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Clinical Cancer Research : An Official... Aug 2017Tumor relapse is the most frequent cause of death in stage 4 neuroblastomas. Since genomic information on the relapse precursor cells could guide targeted therapy, our...
Tumor relapse is the most frequent cause of death in stage 4 neuroblastomas. Since genomic information on the relapse precursor cells could guide targeted therapy, our aim was to find the most appropriate tissue for identifying relapse-seeding clones. We analyzed 10 geographically and temporally separated samples of a single patient by SNP array and validated the data in 154 stage 4 patients. In the case study, aberrations unique to certain tissues and time points were evident besides concordant aberrations shared by all samples. Diagnostic bone marrow-derived disseminated tumor cells (DTCs) as well as the metastatic tumor and DTCs at relapse displayed a 1q deletion, not detected in any of the seven primary tumor samples. In the validation cohort, the frequency of 1q deletion was 17.8%, 10%, and 27.5% in the diagnostic DTCs, diagnostic tumors, and DTCs at relapse, respectively. This aberration was significantly associated with 19q and deletions. We observed a significant increased likelihood of an adverse event in the presence of 19q deletion in the diagnostic DTCs. Different frequencies of 1q and 19q deletions in the primary tumors as compared with DTCs, their relatively high frequency at relapse, and their effect on event-free survival (19q deletion) indicate the relevance of analyzing diagnostic DTCs. Our data support the hypothesis of a branched clonal evolution and a parallel progression of primary and metastatic tumor cells. Therefore, searching for biomarkers to identify the relapse-seeding clone should involve diagnostic DTCs alongside the tumor tissue. .
Topics: Adult; Aged; Aged, 80 and over; Bone Marrow Cells; Child, Preschool; Chromosomes, Human, Pair 19; Clonal Evolution; Disease-Free Survival; Female; Gene Deletion; Genetic Heterogeneity; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasms, Second Primary; Neoplastic Cells, Circulating; Neuroblastoma; Polymorphism, Single Nucleotide; Recurrence; X-linked Nuclear Protein
PubMed: 28228384
DOI: 10.1158/1078-0432.CCR-16-2082 -
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 -
Pediatric Blood & Cancer Jul 2018Craniospinal irradiation (CSI) is an important part of curative radiation therapy (RT) for many types of pediatric brain or solid tumors. After conventional CSI, long...
BACKGROUND
Craniospinal irradiation (CSI) is an important part of curative radiation therapy (RT) for many types of pediatric brain or solid tumors. After conventional CSI, long term survivors may experience sequelae due to unintended dose to normal tissue. Volumetric modulated arc therapy (VMAT) CSI reduces off-target doses at the cost of greater complexity and error risk, and we describe our initial experience in a group of pediatric patients with solid tumors presenting with disseminated or recurrent disease.
PROCEDURE
Pediatric patients with brain tumors were identified at Children's Hospital Los Angeles from 2013 to 2015. Clinical characteristics, acute toxicity, and radiotherapy data were abstracted from their medical records. We identified 19 patients who received VMAT CSI. Quality assurance was performed with a cylindrical detector array and ion chamber measurements at the arc junctions.
RESULTS
Patients had medulloblastoma or supratentorial primitive neuro-ectodermal tumor (n = 14, 11 high risk), germ cell tumors (two), relapsed neuroblastoma (two), and atypical teratoid/rhabdoid tumor (one). The most common acute toxicity was hematologic, including leukopenia (11% grade [Gr] 2, 26% Gr 3, and 63% Gr 4), anemia (89% Gr 2), and thrombocytopenia (16% Gr 1-2, 26% Gr 3, and 37% Gr 4). Despite leukopenia, we encountered only two Gr 3 infections (urinary tract and lung). The majority required blood products (89% red blood cells and 68% platelets). Weight loss was also common (47% Gr 1 and 26% Gr 2).
CONCLUSIONS
VMAT CSI, along with chemotherapy and anesthesia, is feasible with supportive care. Daily image-guided RT improves accuracy and reduces the risk of spinal cord overdose without increasing treatment time. Further research is needed to determine whether reducing doses to organs, such as thyroid, heart, or hippocampus, offsets the risk of increased volume of low-dose irradiation.
Topics: Adolescent; Brain Neoplasms; Child; Child, Preschool; Craniospinal Irradiation; Female; Humans; Male; Organs at Risk; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Intensity-Modulated; Retrospective Studies
PubMed: 29630782
DOI: 10.1002/pbc.27050 -
Nature Communications May 2022Embryonic malignant transformation is concomitant to organogenesis, often affecting multipotent and migratory progenitors. While lineage relationships between malignant...
