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Cancers
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The Tumor Microenvironment of Neuroblastoma
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The Tumor Microenvironment of Neuroblastoma

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (10 March 2021) | Viewed by 37081

Special Issue Editors

Prof. Dr. Alice L. Yu

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Guest Editor
Department of Pediatrics, Rady's Children's Hospital and Moores Cancer Center, School of Medicine, University of California in San Diego, San Diego, CA, USA
Interests: Cancer Immunotherapy; Glycosphingolipids; glycobiology; Neuroblastoma; Cancer stem cells; tumor microenvironment; NKT cells
Dr. Shweta Joshi

E-Mail Website
Guest Editor
Department of Pediatrics, Division of Pediatric Hematology-Oncology, UCSD Rady’s Children’sHospital, University of California in San Diego, La Jolla, CA 92093-0815, USA
Interests: Immuno-oncology; macrophages; myeloid-derived suppressor cells; immunotherapy; immune-suppression in cancer; tumor microenvironment; neuroblastoma; solid tumors; metastasis

Special Issue Information

Dear Colleagues,

Neuroblastoma is a pediatric tumor malignancy that accounts for more than 15 percent of all childhood deaths. Despite intensive multimodal therapy, the chances of long-term survival for high-risk disease patients are less than 40%, and we are very far away from curing this pediatric tumor. Conventional therapies and immunotherapy in neuroblastoma have failed due to an inadequate understanding of the neuroblastoma tumor microenvironment, and immune evasion strategies utilized by neuroblastoma cells to fool the immune system.

Neuroblastoma tumor progression relies on the physiological state of the tumor microenvironment. Genetic alterations in neuroblastoma tumor cells lead to uncontrolled tumor growth and metabolic shift towards anaerobic glycolysis. These events promote hypoxia and acidosis within the TME, initiating extracellular matrix remodeling with support of neighboring stromal cells and immune cells, inducing neovascularization, and ultimately leading to tumor metastasis. Exosomes are also major players in all these events.

In this respect, the current Special Issue invites contributions aimed at exploring different elements that contribute to the complexity and heterogeneity of the neuroblastoma tumor microenvironment, focused on but not limited to malignant cells, host stromal cells, stromal fibroblasts, infiltrating immune cells, secreted growth factors, cytokines, exosomes, miRNAs, tumor metabolism, hypoxia and acidosis, extracellular matrix remodeling, tumor vasculature, and modification of innate and adaptive immune cells. Contributions should also highlight the therapeutic angle of the proposed topic.

Prof. Dr. Alice L. Yu
Dr. Shweta Joshi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (10 papers)

