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Frontiers in Cell and Developmental... 2020Neuropeptide Y (NPY) has been implicated in the regulation of cellular motility under various physiological and pathological conditions, including cancer dissemination....
Neuropeptide Y (NPY) has been implicated in the regulation of cellular motility under various physiological and pathological conditions, including cancer dissemination. Yet, the exact signaling pathways leading to these effects remain unknown. In a pediatric malignancy, neuroblastoma (NB), high NPY release from tumor tissue associates with metastatic disease. Here, we have shown that NPY stimulates NB cell motility and invasiveness and acts as a chemotactic factor for NB cells. We have also identified the Y5 receptor (Y5R) as the main NPY receptor mediating these actions. In NB tissues and cell cultures, Y5R is highly expressed in migratory cells and accumulates in regions of high RhoA activity and dynamic cytoskeleton remodeling. Y5R stimulation activates RhoA and results in Y5R/RhoA-GTP interactions, as shown by pull-down and proximity ligation assays, respectively. This is the first demonstration of the role for the NPY/Y5R axis in RhoA activation and the subsequent cytoskeleton remodeling facilitating cell movement. These findings implicate Y5R as a target in anti-metastatic therapies for NB and other cancers expressing this receptor.
PubMed: 33681186
DOI: 10.3389/fcell.2020.627090 -
International Journal of Environmental... Feb 2021Neuroblastoma is the most common extra-cranial solid tumor in infants and young children, and accounts for approximately 8-10% of all childhood cancers. The...
Neuroblastoma is the most common extra-cranial solid tumor in infants and young children, and accounts for approximately 8-10% of all childhood cancers. The International Neuroblastoma Staging System (The International Neuroblastoma Risk Group Staging System (INRGSS)) is based on the age of patient and preoperative imaging, with attention paid to whether the primary tumor is affected by one or more of specific Image-Defined Risk Factors (IDRFs). Patients are classified into the following groups: locoregional L1 and L2 (absent or present IDRFs respectively), M stage (a disseminated form of neuroblastoma) and Ms (the stage present in children younger than 18 months of age with the disease spread to the bone marrow and/or liver, and/or skin). This publication is aimed to present an unexpected complication associated with an accidental ligation of the celiac trunk during resection of a neuroblastoma tumor in a 2.5-year-old boy after initial chemotherapy, initially with vascular IDRFs, stage L2. The consequences of this complication were pancreatic and spleen ischemia and necrosis, and ischemia and perforation of the common bile duct, gallbladder, stomach, and duodenum. Despite detailed diagnostic imaging (computed tomography, magnetic resonance), the presence of vascular IDRFs may result in an unexpected complication in the surgical treatment of neuroblastoma in children.
Topics: Child; Child, Preschool; Family; Humans; Infant; Magnetic Resonance Imaging; Male; Neoplasm Staging; Neuroblastoma; Risk Factors; Tomography, X-Ray Computed
PubMed: 33672809
DOI: 10.3390/ijerph18041841 -
Medicine Mar 2021Previous studies have investigated the prognostic role of programmed death ligand 1 (PD-L1) expression in patients with neuroblastoma, while the results are still...
BACKGROUND
Previous studies have investigated the prognostic role of programmed death ligand 1 (PD-L1) expression in patients with neuroblastoma, while the results are still controversial. Therefore, we conducted a meta-analysis to clarify the relationship between the expression of PD-L1 and the prognosis of neuroblastoma.
METHODS
Search electronic databases include PubMed, Cochrane, Embase, Scopus and Web of Science, and the search time is set to build the database until January 2021. Hazard ratio (HR) and 95% confidence interval (CI) were used to analyze the included results. Meta-analysis was performed using Stata 15.0 software.
RESULTS
This review will be disseminated in print by peer-review.
CONCLUSION
The study will provide updated evidence for the evaluation of whether the expression of PD-L1 is associated with poor prognosis in patients with neuroblastoma.
ETHICS AND DISSEMINATION
The private information from individuals will not be published. This systematic review also should not damage participants' rights. Ethical approval is not available. The results may be published in a peer-reviewed journal or disseminated in relevant conferences.
OSF REGISTRATION NUMBER
DOI 10.17605/OSF.IO/FBCY6.
