Introduction
Neuroblastoma (NB) is the most frequent extracranial solid tumor in
children, accounting for 8-10% of all pediatric cancers1. These tumors originate from neural crest cells,
which are primitive progenitors of sympathetic ganglia, and can arise
anywhere along the sympathetic nervous system 2. After
tumor formation, it results in a spectrum of clinical diseases ranging
from variably aggressive NBs to well-differentiated benign tumors (i.e.,
ganglioneuroma, GN) 3. Metastases are diagnosed in
about 50% of patients, with the bone marrow, bone, and regional lymph
nodes being
the most commonly affected sites 4. NB treatment
includes a wide range of therapies, depending on patients’ disease risk
classification 1. After induction and consolidation
chemotherapy, approximately half of all patients reportedly develop drug
resistance or suffer disease relapse after the first-line therapy5, 6.
The International NB staging system (INSS) classifies NBs into different
stages (1, 2A/B, 3, 4, and 4S) based on clinical criteria7, 8. In addition, the MYCNoncogene amplification (MNA) is an independent poor prognostic factor
significantly associated with INSS stage 4, and unfavorable histological
features 9. Determination of tumor cell ploidy and the
identification of segmental chromosomal aberrations found most
frequently in 1p, 1q, 3p, 11q, 14q, and 17p have substantially improved
NB risk stratification and the choice of the most effective treatment
regimens 9. Specifically, LOH in chromosome 11q
(Ch11q) in nonamplified-MYCN (NAMN) was found to be associated
with a therapy-resistant metastatic NB subgroup 10, as
well as with high activity of the COX/microsomal prostaglandin E
synthase (mPGES)-1/PGE2 pathway 11.
Prostaglandins (PGs, including PGD2, PGE2, PGF2a, and PGI2) are
arachidonic acid-derived chemical mediators of the inflammatory response12. They are produced by sequential actions of
cyclooxygenases (COX-1 or COX-2) and specific synthases, exerting their
effects mainly through the G-protein–coupled receptors (GPCRs),
activating adenylate cyclase or phospholipase C 12.
Tumor cells are often characterized by aberrant COX-2 expression,
resulting from transcriptional and/or post-transcriptional and
epigenetic alterations 13, 14. COX-2, which is also
released by cancer-associated fibroblasts (CAFs) and type-2 macrophages
(M2) 15, is involved in angiogenesis, tumor cell
proliferation, and survival. It correlates with invasiveness and
resistance to chemotherapeutic drugs in many cancer types, such as
breast, lung, colon, prostate, and bladder 16, 17. In
NBs, high COX-2/PGE2 expression levels promote malignant cell
transformation and inhibit apoptosis via cAMP-mediated β-catenin
stabilization, a process that may be of particular significance in NAMN
cells 18.
Despite the premise that the COX-2 pathway favors tumor progression, the
exact extent of this association has not yet been completely understood.
Network systems biology has been broadly accepted as useful tools that
allow the visualization and analysis of the interaction of multiple
molecular pathways, providing the uncovering of new biomarkers and their
association to disease phenotypes 19. In the current
study, we analyzed COX-2 expression levels in NB tumor samples obtained
during diagnosis and post-chemotherapy. Furthermore, we analyzed the
genomic profile of tumors with Ch11q aberrations and the correlation
with the genes encoding the enzymes involved in the COX/mPGES-1/PGE2 and
other inflammatory pathways using a pipeline of computational systems
biology tools.