Artificial Tumor Microenvironments in Neuroblastoma

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 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.

Bioprinted Cancer Model of Neuroblastoma in a Renal Microenvironment as an Efficiently Applicable Drug Testing Platform

“…Due to species differences, the effects of the TME measured in animal models cannot be relied upon when translated into clinical settings. In contrast, bioprinting can be used to produce a tumor in a human TME and to investigate interactions between the tumor and its TME, as well as its influence on drug treatment, for neuroblastomas and other types of tumors [ 48 ]. In breast cancer, tumor progression is strongly influenced by its microenvironment and particularly by interaction of the cancer cells with adipose tissue, which can be recapitulated in bioprinted models [ 49 ].…”

Beta-Lapachone Attenuates BMSC-Mediated Neuroblastoma Malignant Transformation by Inhibiting Gal-3/Gal-3BP/IL6 Axis

“…In recent decades, progress in effective treatment of NB has lagged far behind other childhood cancers, especially pediatric hematologic malignancies ( Quinn et al, 2021 ). According to the International Neuroblastoma Risk Group (INRG) classification scheme, NB is classified as low, medium and high risk based on MYCN amplification status, metastasis, and whether the patient is older than 18 months ( Monclair et al, 2009 ).…”

Emerging Role and Mechanism of circRNAs in Pediatric Malignant Solid Tumors

“…Currently, many new targeted therapies and immunotherapies have emerged in addition to conventional radiotherapy for NB ( Blavier et al, 2020 ; Bhoopathi et al, 2021 ; Stainczyk and Westermann, 2021 ). NB is heterogeneous, and approximately 85–90% of children with low- and intermediate-risk NB can be cured, while the survival rate of children with high-risk NB is less than 50% ( Aravindan et al, 2020 ; Quinn et al, 2021 ). Children with high-risk NB remain refractory to cure after multiple intensive treatments, and more than 50% of children relapse, with a 5-year survival rate of approximately 40–50% ( Brignole et al, 2021 ).…”