Abstract
Metanephrines (MNs; normetanephrine (NMN), metanephrine (MN) and methoxytyramine (MT)) detected in urine or plasma represent the best biomarker for neuroblastoma (NB) diagnosis, however the metabolism of both catecholamine (CAT) and MNs remains enigmatic in NB. Using patient-derived xenograft (PDX) models derived from primary NB cells, we observed that the plasma levels of MNs in NB-PDX-bearing mice were comparable as in patients. Interestingly, murine plasma displayed an elevated fraction of glucuronidated forms of MNs relative to human plasma where sulfonated forms prevail. In tumors, the concentration ranges of MNs and CAT and the expression levels of the main genes involved in catecholamine metabolism were similar between NB-PDX and human NB tissues. Likewise, plasma and intratumoral profiles of individual MNs, with increased levels of MT and NMN relative to MN, were also conserved in mouse models as in patients. We further demonstrated the downregulation of the Phenylethanolamine N-Methyltransferase gene in NB biopsies and in NB-PDX explaining this biochemical phenotype, and giving a rational to the low levels of epinephrine and MN measured in NB affected patients. Thus, our subcutaneous murine NB-PDX models not only reproduce the phenotype of primary NB tumors, but also the metabolism of catecholamine as observed in patients. This may potentially open new avenues in preclinical studies for the follow up of novel therapeutic options for NB through the quantification of plasma MNs.
Highlights
NB is an embryonic tumor of the sympathetic nervous system, that can arise at any site of the sympathetic chain but most frequently in the abdominal region [1, 2]
DA is internalized into neurosecretory vesicles by the vesicular monoamine transporters (VMAT1, and VMAT2, respectively SLC18A1 and SLC18A2) where it is converted into NE by dopamine beta-hydroxylase (DBH) and NE could be further converted into E in neurosecretory vesicles containing Phenylethanolamine N-Methyltransferase (PNMT) [5]
We developed four novel NB-patient-derived xenograft (PDX) models from either NB cells disseminated in the bone marrow (BM) or from the primary tumor of the NB-1 patient (Table 1)
Summary
NB is an embryonic tumor of the sympathetic nervous system, that can arise at any site of the sympathetic chain but most frequently in the abdominal region [1, 2]. A small proportion of CAT that leak from neurosecretory vesicles is transformed into metanephrines (MNs; normetanephrine (NMN), metanephrine (MN) and methoxytyramine (MT)) by the enzyme COMT (catechol O-methyltransferase) [5]. A large amount of MNs is transformed through multiple steps involving other intermediate products into vanillylmandelic acid (VMA, from MN and NMN) and homovanillic acid (HVA from MT). These two end-stage are filtered by kidneys to be secreted in urine [5, 7, 8]. The large amount of CAT found in tumors and in plasma has been shown to be a consequence of the over-expression of several enzymes involved in CAT synthesis [9, 10]
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