Topics: B7-H1 Antigen; Cell Death; Cell Survival; DNA, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Neuroblastoma; Prognosis; Meta-Analysis as Topic; Systematic Review as Topic
PubMed: 33655954
DOI: 10.1097/MD.0000000000024920 -
JCO Clinical Cancer Informatics Jan 2021Prognosis of high-risk neuroblastoma (HRNB) remains poor despite multimodal therapies. Better prediction of survival could help to refine patient stratification and...
Prognosis of high-risk neuroblastoma (HRNB) remains poor despite multimodal therapies. Better prediction of survival could help to refine patient stratification and better tailor treatments. We established a mechanistic model of metastasis in HRNB relying on two processes: growth and dissemination relying on two patient-specific parameters: the dissemination rate μ and the minimal visible lesion size S. This model was calibrated using diagnosis values of primary tumor size, lactate dehydrogenase circulating levels, and the meta-iodobenzylguanidine International Society for Paediatric Oncology European (SIOPEN) score from nuclear imaging, using data from 49 metastatic patients. It was able to describe the data of total tumor mass (lactate dehydrogenase, R > 0.99) and number of visible metastases (SIOPEN, R = 0.96). A prediction model of overall survival (OS) was then developed using Cox regression. Clinical variables alone were not able to generate a model with sufficient OS prognosis ability ( = .507). The parameter μ was found to be independent of the clinical variables and positively associated with OS ( = .0739 in multivariable analysis). Critically, addition of this computational biomarker significantly improved prediction of OS with a concordance index increasing from 0.675 (95% CI, 0.663 to 0.688) to 0.733 (95% CI, 0.722 to 0.744, < .0001), resulting in significant OS prognosis ability ( = .0422).
Topics: Child; Humans; Models, Theoretical; Neuroblastoma; Prognosis
PubMed: 33439729
DOI: 10.1200/CCI.20.00092 -
Head and Neck Pathology Sep 2021Neuroblastoma is the most common extracranial solid cancer of infancy, occurring mainly in the adrenal gland, with high metastatic potential. However, involvement of the... (Review)
Review
Neuroblastoma is the most common extracranial solid cancer of infancy, occurring mainly in the adrenal gland, with high metastatic potential. However, involvement of the head and neck region is rare. Here, we present two cases of metastatic neuroblastoma of childhood, in which a mandibular swelling was the first sign of disseminated disease. Case 1 describes a 4-year-old boy with a 2-week history of painful swelling in the left mandibular region, body soreness and weakness. Panoramic radiography and computed tomography showed a destructive lesion in the left mandibular ramus. Case 2 describes a 3-year-old boy with a 1-month history of swelling in the right mandibular area. Panoramic radiograph and cone-beam computed tomography showed a destructive lesion in the right body and ramus of the mandible, displacing tooth germs, with the destruction of vestibular and lingual bone cortices. In both cases, microscopic analyses revealed a diffuse proliferation of small, round, and blue cells with hyperchromatic nuclei and scant cytoplasm. While Case 1 was more undifferentiated, Case 2 presented eosinophilic areas suggestive of neuropil. A large immunohistochemical panel was performed, showing expression of neural markers such as CD56, neuron-specific enolase (in Case 2), chromogranin, and synaptophysin. Both lesions presented a high proliferation index (Ki67 > 70% and 80%, respectively). Positron emission tomography-computed tomography revealed ipsilateral adrenal primary lesions in both cases, with multiple bone metastatic lesions. Besides the mandible, multiple sites of the axial and appendicular skeleton were affected. Treatment consisted of induction chemotherapy, adrenalectomy, consolidation chemoradiotherapy, and post-consolidation therapy.
Topics: Adrenal Gland Neoplasms; Child, Preschool; Humans; Male; Mandibular Neoplasms; Neuroblastoma
PubMed: 33394374
DOI: 10.1007/s12105-020-01277-2 -
Frontiers in Cell and Developmental... 2020Neuroblastoma (NB) is a neural crest-derived tumor, which develops before birth or in early childhood, with metastatic dissemination typically preceding diagnosis....
