Artificial Tumor Microenvironments in Neuroblastoma

SIMPLE SUMMARY: Children with high-risk neuroblastoma have limited therapeutic options poor survival rates. The neuroblastoma tumor microenvironment contributes the lack of response to many interventions so innovative methods are needed to study the effects of the tumor microenvironment on new therapies. In this manuscript, we review the current literature related to the components of the tumor microenvironment and to the use of three-dimensional printing as modality to study cancer. This review highlights the potential for using three-dimensional printing to create an artificial tumor microenvironment in the presence of neuroblastoma to provide improved preclinical testing of novel therapies. 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.