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Vesicular monoamine transporter protein expression correlates with clinical features, tumor biology, and MIBG avidity in neuroblastoma: a report from the Children’s Oncology Group

  • William Temple
  • Lori Mendelsohn
  • Grace E. Kim
  • Erin Nekritz
  • W. Clay Gustafson
  • Lawrence Lin
  • Kathy Giacomini
  • Arlene Naranjo
  • Collin Van Ryn
  • Gregory A. Yanik
  • Susan G. Kreissman
  • Michael Hogarty
  • Katherine K. Matthay
  • Steven G. DuBoisEmail author
Original Article

Abstract

Purpose

Vesicular monoamine transporters 1 and 2 (VMAT1 and VMAT2) are thought to mediate MIBG uptake in adult neuroendocrine tumors. In neuroblastoma, the norepinephrine transporter (NET) has been investigated as the principal MIBG uptake protein, though some tumors without NET expression concentrate MIBG. We investigated VMAT expression in neuroblastoma and correlated expression with MIBG uptake and clinical features.

Methods

We evaluated VMAT1 and VMAT2 expression by immunohistochemistry (IHC) in neuroblastoma tumors from 76 patients with high-risk metastatic disease treated in a uniform cooperative group trial (COG A3973). All patients had baseline MIBG diagnostic scans centrally reviewed. IHC results were scored as the product of intensity grading (0 – 3+) and percent of tumor cells expressing the protein of interest. The association between VMAT1 and VMAT2 scores and clinical and biological features was tested using Wilcoxon rank-sum tests.

Results

Patient characteristics were typical of high-risk neuroblastoma, though the cohort was intentionally enriched in patients with MIBG-nonavid tumors (n = 20). VMAT1 and VMAT2 were expressed in 62 % and 75 % of neuroblastoma tumors, respectively. VMAT1 and VMAT2 scores were both significantly lower in MYCN amplified tumors and in tumors with high mitotic karyorrhectic index. MIBG-avid tumors had significantly higher VMAT2 scores than MIBG-nonavid tumors (median 216 vs. 45; p = 0.04). VMAT1 expression did not correlate with MIBG avidity.

Conclusion

VMAT1 and VMAT2 are expressed in the majority of neuroblastomas. Expression correlates with other biological features. The expression level of VMAT2 but not that of VMAT1 correlates with avidity for MIBG.

Keywords

Neuroblastoma Vesicular monoamine transporters VMAT1  VMAT2  MIBG avidity 

Notes

Compliance with ethical standards

Funding

This work was supported by the Campini Foundation (S.G.D. and K.K.M.), the Dougherty Family Foundation (K.K.M.), Alex’s Lemonade Stand Foundation (W.T., S.G.D., and K.K.M.), U10CA09853, U10CA180899, and U24CA114766. The funding sources did not play a role in study design, conduct, data analysis, or interpretation.

Conflict of interest

None.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

For this type of study, formal consent is not required.

Supplementary material

259_2015_3179_MOESM1_ESM.pptx (915 kb)
Supplemental Fig. 1 a–c Representative photomicrographs of tumors with 3+ (a), 2+ (b), and 1+ (c) VMAT1 staining. d–f Representative photomicrographs of tumors with 3+ (d), 2+ (e), and 1+ (f) VMAT2 staining. All photomicrographs are at 200× magnification. (PPTX 915 kb)
259_2015_3179_MOESM2_ESM.pptx (3.6 mb)
Supplemental Fig. 2 Correlation between VMAT1 composite protein expression score and VMAT2 composite protein expression score (r = 0.66, p < 0.001). (PPTX 3648 kb)

References

  1. 1.
    Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet. 2007;369(9579):2106–20.CrossRefPubMedGoogle Scholar
  2. 2.
    Taggart D, Dubois S, Matthay KK. Radiolabeled metaiodobenzylguanidine for imaging and therapy of neuroblastoma. Q J Nucl Med Mol Imaging. 2008;52(4):403–18.PubMedGoogle Scholar
  3. 3.
    DuBois SG, Matthay KK. Radiolabeled metaiodobenzylguanidine for the treatment of neuroblastoma. Nucl Med Biol. 2008;35 Suppl 1:S35–48.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Wilson JS, Gains JE, Moroz V, Wheatley K, Gaze MN. A systematic review of 131I-meta iodobenzylguanidine molecular radiotherapy for neuroblastoma. Eur J Cancer. 2014;50(4):801–15.CrossRefPubMedGoogle Scholar
  5. 5.
    Treuner J, