Abstract
Neuroblastoma diagnostic criteria and therapeutic options have been identified and implemented within the oncology clinical setting as best possible and in a timely manner following the ever-changing advances in modern medical research technologies, as time progressed. Nonetheless, pediatric patients afflicted with this condition and their clinicians are still faced with a plethora of challenges on a daily basis that potentially thwart rapidly efficient and effective diagnosis, management, and treatment of this condition. This chapter serves as a humbling eye-opener on one of the recent, although most crucial, challenges hindering all those involved in neuroblastoma basic/translational research, namely, the influence of noncoding RNAs, with particular reference to the realm of microRNA (miRNA) and long noncoding RNA (lncRNA) theranostics.
Keywords
Diagnosis, Drug, lncRNA, miRNA, Neuroblastoma, Theranostics, Treatment
Introduction
The first cases of neuroblastoma (NB) date back to 1864, as described by Rudolf Virchow, where NB and other pediatric abdominal tumors were initially classified as gliomas . Furthermore, between 1925 and 1962, neuroblastoma incidences reached approximately 10% in England and Wales and other European countries . In addition, one of the major mainstay therapies for NB was the administration of elevated doses of vitamin B12 .
We have come a long way since then with the overwhelming advances in medical and pharmaceutical technologies that paved the road for significantly more rapid diagnosis and more effective therapeutics for NB and other life-threatening conditions. Nevertheless, despite all efforts and a massive improvement in medical science, pediatric patients and their clinicians are still presently facing a plethora of challenges on a daily basis, which potentially thwart rapidly efficient and effective diagnosis, management, and treatment of this condition. This chapter aims to scratch the surface on the current research efforts aiming at improving the level of neuroblastoma clinical management, with particular reference to the realm of microRNA (miRNA) and long noncoding RNA (lncRNA) theranostics.
However, in order to provide an adequate overview of such issues it is important to emphasize the current status of NB theranostic efforts presently being implemented in the oncology clinic on a global scale.
Current Status of Neuroblastoma Theranostics
Diagnostic Protocols
The most prominent and utilized set of diagnostic protocols for suspected cases of NB is undoubtedly known as the International Neuroblastoma Staging System (INSS), which was first established in 1988 . Concomitant with the implementation of the INSS, a similar set of criteria was developed in order to categorize the type and level of treatment effectiveness in NB patients, known as the International Neuroblastoma Response Criteria (INRC) . Since then there have been multiple revisions and analyses of clinical utility for both the INSS and the INRC protocols .
Following the implementation of the INSS and INRC protocols, further adjuvant diagnostic NB staging protocols were created, most notable being the recommendations by the International Neuroblastoma Pathology Committee (INPC) in 1994 . The advantage for oncology clinicians to employ the INPC guidelines was that this diagnostic protocol focuses its NB staging system on the multiple pathological anomalies present in the individual NB tumor, such as the level of neuroblast differentiation and the degree of Schwannian stromal growth as typical criteria . Another diagnostic protocol that was adopted in conjunction with the above described is the International Neuroblastoma Risk Group classification (INRG) and its complementary Staging System (INRGSS), developed in 2008 . The additional versatility that was introduced with the introduction of the INRGSS was that the latter diagnostic protocol focused mainly on image-defined risk factors determining pretreatment NB risk group stratification since the INSS is solely applicable for postsurgical NB cases . In this manner, the INRG and INRGSS allow for global standardization in the pretreatment diagnostic services for all NB patients, both within the clinic and those undergoing novel clinical trials . Coupled with such protocols, the NB risk groups outlined by the Children’s Oncology Group aids in further classification of the individual tumor stage into low, intermediate, or high-risk groups, with such classification depending highly on the level of MYCN amplification .
In essence, all such NB diagnostic protocols create the synergy to provide immense clinical value and the first point of reference for all oncology clinicians that are presented with suspected NB cases. Following the application of the risk group stratifications outlined in these protocols in such suspect cases of NB, particularly utilizing the INRG/SS protocols , the oncologist can have a much higher appreciation of the status of invasiveness and other aggressive characteristics of the NB tumor at hand.
Therapeutic Protocols and Other Options
Following a thorough assessment by the various diagnostic protocols described above, and ultimate confirmation of the presence of an NB tumor from relevant biopsy procedures, the clinician has the responsibility of selecting the most suitable NB management and/or therapeutic options, basing his or her decision on the newly diagnosed NB risk group in the newly diagnosed NB patient.
