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Biomolecules
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Molecular and Biological Enigma of Neuroblastoma: How to Solve It?
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Molecular and Biological Enigma of Neuroblastoma: How to Solve It?

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 27681

Special Issue Editor

Prof. Dr. Akira Nakagawara

E-Mail Website
Guest Editor
Heavy Ion Beam Cancer Therapy Center, Saga HIMAT Foundation, Saga 841-0071, Japan
Interests: molecular biology of cancer; cancer genetics; receptor signaling; neural development; cancer predisposition; DNA repair; transcriptional regulation; cell division; Myc family; p53 family; programmed cell death; microenvironment; drug development; molecular biology and genetics of neuroblastoma; spontaneous regression of neuroblastoma

Special Issue Information

Dear Colleagues,

Neuroblastoma, one of the typical solid tumors in children, originates specifically from the sympathoadrenal lineage of the neural crest. More than half of the patients are diagnosed at stage 4 with distant metastases, and their prognosis is still very poor. The clinical behavior of neuroblastoma spans from spontaneous regression, frequently observed in infants, to aggressive and therapy-resistant growth found in children of more than 18 months of age.

For the last decades, as science and technology have rapidly advanced, we have learned much about the molecular and genetic mechanisms of neuroblastoma. Nevertheless, several unanswered questions concerning neuroblastoma make it difficult to understand its mechanisms and design better patient cures. We know that the master gene causing neuroblastoma is MYCN. However, the biology and clinical behavior of neuroblastoma are strongly reflected by a lineage-specific developmental program and genetic dysfunction, as well as a tumor microenvironment, the mechanisms of which remain elusive.

In this Special Issue, we discuss those problems and how to solve them by focusing on the enigma of neuroblastoma. The title is “Molecular and Biological Enigma of Neuroblastoma: How to Solve It?”

Review articles, original research, and comments about the following subjects are welcome. The actual title of the paper can be modified.

  • Why is the genetic and pathological heterogeneity of neuroblastoma so complex?
  • Where is the origin of stromal Schwann-like cells in neuroblastoma?
  • Why and how does spontaneous regression of neuroblastoma occur? 
  • Why is unknown origin neuroblastoma present?
  • Why is the age a strong prognostic factor in neuroblastoma? 
  • Why is aneuploidy associated with favorable outcome in neuroblastoma?
  • Why is MYCN the master regulator in neuroblastoma?
  • How does epigenetics regulate the development and biology of neuroblastoma?
  • Why doe the initial response and the late resistance occur in high-risk neuroblastoma?
  • Why is immunotherapy promising in neuroblastoma?

Prof. Dr. Akira Nakagawara
Guest Editor

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Keywords

  • neuroblastoma
  • heterogeneity
  • spontaneous regression
  • unknown origin
  • DNA ploidy
  • MYCN
  • epigenetics
  • immunotherapy

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Published Papers (6 papers)

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Research

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17 pages, 1204 KiB  
Article
Retrospective Analysis of INRG Clinical and Genomic Factors for 605 Neuroblastomas in Japan: A Report from the Japan Children’s Cancer Group Neuroblastoma Committee (JCCG-JNBSG)
by Miki Ohira, Yohko Nakamura, Tetsuya Takimoto, Atsuko Nakazawa, Tomoro Hishiki, Kimikazu Matsumoto, Hiroyuki Shichino, Tomoko Iehara, Hiroki Nagase, Takashi Fukushima, Akihiro Yoneda, Tatsuro Tajiri, Akira Nakagawara and Takehiko Kamijo
Biomolecules 2022, 12(1), 18; https://doi.org/10.3390/biom12010018 - 23 Dec 2021
Cited by 10 | Viewed by 3289
Abstract
Neuroblastomas (NBs) exhibit broad and divergent clinical behaviors and tumor risk classification at diagnosis is crucial for the selection of an appropriate therapeutic strategy for each patient. The present study aimed to validate the clinical relevance of International Neuroblastoma Risk Group (INRG) prognostic [...] Read more.
Neuroblastomas (NBs) exhibit broad and divergent clinical behaviors and tumor risk classification at diagnosis is crucial for the selection of an appropriate therapeutic strategy for each patient. The present study aimed to validate the clinical relevance of International Neuroblastoma Risk Group (INRG) prognostic and genomic markers in a Japanese NB cohort using a retrospective analysis. Follow-up data based on 30 common INRG queries in 605 NB cases diagnosed in Japan between 1990 and 2014 were collected and the genome signature of each tumor sample was integrated. As previously indicated, age, tumor stage, MYCN, DNA ploidy, the adrenals as the primary tumor site, serum ferritin and lactate dehydrogenase (LDH) levels, segmental chromosome aberrations, and the number of chromosome breakpoints (BP) correlated with lower survival rates, while the thorax as the primary tumor site and numerical chromosome aberrations correlated with a favorable prognosis. In the patient group with stage 4, MYCN non-amplified tumors (n = 225), one of the challenging subsets for risk stratification, age ≥ 18 months, LDH ≥ 1400 U/L, and BP ≥ 7 correlated with lower overall and event-free survival rates (p < 0.05). The genome subgroup GG-P2s (partial chromosome gain/loss type with 1p/11q losses and 17q gain, n = 30) was strongly associated with a lower overall survival rate (5-year survival rate: 34%, p < 0.05). Therefore, the combination of the tumor genomic pattern (GG-P2s and BP ≥ 7) with age at diagnosis and LDH will be a promising predictor for MYCN-non-amplified high-risk NBs in patient subsets, in accordance with previous findings from the INRG project. Full article
(This article belongs to the Special Issue Molecular and Biological Enigma of Neuroblastoma: How to Solve It?)
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Review