Embryonic malignant transformation is concomitant to organogenesis, often affecting multipotent and migratory progenitors. While lineage relationships between malignant cells and their physiological counterparts are extensively investigated, the contribution of exogenous embryonic signals is not fully known. Neuroblastoma (NB) is a childhood malignancy of the peripheral nervous system arising from the embryonic trunk neural crest (NC) and characterized by heterogeneous and interconvertible tumor cell identities. Here, using experimental models mimicking the embryonic context coupled to proteomic and transcriptomic analyses, we show that signals released by embryonic sympathetic ganglia, including Olfactomedin-1, induce NB cells to shift from a noradrenergic to mesenchymal identity, and to activate a gene program promoting NB metastatic onset and dissemination. From this gene program, we extract a core signature specifically shared by metastatic cancers with NC origin. This reveals non-cell autonomous embryonic contributions regulating the plasticity of NB identities and setting pro-dissemination gene programs common to NC-derived cancers.
Topics: Cell Differentiation; Child; Cues; Humans; Neural Crest; Neuroblastoma; Proteomics
PubMed: 35538114
DOI: 10.1038/s41467-022-30237-3 -
International Journal of Cancer Jan 2018Neuroblastoma is the most common extracranial solid tumor in childhood. The vast majority of metastatic (M) stage patients present with disseminated tumor cells (DTCs)...
Neuroblastoma is the most common extracranial solid tumor in childhood. The vast majority of metastatic (M) stage patients present with disseminated tumor cells (DTCs) in the bone marrow (BM) at diagnosis and relapse. Although these cells represent a major obstacle in the treatment of neuroblastoma patients, insights into their expression profile remained elusive. The present RNA-Seq study of stage 4/M primary tumors, enriched BM-derived diagnostic and relapse DTCs, as well as the corresponding BM-derived mononuclear cells (MNCs) from 53 patients revealed 322 differentially expressed genes in DTCs as compared to the tumors (q < 0.001, |log FC|>2). Particularly, the levels of transcripts encoded by mitochondrial DNA were elevated in DTCs, whereas, for example, genes involved in angiogenesis were downregulated. Furthermore, 224 genes were highly expressed in DTCs and only slightly, if at all, in MNCs (q < 8 × 10 log FC > 6). Interestingly, we found the transcriptome of relapse DTCs largely resembling those of diagnostic DTCs with only 113 differentially expressed genes under relaxed cut-offs (q < 0.01, |log FC|>0.5). Notably, relapse DTCs showed a positional enrichment of 31 downregulated genes on chromosome 19, including five tumor suppressor genes: SIRT6, BBC3/PUMA, STK11, CADM4 and GLTSCR2. This first RNA-Seq analysis of neuroblastoma DTCs revealed their unique expression profile in comparison to the tumors and MNCs, and less pronounced differences between diagnostic and relapse DTCs. The latter preferentially affected downregulation of genes encoded by chromosome 19. As these alterations might be associated with treatment failure and disease relapse, further functional studies on DTCs should be considered.
Topics: Biomarkers, Tumor; Bone Marrow Neoplasms; Disease Progression; High-Throughput Nucleotide Sequencing; Humans; Neoplastic Cells, Circulating; Neuroblastoma; Prognosis; Transcriptome
PubMed: 28921546
DOI: 10.1002/ijc.31053 -
BMC Cancer Jun 2022The bone marrow (BM) is the most common site of dissemination in patients with aggressive, metastatic neuroblastoma (NB). However, the molecular mechanisms underlying...
BACKGROUND
The bone marrow (BM) is the most common site of dissemination in patients with aggressive, metastatic neuroblastoma (NB). However, the molecular mechanisms underlying the aggressive behavior of NB cells in the BM niche are still greatly unknown. In the present study, we explored biological mechanisms that play a critical role in NB cell survival and progression in the BM and investigated potential therapeutic targets.
METHODS
Patient-derived bone marrow (BM) primary cultures were generated using fresh BM aspirates obtained from NB patients. NB cell lines were cultured in the presence of BM conditioned media containing cell-secreted factors, and under low oxygen levels (1% O) to mimic specific features of the BM microenvironment of high-risk NB patients. The BM niche was explored using cytokine profiling assays, cell migration-invasion and viability assays, flow cytometry and analysis of RNA-sequencing data. Selective pharmacological inhibition of factors identified as potential mediators of NB progression within the BM niche was performed in vitro and in vivo.