Apart from conventional chemotherapeutic options, in cases of high-risk NB (including those with bilateral tumors), surgical resection can lead to a very favorable prognosis . In addition, the implementation of metaiodobenzylguanidine (MIBG) scintigraphy can be of significant aid in the diagnosis and management of thecondition . Other therapeutic options include stem-cell transplantation , retinoid therapies , and also immunotherapies . However, the identification of the importance of noncoding RNAs (ncRNAs) in disease progression in the past 15 years also has an essential position as a novel theranostic player in NB management.
Noncoding RNAs
The widespread influences of ncRNAs have been established very well within the scientific literature in this millennium, particularly with specific families of ncRNAs having direct involvement in the RNA interference (RNAi) pathway . Presently, the ncRNA families having the most clinical relevance in modern cancer theranostics would be the microRNA (miRNA) and long noncoding RNA (lncRNA) families. The following sections focus on the currently identified miRNAs and lncRNAs having the highest potential for developing novel diagnostic protocols and therapeutic interventions for NB patients in the near future.
miRNA Influences in NB
The miRNA family of ncRNAs consists of a duplex hairpin structure with the distal 22 bp segment having the regulatory potential of inhibiting the target mRNA translation into effector protein/s . Presently, there exist approximately over 2600 mature miRNAs with potential RNA regulatory properties in humans alone, according to the miRBase miRNA database . miRNAs are the key molecular players in RNAi mediated pathway of gene regulation in humans, with the end effect of posttranscriptional gene silencing through inhibition of translation . Table 13.1 below highlights a comprehensive compendium of miRNAs that have been experimentally recognized to play a major role in NB development and clinical characteristics. However, it is noteworthy to elaborate on specific miRNAs that have been very well described to exert considerable effects on NB physiology:
| miRNA/s | Target/s | Expression | Role | References |
|---|---|---|---|---|
| miR-142-3p | STAU1 | + | Increases neuronal differentiation | |
| miR-424-5p miR-503-5p | ALK | + + | Tumor suppressors | |
| miR-513c | GLS | + | Inhibits NB cell migration/invasion/proliferation | |
| miR-21-5p | PTEN PDCD4 CHL1 | + | Inhibits NB apoptosis | |
| miR-17 | N-myc | + | Oncogene suppressor | |
| miR-34b | DLL1 | + | Oncogene suppressor | |
| miR-1301 | N-Ras | + | Oncogene suppressor | |
| miR-149 | Rap1 | + | Oncogene suppressor | |
| miR-137 | HDAC8 EZH2 | + | Increased doxorubicin sensitivity/NB apoptosis | |
| miR-1303 | GSK3B SFRP1 | + | Increased NB invasiveness | |
| miR-410 | VEGF-A | + | Inhibition of angiogenesis | |
| miR-19b | − | Increased mTOR inhibitor sensitivity | ||
| miR-17-92 cluster | Glucocorticoid receptors | + | Increased NB presence | |
| miR-16 miR-199a | NF-κB pathway | + + | Decreased inflammatory responses post-NB cell mechanical injury trauma | |
| Let-7 | MYCN | + | Oncogene suppressor | |
| miR-93-5p | VEGF IL-8 | + | Reduced angiogenesis | |
| miR-141 | FUS | + | Increased cisplatin chemosensitivity | |
| miR-381 miR-548h miR-580 | + + + | Serum biomarkers for NB progression | ||
| miR-211 miR-17 miR-93 miR-20b miR-106b miR-204 miR-3666 | CHD5 | + + + + + + + | Inhibit tumor suppressive effects of CHD5 | |
| miR-497 | MDR genes | + | Increased conventional chemotherapy drug sensitivity | |
| miR-451 | MMIF | + | Inhibits NB proliferation | |
| miR-29a | Mcl-1 | + | Enhances neuronal apoptosis | |
| miR-153-5p miR-205-5p | HIF-1 pathway | + + | Multiple NB pathways affected | |