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Research

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13 pages, 3308 KiB  
Article
BTK Inhibition Reverses MDSC-Mediated Immunosuppression and Enhances Response to Anti-PDL1 Therapy in Neuroblastoma
by Mehreen Ishfaq, Timothy Pham, Cooper Beaman, Pablo Tamayo, Alice L. Yu and Shweta Joshi
Cancers 2021, 13(4), 817; https://doi.org/10.3390/cancers13040817 - 16 Feb 2021
Cited by 15 | Viewed by 3292
Abstract
MDSCs are immune cells of myeloid lineage that plays a key role in promoting tumor growth. The expansion of MDSCs in tumor-bearing hosts reduces the efficacy of checkpoint inhibitors and CAR-T therapies, and hence strategies that deplete or block the recruitment of MDSCs [...] Read more.
MDSCs are immune cells of myeloid lineage that plays a key role in promoting tumor growth. The expansion of MDSCs in tumor-bearing hosts reduces the efficacy of checkpoint inhibitors and CAR-T therapies, and hence strategies that deplete or block the recruitment of MDSCs have shown benefit in improving responses to immunotherapy in various cancers, including NB. Ibrutinib, an irreversible molecular inhibitor of BTK, has been widely studied in B cell malignancies, and recently, this drug is repurposed for the treatment of solid tumors. Herein we report that BTK is highly expressed in both granulocytic and monocytic murine MDSCs isolated from mice bearing NB tumors, and its increased expression correlates with a poor relapse-free survival probability of NB patients. Moreover, in vitro treatment of murine MDSCs with ibrutinib altered NO production, decreased mRNA expression of Ido, Arg, Tgfβ, and displayed defects in T-cell suppression. Consistent with these findings, in vivo inhibition of BTK with ibrutinib resulted in reduced MDSC-mediated immune suppression, increased CD8+ T cell infiltration, decreased tumor growth, and improved response to anti-PDL1 checkpoint inhibitor therapy in a murine model of NB. These results demonstrate that ibrutinib modulates immunosuppressive functions of MDSC and can be used either alone or in combination with immunotherapy for augmenting antitumor immune responses in NB. Full article
(This article belongs to the Special Issue The Tumor Microenvironment of Neuroblastoma)
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23 pages, 6719 KiB  
Article
Neuroblastoma Invasion Strategies Are Regulated by the Extracellular Matrix
by Cian Gavin, Nele Geerts, Brenton Cavanagh, Meagan Haynes, C. Patrick Reynolds, Daniela Loessner, Andrew J. Ewald and Olga Piskareva
Cancers 2021, 13(4), 736; https://doi.org/10.3390/cancers13040736 - 10 Feb 2021
Cited by 11 | Viewed by 4549
Abstract
Neuroblastoma is a paediatric malignancy of the developing sympathetic nervous system. About half of the patients have metastatic disease at the time of diagnosis and a survival rate of less than 50%. Our understanding of the cellular processes promoting neuroblastoma metastases will be [...] Read more.
Neuroblastoma is a paediatric malignancy of the developing sympathetic nervous system. About half of the patients have metastatic disease at the time of diagnosis and a survival rate of less than 50%. Our understanding of the cellular processes promoting neuroblastoma metastases will be facilitated by the development of appropriate experimental models. In this study, we aimed to explore the invasion of neuroblastoma cells and organoids from patient-derived xenografts (PDXs) grown embedded in 3D extracellular matrix (ECM) hydrogels by time-lapse microscopy and quantitative image analysis. We found that the ECM composition influenced the growth, viability and local invasion of organoids. The ECM compositions induced distinct cell behaviours, with Matrigel being the preferred substratum for local organoid invasion. Organoid invasion was cell line- and PDX-dependent. We identified six distinct phenotypes in PDX-derived organoids. In contrast, NB cell lines were more phenotypically restricted in their invasion strategies, as organoids isolated from cell line-derived xenografts displayed a broader range of phenotypes compared to clonal cell line clusters. The addition of FBS and bFGF induced more aggressive cell behaviour and a broader range of phenotypes. In contrast, the repression of the prognostic neuroblastoma marker, MYCN, resulted in less aggressive cell behaviour. The combination of PDX organoids, real-time imaging and the novel 3D culture assays developed herein will enable rapid progress in elucidating the molecular mechanisms that control neuroblastoma invasion. Full article
(This article belongs to the Special Issue The Tumor Microenvironment of Neuroblastoma)
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23 pages, 2163 KiB  
Article
