The calcium-sensing receptor and parathyroid hormone-related protein are expressed in differentiated, favorable neuroblastic tumors.
BACKGROUND
Differentiated histopathology is a favorable prognostic factor in neuroblastic tumors, and molecular pathways underlying neuroblastoma differentiation can be modulated pharmacologically. The calcium-sensing receptor (CaR) and parathyroid hormone-related protein (PTHrP) regulate differentiation processes in some cellular contexts. CaR is up-regulated when neural stem cells are specified to the oligodendrocyte lineage and regulates PTHrP production in astrocytes. The objective of the current study was to assess whether CaR and PTHrP participate in neuroblastoma differentiation pathways.


METHODS
CaR and PTHrP messenger RNA (mRNA) and protein expression were analyzed in neuroblastic tumors, and correlation with prognostic factors was assessed. CaR and PTHrP expression levels were analyzed in neuroblastoma cell lines treated with all-trans-retinoic acid or 5-bromo-2'-deoxyuridine (BrdU).


RESULTS
CaR expression was correlated with favorable histology, age at diagnosis <1 year, low clinical stage, and low clinical risk. CaR was absent in undifferentiated neuroblasts and was expressed in differentiating neuroblasts. CaR and PTHrP were highly expressed in ganglion and in Schwann-like cells. PTHrP mRNA levels were higher in ganglioneuroblastomas and ganglioneuromas than in neuroblastomas (P < .0001). Both genes were up-regulated in neuroblastomas with treatment-induced maturation features. CaR, but not PTHrP, was up-regulated at early phases of in vitro neuronal differentiation induction. Substrate-adherent, non-neuronal cell lines displayed the highest PTHrP levels among the neuroblastoma cell lines examined. The up-regulation of PTHrP and of 2 glial differentiation markers was observed in 2 cell lines that were treated with BrdU, whereas CaR was induced in only 1 cell line.


CONCLUSIONS
CaR and PTHrP were expressed in differentiated, favorable neuroblastic tumors, and both genes were up-regulated by inducing differentiation.
Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Barcelona, Spain. cdetorres@hsjdbcn.org
Carmen
C
de Torres
Helena
H
Beleta
Rubén
R
Díaz
Núria
N
Toran
Eva
E
Rodríguez
Cinzia
C
Lavarino
Idoia
I
García
Sandra
S
Acosta
Mariona
M
Suñol
Jaume
J
Mora
D001973:Bromodeoxyuridine / Q000494:pharmacology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D018305:Ganglioneuroblastoma / Q000378:metabolism; D005729:Ganglioneuroma / Q000378:metabolism; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia; D009474:Neurons; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044169:Receptors, Calcium-Sensing / Q000235:genetics* / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation
D044162:Parathyroid Hormone-Related Protein; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D014212:Tretinoin; D001973:Bromodeoxyuridine