RESULTS
We identified macrophage migration inhibitory factor (MIF) as a key inflammatory cytokine involved in BM infiltration. Cytokine profiling and RNA-sequencing data analysis revealed NB cells as the main source of MIF in the BM, suggesting a potential role of MIF in tumor invasion. Exposure of NB cells to BM-conditions increased NB cell-surface expression of the MIF receptor CXCR4, which was associated with increased cell viability, enhanced migration-invasion, and activation of PI3K/AKT and MAPK/ERK signaling pathways. Moreover, subcutaneous co-injection of NB and BM cells enhanced tumor engraftment in mice. MIF inhibition with 4-IPP impaired in vitro NB aggressiveness, and improved drug response while delayed NB growth, improving survival of the NB xenograft model.
CONCLUSIONS
Our findings suggest that BM infiltration by NB cells may be mediated, in part, by MIF-CXCR4 signaling. We demonstrate the antitumor efficacy of MIF targeting in vitro and in vivo that could represent a novel therapeutic target for patients with disseminated high-risk NB.
Topics: Animals; Bone Marrow; Bone Marrow Cells; Drug Resistance; Humans; Intramolecular Oxidoreductases; Macrophage Migration-Inhibitory Factors; Mice; Neoplastic Processes; Neuroblastoma; Phosphatidylinositol 3-Kinases; RNA; Receptors, CXCR4; Tumor Microenvironment
PubMed: 35715791
DOI: 10.1186/s12885-022-09725-8 -
BioRxiv : the Preprint Server For... Jan 2024Neuroblastoma remains a formidable challenge in pediatric oncology, representing 15% of cancer-related mortalities in children. Despite advancements in combinatorial and...
Neuroblastoma remains a formidable challenge in pediatric oncology, representing 15% of cancer-related mortalities in children. Despite advancements in combinatorial and targeted treatments improving survival rates, nearly 50% of patients with high-risk neuroblastoma will ultimately succumb to their disease. Dysregulation of the epithelial-mesenchymal transition (EMT) is a key mechanism of tumor cell dissemination, resulting in metastasis and poor outcomes in many cancers. Our prior work identified PRMT5 as a key regulator of EMT via methylation of AKT at arginine 15, enhancing the expression of EMT-driving transcription factors and facilitating metastasis. Here, we identify that PRMT5 directly regulates the transcription of the epidermal growth factor receptor (EGFR). PRMT5, through independent modulation of the EGFR and AKT pathways, orchestrates the activation of NFκB, resulting in the upregulation of the pro-EMT transcription factors ZEB1, SNAIL, and TWIST1. Notably, EGFR and AKT form a compensatory feedback loop, reinforcing the expression of these EMT transcription factors. Small molecule inhibition of PRMT5 methyltransferase activity disrupts EGFR/AKT signaling, suppresses EMT transcription factor expression and ablates tumor growth . Our findings underscore the pivotal role of PRMT5 in the control of the EMT program in high-risk neuroblastoma.
PubMed: 38260418
DOI: 10.1101/2024.01.03.574104 -
Cancer Research Nov 2015Hypoxia-inducible factor (HIF) is a master regulator of cellular responses to oxygen deprival with a critical role in mediating the angiogenic switch in solid tumors....
Hypoxia-inducible factor (HIF) is a master regulator of cellular responses to oxygen deprival with a critical role in mediating the angiogenic switch in solid tumors. Differential expression of the HIF subunits HIF1α and HIF2α occurs in many human tumor types, suggesting selective implications to biologic context. For example, high expression of HIF2α that occurs in neuroblastoma is associated with stem cell-like features, disseminated disease, and poor clinical outcomes, suggesting pivotal significance for HIF2 control in neuroblastoma biology. In this study, we provide novel insights into how HIF2α expression is transcriptionally controlled by hypoxia and how this control is abrogated by inhibition of insulin-like growth factor-1R/INSR-driven phosphoinositide 3-kinase (PI3K) signaling. Reducing PI3K activity was sufficient to decrease HIF2α mRNA and protein expression in a manner with smaller and less vascularized tumors in vivo. PI3K-regulated HIF2A mRNA expression was independent of Akt or mTORC1 signaling but relied upon mTORC2 signaling. HIF2A mRNA was induced by hypoxia in neuroblastoma cells isolated from metastatic patient-derived tumor xenografts, where HIF2A levels could be reduced by treatment with PI3K and mTORC2 inhibitors. Our results suggest that targeting PI3K and mTORC2 in aggressive neuroblastomas with an immature phenotype may improve therapeutic efficacy.