Association of Genetic Polymorphisms and Serum Levels of IL-6 and IL-8 with the Prognosis in Children with Neuroblastoma
by Silvia Selene Moreno-Guerrero, Arturo Ramírez-Pacheco, Luz María Rocha-Ramírez, Gabriela Hernández-Pliego, Pilar Eguía-Aguilar, María Argelia Escobar-Sánchez, Alfonso Reyes-López, Luis Enrique Juárez-Villegas and Juan José Luis Sienra-Monge
Cancers 2021, 13(3), 529; https://doi.org/10.3390/cancers13030529 - 30 Jan 2021
Cited by 11 | Viewed by 2096
Abstract
There is evidence that high circulating levels of IL-6 and IL-8 are markers of a poor prognosis in various types of cancer, including NB. The participation of these cytokines in the tumor microenvironment has been described to promote progression and metastasis. Our objective [...] Read more.
There is evidence that high circulating levels of IL-6 and IL-8 are markers of a poor prognosis in various types of cancer, including NB. The participation of these cytokines in the tumor microenvironment has been described to promote progression and metastasis. Our objective was to evaluate the prognostic role of genetic polymorphisms and serum levels of IL-6 and IL-8 in a cohort of Mexican pediatric patients with NB. The detection of the SNPs rs1800795 IL-6 and rs4073 and rs2227306 IL-8 was carried out by PCR-RFLP and the levels of cytokines were determined by the ELISA method. We found elevated circulating levels of IL-8 and IL-6 in NB patients compared to the control group. The genotype frequencies of the rs1800795 IL-6 and rs4073 IL-8 variants were different between the patients with NB and the control group. Likewise, the survival analysis showed that the GG genotypes of rs1800795 IL-6 (p = 0.014) and AA genotypes of rs4073 IL-8 (p = 0.002), as well as high levels of IL-6 (p = 0.009) and IL-8 (p = 0.046), were associated with lower overall survival. We confirmed the impact on an adverse prognosis in a multivariate model. This study suggests that the SNPs rs1800795 IL-6 and rs4073 IL-8 and their serum levels could be promising biomarkers of a poor prognosis, associated with overall survival, metastasis, and a high risk in Mexican children with NB. Full article
(This article belongs to the Special Issue The Tumor Microenvironment of Neuroblastoma)
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17 pages, 4786 KiB  
Article
Amino Acids Regulate Cisplatin Insensitivity in Neuroblastoma
by Venugopal Gunda, Anup S. Pathania, Srinivas Chava, Philip Prathipati, Nagendra K. Chaturvedi, Don W. Coulter, Manoj K. Pandey, Donald L. Durden and Kishore B. Challagundla
Cancers 2020, 12(9), 2576; https://doi.org/10.3390/cancers12092576 - 10 Sep 2020
Cited by 13 | Viewed by 3047
Abstract
Neuroblastoma are pediatric, extracranial malignancies showing alarming survival prognosis outcomes due to their resilience to current aggressive treatment regimens, including chemotherapies with cisplatin (CDDP) provided in the first line of therapy regimens. Metabolic deregulation supports tumor cell survival in drug-treated conditions. However, metabolic [...] Read more.
Neuroblastoma are pediatric, extracranial malignancies showing alarming survival prognosis outcomes due to their resilience to current aggressive treatment regimens, including chemotherapies with cisplatin (CDDP) provided in the first line of therapy regimens. Metabolic deregulation supports tumor cell survival in drug-treated conditions. However, metabolic pathways underlying cisplatin-resistance are least studied in neuroblastoma. Our metabolomics analysis revealed that cisplatin-insensitive cells alter their metabolism; especially, the metabolism of amino acids was upregulated in cisplatin-insensitive cells compared to the cisplatin-sensitive neuroblastoma cell line. A significant increase in amino acid levels in cisplatin-insensitive cells led us to hypothesize that the mechanisms upregulating intracellular amino acid pools facilitate insensitivity in neuroblastoma. We hereby report that amino acid depletion reduces cell survival and cisplatin-insensitivity in neuroblastoma cells. Since cells regulate their amino acids levels through processes, such as autophagy, we evaluated the effects of hydroxychloroquine (HCQ), a terminal autophagy inhibitor, on the survival and amino acid metabolism of cisplatin-insensitive neuroblastoma cells. Our results demonstrate that combining HCQ with CDDP abrogated the amino acid metabolism in cisplatin-insensitive cells and sensitized neuroblastoma cells to sub-lethal doses of cisplatin. Our results suggest that targeting of amino acid replenishing mechanisms could be considered as a potential approach in developing combination therapies for treating neuroblastomas. Full article
(This article belongs to the Special Issue The Tumor Microenvironment of Neuroblastoma)
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Review