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17 pages, 2206 KiB  
Review
Anti-GD2 Directed Immunotherapy for High-Risk and Metastatic Neuroblastoma
by Godfrey Chi-Fung Chan and Carol Matias Chan
Biomolecules 2022, 12(3), 358; https://doi.org/10.3390/biom12030358 - 24 Feb 2022
Cited by 32 | Viewed by 9970
Abstract
Neuroblastoma is one of the few childhood cancers that carries a tumor-specific antigen in the form of a glycolipid antigen known as GD2. It has restricted expression in normal tissue, such as peripheral afferent nerves. Monoclonal antibodies targeting GD2 have been applied clinically [...] Read more.
Neuroblastoma is one of the few childhood cancers that carries a tumor-specific antigen in the form of a glycolipid antigen known as GD2. It has restricted expression in normal tissue, such as peripheral afferent nerves. Monoclonal antibodies targeting GD2 have been applied clinically to high-risk neuroblastoma with significant success. However, there are different anti-GD2 products and administration regimens. For example, anti-GD2 has been used in combination with chemotherapy during the induction phase or with retinoic acid during the maintenance stage. Regimens also vary in the choice of whether to add cytokines (i.e., IL-2, GMCSF, or both). Furthermore, the addition of an immune enhancer, such as β-glucan, or allogeneic natural killer cells also becomes a confounder in the interpretation. The question concerning which product or method of administration is superior remains to be determined. So far, most studies agree that adding anti-GD2 to the conventional treatment protocol can achieve better short- to intermediate-term event-free and overall survival, but the long-term efficacy remains to be verified. How to improve its efficacy is another challenge. Late relapse and central nervous system metastasis have emerged as new problems. The methods to overcome the mechanisms related to immune evasion or resistance to immunotherapy represent new challenges to be resolved. The newer anti-GD2 strategies, such as bispecific antibody linking of anti-GD2 with activated T cells or chimeric antigen receptor T cells, are currently under clinical trials, and they may become promising alternatives. The use of anti-GD2/GD3 tumor vaccine is a novel and potential approach to minimizing late relapse. How to induce GD2 expression from tumor cells using the epigenetic approach is a hot topic nowadays. We expect that anti-GD2 treatment can serve as a model for the use of monoclonal antibody immunotherapy against cancers in the future. Full article
(This article belongs to the Special Issue Molecular and Biological Enigma of Neuroblastoma: How to Solve It?)
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23 pages, 34169 KiB  
Review
Genetic and Histopathological Heterogeneity of Neuroblastoma and Precision Therapeutic Approaches for Extremely Unfavorable Histology Subgroups
by Hiroyuki Shimada and Naohiko Ikegaki
Biomolecules 2022, 12(1), 79; https://doi.org/10.3390/biom12010079 - 5 Jan 2022
Cited by 16 | Viewed by 4912
Abstract
Peripheral neuroblastic tumors (neuroblastoma, ganglioneuroblastoma and ganglioneuroma) are heterogeneous and their diverse and wide range of clinical behaviors (spontaneous regression, tumor maturation and aggressive progression) are closely associated with genetic/molecular properties of the individual tumors. The International Neuroblastoma Pathology Classification, a biologically relevant [...] Read more.
Peripheral neuroblastic tumors (neuroblastoma, ganglioneuroblastoma and ganglioneuroma) are heterogeneous and their diverse and wide range of clinical behaviors (spontaneous regression, tumor maturation and aggressive progression) are closely associated with genetic/molecular properties of the individual tumors. The International Neuroblastoma Pathology Classification, a biologically relevant and prognostically significant morphology classification distinguishing the favorable histology (FH) and unfavorable histology (UH) groups in this disease, predicts survival probabilities of the patients with the highest hazard ratio. The recent advance of neuroblastoma research with precision medicine approaches demonstrates that tumors in the UH group are also heterogeneous and four distinct subgroups—MYC, TERT, ALT and null—are identified. Among them, the first three subgroups are collectively named extremely unfavorable histology (EUH) tumors because of their highly aggressive clinical behavior. As indicated by their names, these EUH tumors are individually defined by their potential targets detected molecularly and immunohistochemically, such as MYC-family protein overexpression, TERT overexpression and ATRX (or DAXX) loss. In the latter half on this paper, the current status of therapeutic targeting of these EUH tumors is discussed for the future development of effective treatments of the patients. Full article
