Skip to main content

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

Child's Nervous System volume 32, pages 2061–2067 (2016)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3

References

  1. Wisoff JH, Sanford RA, Heier LA, Sposto R, Burger PC, Yates AJ, Holmes EJ, Kun LE (2011) Primary neurosurgery for pediatric low-grade gliomas: a prospective multi-institutional study from the Children’s oncology group. Neurosurgery 68:1548–1554 discussion 1554-1545

    Article  PubMed  Google Scholar 

  2. Scheinemann K, Bartels U, Tsangaris E, Hawkins C, Huang A, Dirks P, Fried I, Bouffet E, Tabori U (2011) Feasibility and efficacy of repeated chemotherapy for progressive pediatric low-grade gliomas. Pediatr Blood Cancer 57:84–88

    Article  PubMed  Google Scholar 

  3. von Hornstein S, Kortmann RD, Pietsch T, Emser A, Warmuth-Metz M, Soerensen N, Straeter R, Graf N, Thieme B, Gnekow AK (2011) Impact of chemotherapy on disseminated low-grade glioma in children and adolescents: report from the HIT-LGG 1996 trial. Pediatr Blood Cancer 56:1046–1054

    Article  Google Scholar 

  4. Ogiwara H, Bowman RM, Tomita T (2012) Long-term follow-up of pediatric benign cerebellar astrocytomas. Neurosurgery 70:40–47 discussion 47-48

    Article  PubMed  Google Scholar 

  5. Laprairie RB, Kelly ME, Denovan-Wright EM (2012) The dynamic nature of type 1 cannabinoid receptor (CB(1)) gene transcription. Br J Pharmacol 167:1583–1595

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Pisanti S, Picardi P, Pallottini V, Martini C, Petrosino S, Proto MC, Vitale M, Laezza C, Gazzerro P, Di Marzo V, Bifulco M (2015) Anandamide drives cell cycle progression through CB1 receptors in a rat model of synchronized liver regeneration. J Cell Physiol 230:2905–2914

    CAS  Article  PubMed  Google Scholar 

  7. Velasco G, Sanchez C, Guzman M (2016) Anticancer mechanisms of cannabinoids. Curr Oncol 23:S23–S32

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Velasco G, Hernandez-Tiedra S, Davila D, Lorente M (2016) The use of cannabinoids as anticancer agents. Prog Neuro-Psychopharmacol Biol Psychiatry 64:259–266

    CAS  Article  Google Scholar 

  9. Ramer R, Hinz B (2015) New insights into antimetastatic and antiangiogenic effects of cannabinoids. Int Rev Cell Mol Biol 314:43–116

    Article  PubMed  Google Scholar 

  10. Blazquez C, Casanova ML, Planas A, Gomez Del Pulgar T, Villanueva C, Fernandez-Acenero MJ, Aragones J, Huffman JW, Jorcano JL, Guzman M (2003) Inhibition of tumor angiogenesis by cannabinoids. FASEB J 17:529–531

    CAS  PubMed  Google Scholar 

  11. Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, Cravatt BF (2010) Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 140:49–61

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Guzman M (2003) Cannabinoids: potential anticancer agents. Nat Rev Cancer 3:745–755

    CAS  Article  PubMed  Google Scholar 

  13. Velasco G, Sanchez C, Guzman M (2012) Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer 12:436–444

    CAS  Article  PubMed  Google Scholar 

  14. Galve-Roperh I, Sanchez C, Cortes ML, Gomez del Pulgar T, Izquierdo M, Guzman M (2000) Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 6:313–319

    CAS  Article  PubMed  Google Scholar 

  15. Velasco G, Carracedo A, Blazquez C, Lorente M, Aguado T, Haro A, Sanchez C, Galve-Roperh I, Guzman M (2007) Cannabinoids and gliomas. Mol Neurobiol 36:60–67

    CAS  Article  PubMed  Google Scholar 

  16. Torres S, Lorente M, Rodriguez-Fornes F, Hernandez-Tiedra S, Salazar M, Garcia-Taboada E, Barcia J, Guzman M, Velasco G (2011) A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol Cancer Ther 10:90–103

    CAS  Article  PubMed  Google Scholar 

  17. Blazquez C, Salazar M, Carracedo A, Lorente M, Egia A, Gonzalez-Feria L, Haro A, Velasco G, Guzman M (2008) Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. Cancer Res 68:1945–1952

    CAS  Article  PubMed  Google Scholar 

  18. Freund TF, Katona I, Piomelli D (2003) Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83:1017–1066

    CAS  Article  PubMed  Google Scholar 

  19. Chakravarti B, Ravi J, Ganju RK (2014) Cannabinoids as therapeutic agents in cancer: current status and future implications. Oncotarget 5:5852–5872

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bifulco M, Laezza C, Pisanti S, Gazzerro P (2006) Cannabinoids and cancer: pros and cons of an antitumour strategy. Br J Pharmacol 148:123–135

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

Funded by the Voices Against Brain Cancer Foundation (Fund#925432) and the Lurie Children’s Hospital Faculty Practice Plan Development Funding (Fund#931220).

We thank Kashyap Patel MS and Naira Margaryan DVM, Ph.D. for technical support; Aline T. Sredni and Jessica Jakubowski BS for editorial assistance.

Author information

Authors and Affiliations

  1. 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

    Simone Treiger Sredni, Mario Suzuki, Tatiana Pundy & Tadanori Tomita

  2. Feinberg School of Medicine, Department of Surgery, Northwestern University, 303 E Chicago Ave, Chicago, IL, 60611, USA

    Simone Treiger Sredni & Tadanori Tomita

  3. Cancer Biology and Epigenomics, Stanley Manne Children’s Research Institute, 2430 North Halsted St., Chicago, IL, 60614, USA

    Simone Treiger Sredni

  4. Joseph J. Zilber School of Public Health, University of Wisconsin, 1240 N 10th St, Milwaukee, WI, 53205, USA

    Chiang-Ching Huang

  5. Department of Neurosurgery, Juntendo University, School of Medicine, Hongo, 2-1-1 Bunkyo-ku, Tokyo, 113-8421, Japan

    Mario Suzuki

  6. 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

    Pauline Chou

  7. Feinberg School of Medicine, Department of Pediatrics, Northwestern University, 303 E Chicago Ave, Chicago, IL, 60611, USA

    Pauline Chou

Authors
  1. Simone Treiger Sredni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chiang-Ching Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mario Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tatiana Pundy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pauline Chou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tadanori Tomita
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Simone Treiger Sredni.

Ethics declarations

Conflicts of interest

The authors declare no conflicts of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sredni, S.T., Huang, CC., Suzuki, M. et al. 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. Childs Nerv Syst 32, 2061–2067 (2016). https://doi.org/10.1007/s00381-016-3243-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00381-016-3243-7

Keywords

  • CB1
  • miR-29b
  • Anandamide
  • Prognosis
  • Brain neoplasm
  • Children