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22 pages, 7434 KiB  
Review
A New Player in Neuroblastoma: YAP and Its Role in the Neuroblastoma Microenvironment
by Jenny Shim and Kelly C. Goldsmith
Cancers 2021, 13(18), 4650; https://doi.org/10.3390/cancers13184650 - 16 Sep 2021
Cited by 5 | Viewed by 2898
Abstract
Neuroblastoma is the most common extra-cranial pediatric solid tumor that accounts for more than 15% of childhood cancer-related deaths. High risk neuroblastomas that recur during or after intense multimodal therapy have a <5% chance at a second sustained remission or cure. The solid [...] Read more.
Neuroblastoma is the most common extra-cranial pediatric solid tumor that accounts for more than 15% of childhood cancer-related deaths. High risk neuroblastomas that recur during or after intense multimodal therapy have a <5% chance at a second sustained remission or cure. The solid tumor microenvironment (TME) has been increasingly recognized to play a critical role in cancer progression and resistance to therapy, including in neuroblastoma. The Yes-Associated Protein (YAP) in the Hippo pathway can regulate cancer proliferation, tumor initiation, and therapy response in many cancer types and as such, its role in the TME has gained interest. In this review, we focus on YAP and its role in neuroblastoma and further describe its demonstrated and potential effects on the neuroblastoma TME. We also discuss the therapeutic strategies for inhibiting YAP in neuroblastoma. Full article
(This article belongs to the Special Issue The Tumor Microenvironment of Neuroblastoma)
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16 pages, 787 KiB  
Review
Bone Marrow Environment in Metastatic Neuroblastoma
by Chiara Brignole, Fabio Pastorino, Patrizia Perri, Loredana Amoroso, Veronica Bensa, Enzo Calarco, Mirco Ponzoni and Maria Valeria Corrias
Cancers 2021, 13(10), 2467; https://doi.org/10.3390/cancers13102467 - 19 May 2021
Cited by 5 | Viewed by 2512
Abstract
The study of the interactions occurring in the BM environment has been facilitated by the peculiar nature of metastatic NB. In fact: (i) metastases are present at diagnosis; (ii) metastases are confined in a very specific tissue, the BM, suggestive of a strong [...] Read more.
The study of the interactions occurring in the BM environment has been facilitated by the peculiar nature of metastatic NB. In fact: (i) metastases are present at diagnosis; (ii) metastases are confined in a very specific tissue, the BM, suggestive of a strong attraction and possibility of survival; (iii) differently from adult cancers, NB metastases are available because the diagnostic procedures require morphological examination of BM; (iv) NB metastatic cells express surface antigens that allow enrichment of NB metastatic cells by immune–magnetic separation; and (v) patients with localized disease represent an internal control to discriminate specific alterations occurring in the metastatic niche from generic alterations determined by the neoplastic growth at the primary site. Here, we first review the information regarding the features of BM-infiltrating NB cells. Then, we focus on the alterations found in the BM of children with metastatic NB as compared to healthy children and children with localized NB. Specifically, information regarding all the BM cell populations and their sub-sets will be first examined in the context of BM microenvironment in metastatic NB. In the last part, the information regarding the soluble factors will be presented. Full article
(This article belongs to the Special Issue The Tumor Microenvironment of Neuroblastoma)
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25 pages, 1548 KiB  
Review
Combined Effects of Myeloid Cells in the Neuroblastoma Tumor Microenvironment
by Jennifer Frosch, Ilia Leontari and John Anderson
Cancers 2021, 13(7), 1743; https://doi.org/10.3390/cancers13071743 - 6 Apr 2021
Cited by 8 | Viewed by 3519
Abstract
Despite multimodal treatment, survival chances for high-risk neuroblastoma patients remain poor. Immunotherapeutic approaches focusing on the activation and/or modification of host immunity for eliminating tumor cells, such as chimeric antigen receptor (CAR) T cells, are currently in development, however clinical trials have failed [...] Read more.
Despite multimodal treatment, survival chances for high-risk neuroblastoma patients remain poor. Immunotherapeutic approaches focusing on the activation and/or modification of host immunity for eliminating tumor cells, such as chimeric antigen receptor (CAR) T cells, are currently in development, however clinical trials have failed to reproduce the preclinical results. The tumor microenvironment is emerging as a major contributor to immune suppression and tumor evasion in solid cancers and thus has to be overcome for therapies relying on a functional immune response. Among the cellular components of the neuroblastoma tumor microenvironment, suppressive myeloid cells have been described as key players in inhibition of antitumor immune responses and have been shown to positively correlate with more aggressive disease, resistance to treatments, and overall poor prognosis. This review article summarizes how neuroblastoma-driven inflammation induces suppressive myeloid cells in the tumor microenvironment and how they in turn sustain the tumor niche through suppressor functions, such as nutrient depletion and generation of oxidative stress. Numerous preclinical studies have suggested a range of drug and cellular therapy approaches to overcome myeloid-derived suppression in neuroblastoma that warrant evaluation in future clinical studies. Full article
(This article belongs to the Special Issue The Tumor Microenvironment of Neuroblastoma)
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17 pages, 967 KiB  
Review
Artificial Tumor Microenvironments in Neuroblastoma
by Colin H. Quinn, Andee M. Beierle and Elizabeth A. Beierle
