Inflammation plays a crucial role in wound healing and the host immune response following pathogenic invasion. However, unresolved chronic inflammation can result in tissue fibrosis and genetic alterations that contribute to the pathogenesis of human diseases such as cancer. Recent scientific advancements exploring the underlying mechanisms of malignant cellular transformations and cancer progression have exposed significant disparities between pediatric and adult-onset cancers. For instance, pediatric cancers tend to have lower mutational burdens and arise in actively developing tissues, where cell-cycle dysregulation leads to gene, chromosomal, and fusion gene development not seen in adult-onset counterparts. As such, scientific findings in adult cancers cannot be directly applied to pediatric cancers, where unique mutations and inherent etiologies remain poorly understood. Here, we review the role of chronic inflammation in processes of genetic and chromosomal instability, the tumor microenvironment, and immune response that result in pediatric tumorigenesis transformation and explore current and developing therapeutic interventions to maintain and/or restore inflammatory homeostasis.

Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents. Unfortunately, drug resistance limits the efficacy of chemotherapeutic treatment and compromises therapeutic outcomes in a substantial proportion of cases. Aberrant CpG island methylation-associated transcriptional silencing contributes to chemoresistance in pediatric solid tumors. Here, using whole-genome DNA methylation screening on 16 human primary OS specimens, we identify receptor interacting protein kinase-3 (RIPK3), a molecular regulator of the necroptosis programmed cell death pathway, as a gene target of aberrant CpG methylation and demonstrate its role in human OS chemoresistance. We validated these findings via enforced expression and DsiRNA silencing, and evaluated the role of RIPK3 in cisplatin chemosensitivity and necroptosis activation through MLKL phosphorylation. We found that CpG island methylation results in RIPK3 silencing in primary human OS samples and cell lines. Enforced RIPK3 expression significantly enhanced cisplatin cytotoxicity in OS cells and DsiRNA knockdown reversed the cisplatin-sensitive phenotype. In cells with enforced RIPK3 expression, cisplatin treatment significantly increased phosphorylation of both RIPK3 and its target, MLKL, indicative of induction of necroptosis. Here, we identify RIPK3 as an important mediator of chemoresistance in OS and a potential pharmacologic target to improve chemotherapy efficacy in drug-resistant tumors.

The etiology of pediatric cancers is unique, stemming from developmental dysregulation rather than acquired mutations from carcinogenic exposure. These diseases demonstrate vastly different underlying genetic and epigenetic alterations and unique tissue microenvironments which are only now beginning to be explored. While many pediatric cancers have seen improved overall and event-free survival rates thanks to innovations in diagnosis and treatment, many have seen little to no improvement in patient outcomes. This highlights a critical need for additional research into the underlying genetic and epigenetic alterations in these pathologies. Non-coding RNAs (ncRNAs) are functional RNA molecules known to regulate gene expression at epigenetic, transcriptional, and translational levels and can serve as biomarkers of disease. Here, we examine current knowledge of the roles of microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in the onset, progression, and therapeutic response of pediatric solid tumors. We discuss the current and future potential and pitfalls of these molecules as therapeutics and biomarkers and highlight critical knowledge gaps where future research might provide insight to improve current therapeutic strategies and improve clinical outcomes.