Neuroblastoma aggressiveness in relation to sympathetic neuronal differentiation stage

Mohlin, Sofie; Wigerup, Caroline; Påhlman, Sven

doi:10.1016/j.semcancer.2011.09.002

Cited by 29 publications

(31 citation statements)

References 92 publications

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“…Present ultrastructural findings support previous findings that cells in tumours with an unfavorable prognosis appear less differentiated (2). Our finding of the NSGs in cell bodies could, therefore, imply that NSGs have not yet extended from cell bodies into cell processes.…”

Section: Discussionsupporting

confidence: 90%

“…Peripheral neuroblastic tumours display a correlation between their morphological characteristics and prognoses, which could imply that systematic investigation of these differences between tumour cells, with varying outcomes and levels of differentiation, could prove to be useful in revealing the mechanisms of biological development of the said tumours (2).…”

Section: Discussionmentioning

confidence: 99%

“…the organ of Zuckerkandl) (1). Carcinogenesis initiates in the fetal or early neonatal period, disabling further differentiation of cells of the future adrenal medulla, autonomic nervous system, Schwann cells, melanocytes and some members of the diffuse neuroendocrine system (DNES) (2). These tumours represent a type of the most frequently diagnosed solid, extracranial growths of early childhood and additionally stand out by the heterogeneous wide scope of clinical symptoms their diagnosis entails (1).…”

Section: Introductionmentioning

confidence: 99%

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Ultrastructural morphometry of neurosecretory granules in the neuroblastomas of paediatric patients

Jovanović¹,

Kravić-Stevović²

2018

Medicinski podmladak

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Introduction: Peripheral neuroblastic tumours are among the most frequently detected tumours in paediatric patients. A correlation between the aggressiveness of these tumours and their clinical prognosis has been discovered. Neurosecretory granules containing neurotransmitters, an ultrastructural feature of neurons, were found in the cells of peripheral neuroblastic tumours, as well.Aim: The aim of this study was to compare the number of neurosecretory granules found in cells of tumours, with a favourable prognosis to the corresponding number in cells of tumours and with an unfavourable one with the use of transmission electron microscopy (TEM).Material and Methods: Ten tissue biopsies were obtained from paediatric patients diagnosed with peripheral neuroblastic tumours. The tumour samples were first frozen, then fixed in glutaraldehyde, and embedded in epoxy resin. Ultrastructural morphometric analysis was performed on ultrathin sections.Results: When observed under a transmission electron microscope (TEM), neurosecretory granules appear as round structures of a small diameter, with an electron dense centre surrounded by an electron lucent, peripheral halo. It was found that the cells of tumours with an unfavourable prognosis have more neurosecretory granules (141.2 ± 89.18 per 60 cells per sample, on average) in their cytoplasm than the cells of tumours with a favourable one (37.2 ± 41.17 per 60 cells per sample, on average). Conclusion:The larger number of neurosecretory granules found in cells of tumours with an unfavourable prognosis could potentially shed some light on the role these structures play in tumourigenesis of peripheral neuroblastic tumours.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ultrastructural morphometry of neurosecretory granules in the neuroblastomas of paediatric patients

Jovanović¹,

Kravić-Stevović²

2018

Medicinski podmladak

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“…A homing to the perivascular niche is in line with the notion that NB could be considered a stem cell disease of the sympathetic nervous system (5) and that the perivascular niche supports stem cell self-renewal capacity and an undifferentiated state of neural tumor cells (22).…”

Section: Discussionsupporting

confidence: 71%

“…Neuroblastoma is a small round cell tumor of childhood and is considered to arise from dedifferentiation of primordial neural crest cells that populate the sympathetic trunks and the adrenal medulla (reviewed in ref. 5). During this process, an aberrant response to microenvironment cues may play an important role in modulating the tumor phenotype, and hence also lead to the variable clinical presentations of NB in patients.…”

Section: Introductionmentioning

confidence: 99%

Neuroblastoma cells injected into experimental mature teratoma reveal a tropism for embryonic loose mesenchyme