(This article belongs to the Special Issue Molecular and Biological Enigma of Neuroblastoma: How to Solve It?)
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15 pages, 1493 KiB  
Review
How Do Telomere Abnormalities Regulate the Biology of Neuroblastoma?
by Jesmin Akter and Takehiko Kamijo
Biomolecules 2021, 11(8), 1112; https://doi.org/10.3390/biom11081112 - 28 Jul 2021
Cited by 9 | Viewed by 3263
Abstract
Telomere maintenance plays important roles in genome stability and cell proliferation. Tumor cells acquire replicative immortality by activating a telomere-maintenance mechanism (TMM), either telomerase, a reverse transcriptase, or the alternative lengthening of telomeres (ALT) mechanism. Recent advances in the genetic and molecular characterization [...] Read more.
Telomere maintenance plays important roles in genome stability and cell proliferation. Tumor cells acquire replicative immortality by activating a telomere-maintenance mechanism (TMM), either telomerase, a reverse transcriptase, or the alternative lengthening of telomeres (ALT) mechanism. Recent advances in the genetic and molecular characterization of TMM revealed that telomerase activation and ALT define distinct neuroblastoma (NB) subgroups with adverse outcomes, and represent promising therapeutic targets in high-risk neuroblastoma (HRNB), an aggressive childhood solid tumor that accounts for 15% of all pediatric-cancer deaths. Patients with HRNB frequently present with widely metastatic disease, with tumors harboring recurrent genetic aberrations (MYCN amplification, TERT rearrangements, and ATRX mutations), which are mutually exclusive and capable of promoting TMM. This review provides recent insights into our understanding of TMM in NB tumors, and highlights emerging therapeutic strategies as potential treatments for telomerase- and ALT-positive tumors. Full article
(This article belongs to the Special Issue Molecular and Biological Enigma of Neuroblastoma: How to Solve It?)
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14 pages, 571 KiB  
Review
Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?
by Kiyohiro Ando and Akira Nakagawara
Biomolecules 2021, 11(5), 750; https://doi.org/10.3390/biom11050750 - 18 May 2021
Cited by 11 | Viewed by 3396
Abstract
Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to [...] Read more.
Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas. Full article
(This article belongs to the Special Issue Molecular and Biological Enigma of Neuroblastoma: How to Solve It?)
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Other

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3 pages, 522 KiB  
Commentary
Why Is Aneuploidy Associated with Favorable Outcome in Neuroblastoma?
by Gian Paolo Tonini
Biomolecules 2021, 11(8), 1116; https://doi.org/10.3390/biom11081116 - 29 Jul 2021
Cited by 1 | Viewed by 1707
Abstract
Neuroblastoma is a pediatric cancer, onset with localized as well as metastatic disease. Localized tumors usually show a high content of aneuploid cells. It is suggested that aneuploid cells with numerical copy number variation (CNV) are generated by chromosome instability (CIN). Patients with [...] Read more.
Neuroblastoma is a pediatric cancer, onset with localized as well as metastatic disease. Localized tumors usually show a high content of aneuploid cells. It is suggested that aneuploid cells with numerical copy number variation (CNV) are generated by chromosome instability (CIN). Patients with a localized tumor respond well to the therapy and show a good outcome. On the contrary, patients with a metastatic tumor have worse outcomes and the cells with structural CNV show high levels of CIN. It is proposed that a favorable outcome in patients with localized disease is associated to the grade of CIN. Full article
(This article belongs to the Special Issue Molecular and Biological Enigma of Neuroblastoma: How to Solve It?)
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