Topics: Adaptor Proteins, Signal Transducing; Animals; Antigens, CD; Basic Helix-Loop-Helix Transcription Factors; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Mice, Nude; Multiprotein Complexes; Neovascularization, Pathologic; Neuroblastoma; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; RNA Interference; RNA, Messenger; RNA, Small Interfering; Receptor, IGF Type 1; Receptor, IGF Type 2; Receptor, Insulin; Receptors, Somatomedin; Regulatory-Associated Protein of mTOR; Signal Transduction; TOR Serine-Threonine Kinases; Transcription, Genetic
PubMed: 26432405
DOI: 10.1158/0008-5472.CAN-15-0708 -
Oncology Letters Jun 2017Disseminated carcinomatosis of the bone marrow (DCBM) is a condition in which bone marrow (BM) metastases diffusely invade the BM, and is frequently accompanied by...
Disseminated carcinomatosis of the bone marrow with disseminated intravascular coagulation as the first symptom of recurrent rectal cancer successfully treated with chemotherapy: A case report and review of the literature.
Disseminated carcinomatosis of the bone marrow (DCBM) is a condition in which bone marrow (BM) metastases diffusely invade the BM, and is frequently accompanied by disseminated intravascular coagulation (DIC). While prostate, lung, breast and stomach malignancies, in addition to neuroblastoma, are the most prevalent non-hematological malignancies to metastasize frequently to the BM, colorectal cancer is a malignancy that rarely metastasizes to the BM. The present case describes a 65-year-old male patient treated by resection and one course adjuvant chemotherapy for stage IIIC rectal cancer who presented with nasal bleeding at 8 months post-surgery. A blood test exhibited DIC. A BM biopsy was performed and the definitive diagnosis was DCBM with DIC. Promptly, anti-DIC treatment and chemotherapy with a modified FOLFOX6 (folinic acid, leucovorin (LV), 5-fluorouracil (5-FU) and oxaplatin) regimen was started. Following 1 cycle of chemotherapy, DIC was improved and subsequent to 2 cycles of modified FOLFOX6 the patient was discharged. The patient was alive 263 days subsequent to the diagnosis of DIC, but succumbed to carcinomatous meningitis as a result of disease progression. To the best of our knowledge, this is the first report of DCBM with DIC of curatively resected rectal cancer as the first presentation of relapse that was successfully treated with aggressive therapy, including chemotherapy.
PubMed: 28599429
DOI: 10.3892/ol.2017.5983 -
Pediatric and Developmental Pathology :... 2022Neuroblastoma (NB) is among the most common cancers in children. A highly aggressive form of cancer, NB relies on cells in the microenvironment for dissemination...
BACKGROUND
Neuroblastoma (NB) is among the most common cancers in children. A highly aggressive form of cancer, NB relies on cells in the microenvironment for dissemination particularly cancer associated fibroblast (CAFs). CAFs synthesise the extracellular matrix to create a scaffold for tumor growth thus enabling the carcinogenesis of NB, Collagen, an abundant scaffold protein produced by CAFs, has been implicated in the creation of an optimal tumor microenvironment, however, the expression profile of collagen within NB is not yet known.
METHODS
We characterised collagen expression within the tumor-stroma boundary by microarray and confirmed by qRT-PCR and immunohistochemistry.
RESULTS
The collagen marker, COL11A1, was also upregulated in NB CD45+ cells and SMA+ CAFs. Furthermore, SMA+ CAFs led to neuroblastoma cell invasion in an in vitro co-culture system which was subsequently attenuated by gene silencing COL11A1. Immunohistochemical staining of clinical tumor samples revealed that high COL11A1 expression in the stroma adjacent to tumour site, significantly associated with advanced cancer stages, age ≥18 months, undifferentiated tumor status, relapse and poor overall survival.
CONCLUSION
Collectively, these results suggest that a COL11A1 signature in the NB microenvironment could represent a novel target for therapeutic intervention.
Topics: Cancer-Associated Fibroblasts; Child; Collagen; Collagen Type XI; Humans; Infant; Neoplasm Recurrence, Local; Neuroblastoma; Tumor Microenvironment
PubMed: 34460335
DOI: 10.1177/10935266211039200