Spontaneous involution of pediatric low-grade gliomas: high expression of cannabinoid receptor 1 (CNR1) at the time of diagnosis may indicate involvement of the endocannabinoid system.
BACKGROUND
Pediatric low-grade gliomas (P-LGG) consist of a mixed group of brain tumors that correspond to the majority of CNS tumors in children. Notably, they may exhibit spontaneous involution after subtotal surgical removal (STR). In this study, we investigated molecular indicators of spontaneous involution in P-LGG.


METHODS
We performed an integrated molecular analysis including high throughput gene expression (GE), microRNA (miRNA) expression data of primary, untreated tumors from patients with P-LGG who underwent STR at our institution, with at least 10 years follow-up.


RESULTS
We identified a set of protein-coding genes and miRNAs significantly differentially expressed in P-LGG that presented spontaneous involution (involution-I) or without progression (stable-S) after STR alone. The cannabinoid receptor 1 (CNR1 or CB1) gene (FC = 2.374; p value = 0.007) was at the top of the list and predicted to be regulated by hsa-miR-29b-3p (FC = -2.353, p value = 0.0001). CNR1 also showed a trend to be higher expressed in S/I by immunohistochemistry.


CONCLUSIONS
The P-LGG, which remained stable or that presented spontaneous involution after STR, showed significantly higher CNR1 expression at the time of diagnosis. We hypothesize that high expression levels of CNR1 provide tumor susceptibility to the antitumor effects of circulating endocannabinoids like anandamide, resulting in tumor involution. This corroborates with reports suggesting that CNR1 agonists and activators of the endocannabinoid system may represent therapeutic opportunities for children with LGG. We also suggest that CNR1 may be a prognostic marker for P-LGG. This is the first time spontaneous involution of P-LGG has been suggested to be induced by endocannabinoids.
Ann and Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Neurosurgery, Hospital of Chicago, 225 E Chicago Ave., Chicago, IL, 60611, USA. ssredni@luriechildrens.org.|Feinberg School of Medicine, Department of Surgery, Northwestern University, 303 E Chicago Ave, Chicago, IL, 60611, USA. ssredni@luriechildrens.org.|Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute, 2430 North Halsted St., Chicago, IL, 60614, USA. ssredni@luriechildrens.org.
Simone Treiger
ST
Sredni
Joseph J. Zilber School of Public Health, University of Wisconsin, 1240 N 10th St, Milwaukee, WI, 53205, USA.
Chiang-Ching
CC
Huang
Ann and Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Neurosurgery, Hospital of Chicago, 225 E Chicago Ave., Chicago, IL, 60611, USA.|Department of Neurosurgery, Juntendo University, School of Medicine, Hongo, 2-1-1 Bunkyo-ku, Tokyo, 113-8421, Japan.
Mario
M
Suzuki
Ann and Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Neurosurgery, Hospital of Chicago, 225 E Chicago Ave., Chicago, IL, 60611, USA.
Tatiana
T
Pundy
Ann and Robert H. Lurie Children's Hospital of Chicago, Department of Pathology and Laboratory Medicine, Hospital of Chicago, 225 E Chicago Ave., Chicago, IL, 60611, USA.|Feinberg School of Medicine, Department of Pediatrics, Northwestern University, 303 E Chicago Ave, Chicago, IL, 60611, USA.
Pauline
P
Chou
Ann and Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Neurosurgery, Hospital of Chicago, 225 E Chicago Ave., Chicago, IL, 60611, USA.|Feinberg School of Medicine, Department of Surgery, Northwestern University, 303 E Chicago Ave, Chicago, IL, 60611, USA.
Tadanori
T
Tomita
D000293:Adolescent; D014408:Biomarkers, Tumor / Q000032:analysis; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D063388:Endocannabinoids / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D060787:Neoplasm Grading; D043884:Receptor, Cannabinoid, CB1 / Q000032:analysis / Q000096:biosynthesis*; D012074:Remission Induction
D014408:Biomarkers, Tumor; C571130:CNR1 protein, human; D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1
Anandamide; Brain neoplasm; CB1; Children; Prognosis; miR-29b