Neuroblastoma (NB) is a neural crest-derived tumor, which develops before birth or in early childhood, with metastatic dissemination typically preceding diagnosis. Tumors are characterized by a highly heterogeneous combination of cellular phenotypes demonstrating varying degrees of differentiation along different lineage pathways, and possessing distinct super-enhancers and core regulatory circuits, thereby leading to highly varied malignant potential and divergent clinical outcomes. Cytoskeletal reorganization is fundamental to cellular transformations, including the processes of cellular differentiation and epithelial to mesenchymal transition (EMT), previously reported by our lab and others to coincide with chemotherapy resistance and enhanced metastatic ability of tumor cells. This study set out to investigate the ability of the neuronal miR-124-3p to reverse the cellular transformation associated with drug resistance development and assess the anti-oncogenic role of this miRNA in models of drug-resistant adrenergic (ADRN) and mesenchymal (MES) neuroblastoma cell lines. Low expression of miR-124-3p in a cohort of neuroblastomas was significantly associated with poor overall and progression-free patient survival. Over-expression of miR-124-3p inhibited cell viability through the promotion of cell cycle arrest and induction of apoptosis in addition to sensitizing drug-resistant cells to chemotherapeutics in a panel of morphologically distinct neuroblastoma cell lines. Finally, we describe miR-124-3p direct targeting and repression of key up-regulated cytoskeletal genes including , and and the reversal of the resistance-associated EMT and enhanced invasive capacity previously reported in our model (SK-N-ASCis24).
PubMed: 33330445
DOI: 10.3389/fcell.2020.559553 -
Pharmaceuticals (Basel, Switzerland) Oct 2020The survival rate among children with relapsed neuroblastomas continues to be poor, and thus new therapeutic approaches identified by reliable preclinical drug testing...
The survival rate among children with relapsed neuroblastomas continues to be poor, and thus new therapeutic approaches identified by reliable preclinical drug testing models are urgently needed. Zebrafish are a powerful vertebrate model in preclinical cancer research. Here, we describe a zebrafish neuroblastoma yolk sac model to evaluate efficacy and toxicity of histone deacetylase (HDAC) inhibitor treatments. Larvae were engrafted with fluorescently labeled, genetically diverse, established cell lines and short-term cultures of patient-derived primary cells. Engrafted tumors progressed locally and disseminated remotely in an intact environment. Combination treatments involving the standard chemotherapy doxorubicin and HDAC inhibitors substantially reduced tumor volume, induced tumor cell death, and inhibited tumor cell dissemination to the tail region. Hence, this model allows for fast, cost-efficient, and reliable in vivo evaluation of toxicity and response of the primary and metastatic tumor sites to drug combinations.
PubMed: 33121173
DOI: 10.3390/ph13110345 -
Cancer Medicine Jul 2020Regular off-treatment imaging is often used to assess for recurrence of disease after childhood cancer treatment. It is unclear if this increases survival, or what...
BACKGROUND
Regular off-treatment imaging is often used to assess for recurrence of disease after childhood cancer treatment. It is unclear if this increases survival, or what burden surveillance places on patients, families, or health-care services. This systematic review examines the impact of routine surveillance imaging after treatment of pediatric extracranial solid tumors.
METHODS
Collaborative patient and public involvement informed the design and interpretation of this work. Thirteen electronic databases, conference proceedings, and trial registries were searched alongside reference list checking and forward citation searching from 1990 onwards. Studies were screened and data were extracted by two researchers. Risk of bias was assessed using a modified ROBINS-I tool. Relevant outcomes were overall survival, psychological distress indicators, number of imaging tests, cost-effectiveness, and qualitative data regarding experiences of surveillance programs. PROSPERO (CRD42018103764).
RESULTS
Of 17 727 records identified, 55 studies of 10 207 patients were included. All studies used observational methods. Risk of bias for all except one study was moderate, serious, or critical. Data were too few to conduct meta-analysis; however, narrative synthesis was performed. Surveillance strategies varied, and poorly reported, involving many scans and substantial radiation exposure (eg, neuroblastoma, median 133.5 mSv). For most diseases, surveillance imaging was not associated with increased overall survival, with the probable exception of Wilms tumor. No qualitative or psychological distress data were identified.
CONCLUSIONS
At present, there is insufficient evidence to evaluate the effects of routine surveillance imaging on survival in most pediatric extracranial solid tumors. More high-quality data are required, preferably through randomized controlled trials with well-conducted qualitative elements.
Topics: Diagnostic Imaging; Female; Humans; Male; Neoplasms; Population Surveillance; Survival Analysis
PubMed: 32431088
DOI: 10.1002/cam4.3110 -
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 -
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