Connecting telomere maintenance and regulation to the developmental origin and differentiation states of neuroblastoma tumor cells

Abstract

A cardinal feature that distinguishes clinically high-risk neuroblastoma from low-risk tumors is telomere maintenance. Specifically, neuroblastoma tumors with either active telomerase or alternative lengthening of telomeres exhibit aggressive growth characteristics that lead to poor outcomes, whereas tumors without telomere maintenance can be managed with observation or minimal treatment. Even though the need for cancer cells to maintain telomere DNA—in order to sustain cell proliferation—is well established, recent studies suggest that the neural crest origin of neuroblastoma may enforce unique relationships between telomeres and tumor malignancy. Specifically in neuroblastoma, telomere structure and telomerase activity are correlated with the adrenergic/mesenchymal differentiation states, and manipulating telomerase activity can trigger tumor cell differentiation. Both findings may reflect features of normal neural crest development. This review summarizes recent advances in the characterization of telomere structure and telomere maintenance mechanisms in neuroblastoma and discusses the findings in the context of relevant literature on telomeres during embryonic and neural development. Understanding the canonical and non-canonical roles of telomere maintenance in neuroblastoma could reveal vulnerabilities for telomere-directed therapies with potential applications to other pediatric malignancies.

Two bullets in the gun: combining immunotherapy with chemotherapy to defeat neuroblastoma by targeting adrenergic-mesenchymal plasticity

“…The phenotypic characteristics of these two cell populations are largely determined by the activation of specific transcriptional circuitries: while ADRN cells express markers of sympatho-adrenergic differentiation, MES cells appear undifferentiated and more similar to their neural crest progenitors ( 7 , 8 ). Interestingly, the ADRN and MES classification coincides with the characteristics previously described for N/I-type and S-type cells, respectively ( 10 ).…”

Long-Term Survival of Neuroblastoma Patients Receiving Surgery, Chemotherapy, and Radiotherapy: A Propensity Score Matching Study

“…Firstly, due to a lack of individual-level records, we could not obtain specific treatment details of the patients, including the surgical techniques and chemotherapy or radiotherapy plans adopted, which restricted our further evaluation of their impact on the long-term survival of the patients. Secondly, recent studies have shown that specific molecular characteristics of neuroblastoma are associated with tumor sub-categories [38,39] and clinical outcomes [34,40]. Although we applied stratification factors to reduce data bias, cytogenetic, molecular, or unknown factors related to patients' survival were still unavoidably omitted.…”

Long Non-Coding RNAs in Neuroblastoma: Pathogenesis, Biomarkers and Therapeutic Targets

“…Furthermore, the presence of TMM correlates with more frequent relapse in patients with high-risk neuroblastoma, with the majority of relapse cases also exhibiting activation of TMMs [ 110 ]. Conversely, there is a clear association between low-risk neuroblastoma, which often undergoes spontaneous tumor regression, and the absence of TLM activation [ 111 ]. It is speculated that spontaneous regression in low-risk neuroblastoma takes place when telomere reserves are exhausted due to the lack of TMM and the inability to counteract telomere shortening pathways [ 111 ].…”

“…Conversely, there is a clear association between low-risk neuroblastoma, which often undergoes spontaneous tumor regression, and the absence of TLM activation [ 111 ]. It is speculated that spontaneous regression in low-risk neuroblastoma takes place when telomere reserves are exhausted due to the lack of TMM and the inability to counteract telomere shortening pathways [ 111 ]. These findings underscore the potential prognostic and therapeutic significance of TMMs in neuroblastoma.…”