| miR-4487 miR-595 | ULK1 | + + | Modulate NB autophagy | |
| miR-125b miR-27b miR-93 miR-20a miR-1224-3p miR-1260 | (various) | − − − − + + | NB metastasis modulation | |
| miR-204 | PHOX2B | + | Oncogene suppressor | |
| miR-203 | Sam68 | + | Oncogene suppressor | |
| miR-337-3p miR-584-5p | MMP14 | + | Oncogene suppressor | |
| miR-362-5p | PI3K–C2B | + | Inhibits NB proliferation/migration | |
| miR-659-3p | Focal adhesion pathway | + | Bone marrow NB infiltration | |
| miR-21 miR-155 | TERF1 | + + | Exacerbated NB chemoresistance | |
| miR-449a | MFAP4 PKP4 TSEN15 | + | Tumor suppressor | |
| miRNA-558 | HPSE | + | NB tumorigenesis | |
| miR-181 family | CDON | + | Oncogene suppressor | |
| miR-520f | NAIP | − | NB chemoresistance | |
| miR-542-3p | Survivin | + | Oncogene suppressor | |
| miR-421 | Menin | + | Increased NB proliferation/migration | |
| miR-200a | Ap-2G | + | Inhibits tumor proliferation | |
| miR-34a | (various) | + | Tumor suppressor | |
| miR-23a | CDH1 | + | Exacerbates NB metastasis | |
| miR-181c | Smad7 | + | Modulates NB proliferation/migration/invasion | |
| miR-202 | E2F1 | + | Oncogene suppressor | |
| miR-329 | KDM1A | + | NB growth/motility | |
| miR-192 | Dicer1 | + | Lowers NB prognosis | |
| miR-338-3p | PREX2a | + | Modulates NB proliferation/migration/invasion | |
| miR-16 | BDNF | + | Cisplatin-induced cytotoxic effector | |
| miR-137 | CAR | + | Enhances doxorubicin sensitivity | |
| miR-335 miR-363 | GRP-R | + + | Reduce NB tumorigenesis/metastasis | |
| miR-183 | Regulated by MYCN/HDAC2 | − | Antiapoptotic effect | |
| miR-138 | Apigenin | + | Apoptotic effect | |
| miR-497 | WEE1 | + | Apoptotic effect | |
| miR-137 | KDM1 | + | Oncogene suppressor | |
| miR-145 | HIF-2a | + | Inhibits growth/metastasis/angiogenesis | |
| miR-15a | RECK | + | Exacerbates metastasis | |
| miR-210 | Bcl-2 | + | Enhances hypoxia-induced apoptosis | |
| miR-21 | PTEN | + | Increases NB cisplatin chemoresistance | |
| miR-204 | BCL2 TrkB | + | Reduces NB cisplatin chemoresistance | |
| miR-9 | MMP14 | + | Inhibit invasion/metastasis/angiogenesis | |
| miR-96 | ALK | + | Oncogene suppressor | |
| miR-335 | (Various) | + | Decreases NB invasiveness | |
| miR-27b | PPARy | + | Inhibits growth/tumor progression/inflammatory process | |
| miR-124 | AHR | − | Induces cell differentiation/cell cycle arrest/apoptosis | |
| miR-487b miR-410 | N/A | + + | Associated with low-risk NB group | |
| miR-17-92 cluster | Dickkopf-3 | + | Oncogenic miRNA cluster | |
| Let-7 miR-101 | MYCN | + | Oncogene suppressors | |
| miR-103 miR-107 | CDK5R1 | + + | Oncogene suppressors | |
| miR-92 | DKK3 | + | Inhibits tumor suppressor | |
| miR-542-5p | N/A | + | Tumour suppressor | |
| miR-885-5p | CDK2 MCM5 | + | Inhibits NB proliferation/survival | |
| miR-10a miR-10b | NCOR2 | + + | Enhances NB differentiation | |
| miR-17-92 cluster | TGF-β pathway | + | Oncogenic cluster | |
| miR-128 | NTRK3 | + | Oncogene suppressor | |
| miR-380-5p | p53 | + | Associated with poor NB prognosis | |
| miR-152 miR-200b miR-338 | + + + | Neuroblast differentiation/apoptosis | ||
| miR-9 | E-Cadherin | + | Induces metastasis | |
| miR-128 | Reelin DCX | + | Reduces NB motility/invasiveness | |
| miR-34a | + | Tumor suppressor | ||
| miR-17-5p | p21 BIM | + | Induces NB chemoresistance |
Related posts:
Role of Genetic and Epigenetic Alterations in Pathogenesis of Neuroblastoma
Role of Stemness Factors in Neuroblastoma: Neuroblastoma Stem Cells, Tumor Microenvironment, and Chemoresistance
Current Pharmacotherapy for Neuroblastoma
Current and Future Strategies for Treatment of Relapsed Neuroblastoma
Novel Therapeutic Targets in Neuroblastoma
Molecular Imaging in Neuroblastoma
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