant systemic metastases are not uncommon, but remote leptomeningeal dissemination is extremely rare.
CASE DESCRIPTION
We report 2 cases of ON previously treated with endoscopic endonasal radical surgical resection and radiotherapy. After a relatively long period of disease-free survival, multiple leptomeningeal lesions were seen around the sagittal sinus giving a radiologic appearance of parasagittal meningiomas. Both patients underwent surgery and multimodal treatment with radiotherapy and chemotherapy for the disseminated disease. Pathologic examination confirmed the parasagittal lesions as metastatic ON.
CONCLUSIONS
A high suspicion of secondary disease should be maintained in patients with previous history of ON and parasagittal leptomeningeal enhancing lesion, particularly when multiple lesions are detected around the sagittal sinus. Radical resection and multimodal treatment are warranted to improve long-term outcome. Understanding the venous drainage route as a potential pathway for remote seeding from the primary site of disease has therapeutic implications. We postulate that en-bloc tumor resection and proximal sagittal sinus ligation might reduce potential for leptomeningeal metastasis.
Topics: Adult; Diagnosis, Differential; Esthesioneuroblastoma, Olfactory; Humans; Male; Meningeal Carcinomatosis; Meningeal Neoplasms; Meningioma; Middle Aged; Nasal Cavity; Nose Neoplasms; Superior Sagittal Sinus
PubMed: 31734430
DOI: 10.1016/j.wneu.2019.11.042 -
The Gulf Journal of Oncology Sep 2019Disseminated intravascular coagulation or consumption coagulopathy is a well-recognized entity both in various malignant and non-malignant conditions. Most data in... (Review)
Review
INTRODUCTION
Disseminated intravascular coagulation or consumption coagulopathy is a well-recognized entity both in various malignant and non-malignant conditions. Most data in paediatric solid tumours are isolated case reports, while there is sparse data in paediatric acute leukaemia.
OBJECTIVE
The study was conducted to analyze the incidence of DIC in our population of paediatric solid tumours.
DESIGN
All records of children <15 years of age registered in the Paediatric Oncology department of our institute with a diagnosis of solid tumour malignancy were retrospectively reviewed for evidence of DIC.
RESULTS
Out of the 73 children, 4 have developed DIC, an incidence of 5.5%. The mean age of children who developed DIC was 4.6 years (Range- 2months -15 years) and the majority (2/4- 50%) children were less than 1 year of age. Children with DIC had a male predominance (75%) and the majority (75%) presented in advanced stages of the disease. Of the 10 children with neuroblastoma, 2 (20%) had evidence of DIC. Statistical analysis was done to determine whether any patient characteristic had the propensity to develop DIC. The only factor that attained statistical significance was younger age.
CONCLUSION
Disseminated intravascular coagulation though uncommon in children should always be thought of in a child with advanced disease presenting with thrombocytopenia or clinical manifestations of bleeding tendency. An index of suspicion is important for early diagnosis and emergent treatment which eventually improves survival.
Topics: Adolescent; Blood Coagulation Disorders; Child; Child, Preschool; Female; Humans; Infant; Male; Neoplasms; Retrospective Studies
PubMed: 31591993
DOI: No ID Found