Jamil

Cedervall

Hultman

et al. 2013

International Journal of Oncology

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Abstract. Embryonic neural tumors are responsible for a disproportionate number of cancer deaths in children. Although dramatic improvements in survival for pediatric malignancy has been achieved in previous years advancements seem to be slowing down. For the development of new enhanced therapy and an increased understanding of the disease, pre-clinical models better capturing the neoplastic niche are essential. Tumors of early childhood present in this respect a particular challenge. Here, we explore how components of the embryonic process in stem-cell induced mature teratoma can function as an experimental in vivo microenvironment instigating the growth of injected childhood neuroblastoma (NB) cell lines. Three human NB cell lines, IMR-32, Kelly and SK-N-BE(2), were injected into mature pluripotent stem cell-induced teratoma (PSCT) and compared to xenografts of the same cell lines. Proliferative NB cells from all lines were readily detected in both models with a typical histology of a poorly differentiated NB tumor with a variable amount of fibrovascular stroma. Uniquely in the PSCT microenvironment, NB cells were found integrated in a non-random fashion. Neuroblastoma cells were never observed in areas with well-differentiated somatic tissue i.e. bone, muscle, gut or areas of other easily identifiable tissue types. Instead, the three cell lines all showed initial growth exclusively occurring in the embryonic loose mesenchymal stroma, resulting in a histology recapitulating NB native presentation in vivo. Whether this reflects the 'open' nature of loose mesenchyme more easily giving space to new cells compared to other more dense tissues, the rigidity of matrix providing physical cues modulating NB characteristics, or if embryonic loose mesenchyme may supply developmental cues that attracted or promoted the integration of NB, remains to be tested. We tentatively hypothesize that mature PSCT provide an embryonic niche well suited for in vivo studies on NB. IntroductionKey knowledge is still missing for the successful cure of aggressive neuroblastoma (NB), representing one of the most deadly pediatric malignancies (1-4). Neuroblastoma is a small round cell tumor of childhood and is considered to arise from dedifferentiation of primordial neural crest cells that populate the sympathetic trunks and the adrenal medulla (reviewed in ref. 5). During this process, an aberrant response to microenvironment cues may play an important role in modulating the tumor phenotype, and hence also lead to the variable clinical presentations of NB in patients. The clinical presentation spans from a benign type with the ability to spontaneously regress to a variant with a high rate of recurrence, metastatic spread and a high frequency of therapy-resistance. Current consensus supports the importance of a strong interplay with the surrounding tissue promoting tumor growth and spread (6). Thus, pre-clinical studies of childhood NB would for increased relevance benefit from in vivo models better matching the embryonic neoplastic niche i...

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Identification of a novel gene signature for neuroblastoma differentiation using a Boolean implication network

Zage

Huo

Subramonian

et al. 2023

Genes Chromosomes & Cancer

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Although induction of differentiation represents an effective strategy for neuroblastoma treatment, the mechanisms underlying neuroblastoma differentiation are poorly understood. We generated a computational model of neuroblastoma differentiation consisting of interconnected gene clusters identified based on symmetric and asymmetric gene expression relationships. We identified a differentiation signature consisting of series of gene clusters comprised of 1251 independent genes that predicted neuroblastoma differentiation in independent datasets and in neuroblastoma cell lines treated with agents known to induce differentiation. This differentiation signature was associated with patient outcomes in multiple independent patient cohorts and validated the role of MYCN expression as a marker of neuroblastoma differentiation. Our results further identified novel genes associated with MYCN via asymmetric Boolean implication relationships that would not have been identified using symmetric computational approaches and that were associated with both neuroblastoma differentiation and patient outcomes. Our differentiation signature included a cluster of genes involved in intracellular signaling and growth factor receptor trafficking pathways that is strongly associated with neuroblastoma differentiation, and we validated the associations of UBE4B, a gene within this cluster, with neuroblastoma cell and tumor differentiation. Our findings demonstrate that Boolean network analyses of symmetric and asymmetric gene expression relationships can identify novel genes and pathways relevant for neuroblastoma tumor differentiation that could represent potential therapeutic targets.

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Neuroblastoma aggressiveness in relation to sympathetic neuronal differentiation stage

Cited by 29 publications

References 92 publications

Ultrastructural morphometry of neurosecretory granules in the neuroblastomas of paediatric patients

Ultrastructural morphometry of neurosecretory granules in the neuroblastomas of paediatric patients

Neuroblastoma cells injected into experimental mature teratoma reveal a tropism for embryonic loose mesenchyme

Identification of a novel gene signature for neuroblastoma differentiation using a Boolean implication network

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