Neuroblastoma Origin and Therapeutic Targets for Immunotherapy

Холоденко, И. В.; Kalinovsky, Daniel V.; Doronin, Igor I.; Deyev, Sergey M.; Холоденко, Р. В.

doi:10.1155/2018/7394268

Cited by 134 publications

(124 citation statements)

References 251 publications

(267 reference statements)

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“…Gangliosides, including GM2 or GD2, belong to the family of glycosphingolipids (GSL) and contain one or more sialic acids, N-acetyl derivatives of neuraminic acid, in their hydrophilic oligosaccharide chain. 13 Gangliosides are sialic acid-containing glycosphingolipids that are most Results GM2/GD2 expression status in melanoma and neuroblastoma cell lines. To assess the GM2/ GD2 expression level, four melanoma (A-375, RPMI-7951, WM115 and SH4) and two neuroblastoma cell lines (IMR32 and RTBM1) were measured by flow cytometry.…”

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confidence: 99%

B4GALNT1 induces angiogenesis, anchorage independence growth and motility, and promotes tumorigenesis in melanoma by induction of ganglioside GM2/GD2

Yoshida

Koodie

Jacobsen

et al. 2020

Sci Rep

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β-1,4-N-Acetyl-Galactosaminyltransferase 1 (B4GALNT1) encodes the key enzyme B4GALNT1 to generate gangliosides GM2/GD2. GM2/GD2 gangliosides are surface glycolipids mainly found on brain neurons as well as peripheral nerves and skin melanocytes and are reported to exacerbate the malignant potential of melanomas. In order to elucidate the mechanism, we performed functional analyses of B4GALNT1-overexpressing cells. We analyzed ganglioside pattern on four melanoma and two neuroblastoma cell lines by high performance liquid chromatography (HPLC). We overexpressed B4GALNT1 in GM2/GD2-negative human melanoma cell line (SH4) and confirmed production of GM2/GD2 by HPLC. They showed higher anchorage independence growth (AIG) in colony formation assay, and exhibited augmented motility. In vitro, cell proliferation was not affected by GM2/GD2 expression. In vivo, GM2/GD2-positive SH4 clones showed significantly higher tumorigenesis in NOD/ Scid/IL2Rγ-null mice, and immunostaining of mouse CD31 revealed that GM2/GD2 induced remarkable angiogenesis. No differences were seen in melanoma stem cell and Epithelial-Mesenchymal Transition markers between GM2/GD2-positive and -negative SH4 cells. We therefore concluded that B4GALNT1, and consequently GM2/GD2, enhanced tumorigenesis via induction of angiogenesis, AIG, and cell motility. RNA-Seq suggested periostin as a potential key factor for angiogenesis and AIG. These findings may lead to development of novel therapy for refractory melanoma.abundant in the nervous system, especially brain neurons 14 . They also exist in peripheral nerves and skin melanocytes 15,16 . These molecules are reported to have important biological functions, such as intercellular communication, cell cycling, cell growth, adhesion, differentiation, and cell motility [17][18][19] . Gangliosides are not only detected at high levels in tumors of neuroectodermal cell origin but also related to the biological and clinical behavior of many kinds of tumors 20 . Recently, some analysis revealed that patients with higher expression of B4GALNT1 and GM2/GD2 correlated with poorer prognosis in renal cell carcinoma (TCGA data set; Human Protein Atlas), neuroblastoma 21 , and melanoma 22 . Thus, B4GALNT1 gene is considered to be key tumor-associated antigens [23][24][25][26][27] , indicating that their expression is a meaningful marker for metastatic condition and are potential therapeutic targets for melanoma.Our findings indicate the involvement of B4GALNT1 and GM2/GD2 in tumor establishment and progression as well as a potential direction of therapeutic approach via controlling B4GALNT1, and consequently GM2/GD2 expression in cancers such as melanoma. Scientific RepoRtS |(2020) 10:1199 | https://doi.Generation of GM2/GD2-positive SH4 melanoma clones. The SH4 cells were transfected with expression vectors with or without B4GALNT1 gene cassette, to establish GM2/GD2-positive and -negative SH4 clones. Two GM2/GD2-high clones were selected by single cell isolation (#4 and #5, Fig. S2A). These two clones showed significa...