Cancers 2021, 13(7), 1629; https://doi.org/10.3390/cancers13071629 - 1 Apr 2021
Cited by 13 | Viewed by 2975
Abstract
In the quest to advance neuroblastoma therapeutics, there is a need to have a deeper understanding of the tumor microenvironment (TME). From extracellular matrix proteins to tumor associated macrophages, the TME is a robust and diverse network functioning in symbiosis with the solid [...] Read more.
In the quest to advance neuroblastoma therapeutics, there is a need to have a deeper understanding of the tumor microenvironment (TME). From extracellular matrix proteins to tumor associated macrophages, the TME is a robust and diverse network functioning in symbiosis with the solid tumor. Herein, we review the major components of the TME including the extracellular matrix, cytokines, immune cells, and vasculature that support a more aggressive neuroblastoma phenotype and encumber current therapeutic interventions. Contemporary treatments for neuroblastoma are the result of traditional two-dimensional culture studies and in vivo models that have been translated to clinical trials. These pre-clinical studies are costly, time consuming, and neglect the study of cofounding factors such as the contributions of the TME. Three-dimensional (3D) bioprinting has become a novel approach to studying adult cancers and is just now incorporating portions of the TME and advancing to study pediatric solid. We review the methods of 3D bioprinting, how researchers have included TME pieces into the prints, and highlight present studies using neuroblastoma. Ultimately, incorporating the elements of the TME that affect neuroblastoma responses to therapy will improve the development of innovative and novel treatments. The use of 3D bioprinting to achieve this aim will prove useful in developing optimal therapies for children with neuroblastoma. Full article
(This article belongs to the Special Issue The Tumor Microenvironment of Neuroblastoma)
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16 pages, 1189 KiB  
Review
The Tumor Microenvironment in Neuroblastoma: New Players, New Mechanisms of Interaction and New Perspectives
by Laurence Blavier, Ren-Ming Yang and Yves A. DeClerck
Cancers 2020, 12(10), 2912; https://doi.org/10.3390/cancers12102912 - 10 Oct 2020
Cited by 39 | Viewed by 5160
Abstract
The contribution of the tumor microenvironment (TME) to cancer progression has been well recognized in recent decades. As cancer therapeutic strategies are increasingly precise and include immunotherapies, knowledge of the nature and function of the TME in a tumor becomes essential. Our understanding [...] Read more.
The contribution of the tumor microenvironment (TME) to cancer progression has been well recognized in recent decades. As cancer therapeutic strategies are increasingly precise and include immunotherapies, knowledge of the nature and function of the TME in a tumor becomes essential. Our understanding of the TME in neuroblastoma (NB), the second most common solid tumor in children, has significantly progressed from an initial focus on its Schwannian component to a better awareness of its complex nature, which includes not only immune but also non-immune cells such as cancer-associated fibroblasts (CAFs), the contribution of which to inflammation and interaction with tumor-associated macrophages (TAMs) is now recognized. Recent studies on the TME landscape of NB tumors also suggest significant differences between MYCN-amplified (MYCN-A) and non-amplified (MYCN-NA) tumors, in their content in stromal and inflammatory cells and their immunosuppressive activity. Extracellular vesicles (EVs) released by cells in the TME and microRNAs (miRs) present in their cargo could play important roles in the communication between NB cells and the TME. This review article discusses these new aspects of the TME in NB and the impact that information on the TME landscape in NB will have in the design of precise, biomarker-integrated clinical trials. Full article
(This article belongs to the Special Issue The Tumor Microenvironment of Neuroblastoma)
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22 pages, 741 KiB  
Review
Targeting the Tumor Microenvironment in Neuroblastoma: Recent Advances and Future Directions
by Shweta Joshi
Cancers 2020, 12(8), 2057; https://doi.org/10.3390/cancers12082057 - 25 Jul 2020
Cited by 45 | Viewed by 5608
Abstract
Neuroblastoma (NB) is the most common pediatric tumor malignancy that originates from the neural crest and accounts for more than 15% of all the childhood deaths from cancer. The neuroblastoma cancer research has long been focused on the role of MYCN oncogene amplification [...] Read more.
Neuroblastoma (NB) is the most common pediatric tumor malignancy that originates from the neural crest and accounts for more than 15% of all the childhood deaths from cancer. The neuroblastoma cancer research has long been focused on the role of MYCN oncogene amplification and the contribution of other genetic alterations in the progression of this malignancy. However, it is now widely accepted that, not only tumor cells, but the components of tumor microenvironment (TME), including extracellular matrix, stromal cells and immune cells, also contribute to tumor progression in neuroblastoma. The complexity of different components of tumor stroma and their resemblance with surrounding normal tissues pose huge challenges for therapies targeting tumor microenvironment in NB. Hence, the detailed understanding of the composition of the TME of NB is crucial to improve existing and future potential immunotherapeutic approaches against this childhood cancer. In this review article, I will discuss different components of the TME of NB and the recent advances in the strategies, which are used to target the tumor microenvironment in neuroblastoma. Full article
(This article belongs to the Special Issue The Tumor Microenvironment of Neuroblastoma)
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