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confidence: 99%

B4GALNT1 induces angiogenesis, anchorage independence growth and motility, and promotes tumorigenesis in melanoma by induction of ganglioside GM2/GD2

Yoshida

Koodie

Jacobsen

et al. 2020

Sci Rep

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“…The high heterogeneity of NB derives from its transient embryonic structure, leading to a wide range of cellular phenotypes, sometimes present even in a single tumor (Aygun, 2018). The phenotypic analysis has uncovered miscellaneous types of highly expressed surface markers that can also act in tumorigenesis or contribute to progression of the oncologic process [e.g., CD117, CD133, CD114, CD57, CD171, or disialoganglioside 2 (GD2)] (Malone and Stegmaier, 2017;Kholodenko et al, 2018).…”

Section: Therapeutic Strategies In Neuroblastoma: Targeting High-riskmentioning

confidence: 99%

“…This immunotherapeutic approach is in many cases administered along with interleukin-2 and isotretinoin in the maintenance therapy. Clinicians have reported that the combination of this anti-GD2 antibody with other therapies increased the 5-year survival rates of NB patients by 20% (Kholodenko et al, 2018). An incoming Children's Oncology Group trial is planning to include immunotherapy in the induction stage to evaluate the benefits when combined with chemotherapy.…”

Section: Therapeutic Strategies In Neuroblastoma: Targeting High-riskmentioning

confidence: 99%

Therapeutic Opportunities in Neuroblastoma Using Nanotechnology

Rodríguez-Nogales

Noguera

Couvreur

et al. 2019

J Pharmacol Exp Ther

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Neuroblastoma (NB) is the most common extracranial solid tumor preferentially occurring in preschoolers. Its characteristic aggressiveness and heterogeneous clinical behavior are especially visible in relapsed or refractory cases and hamper therapeutic success. Although the introduction of novel antitumor agents, such as dinutuximab, isotretinoin, irinotecan, or I-131-metaiodobenzylguanidine, has increased survival rates, the situation in high-risk NB remains dismal. Moreover, treatment is particularly aggressive in these patients, leading to short-and long-term toxicities. The extensive research performed using nanotechnology in recent decades has prompted its application as a therapeutic alternative to overcome some of the common limitations of conventional chemotherapy. Nevertheless, the therapeutic role of nanomedicine in pediatric tumors like NB is not fully elucidated, and to date, only albuminbound paclitaxel nanoparticles have reached clinic stages. In this review, we summarize the current therapeutic strategies for NB with special attention to the use of nanomedicine. We also highlight the preclinical studies on passive and active targeting nanodelivery of therapeutics in experimental NB models.

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“…Neuroblastoma (NB) is the most common extracranial solid tumor in children, accounting for 7% of all pediatric tumors in patients under 15 years of age, and 15% of all pediatric deaths caused by cancer. The world mortality rate is 0.85-1.1 per 100,000 children under 15 years of age [1]. At present, the overall survival rate (OS) of low-and medium-risk NB is above 90% [2,3].…”

Section: Introductionmentioning

confidence: 99%

Bioinformatics Analysis Combined with Experiments to Explore Neuroblastoma Prognostic Indicators Based on Immune-related Genes.

Shao

Wang

2020

Preprint

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Background：Due to the extremely high mortality rate of children with high-risk Neuroblastoma (NB), there is an urgent need for new indicators to further classify children in the high-risk group for more precise treatment. The purpose of our research is to explore the immune-related genes in NB in the high-risk group, and to further identify and develop a prognostic nomogram based on immune IRG signatures. Methods：Through bioinformatics analysis to explore the abnormal expression of immune-related genes in the high-risk group. Cox regression and the least absolute shrinkage and selection operator (LASSO) analysis were conducted to identify the immune and overall survival (OS) related mRNA. The accuracy of the risk score is evaluated by Kaplan-Meier method and receiver operating characteristics (ROC) analysis, which is used to build a nomogram in combination with other clinical characteristics.. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the accuracy of our results. Results：A total of 127 common differentially expressed immune genes were found between the high-risk group and the non-high-risk group of the two data sets. Four immune-related genes (IRG) related to prognosis were identified and a risk score was established. Kaplan–Meier survival analysis and time-dependent ROC analysis showed that the 4-IRG risk score has satisfactory predictive potential and achieved consistency in the verification of external data sets. Subsequently, the risk score combined with clinical characteristics draws a nomogram. The reliability of the results was verified on 29 cases of NB tissues by qRT-PCR. Conclusions：Overall, we have developed a powerful multi-gene classifier that can effectively classify NB patients into low- and high-risk groups with poor prognosis, and draw a nomogram for children in the high-risk group. This feature can help select high-risk patients who need more aggressive adjuvant target therapy or immunotherapy.

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Neuroblastoma Origin and Therapeutic Targets for Immunotherapy

Cited by 134 publications

References 251 publications

B4GALNT1 induces angiogenesis, anchorage independence growth and motility, and promotes tumorigenesis in melanoma by induction of ganglioside GM2/GD2

B4GALNT1 induces angiogenesis, anchorage independence growth and motility, and promotes tumorigenesis in melanoma by induction of ganglioside GM2/GD2

Therapeutic Opportunities in Neuroblastoma Using Nanotechnology

Bioinformatics Analysis Combined with Experiments to Explore Neuroblastoma Prognostic Indicators Based on Immune-related Genes.

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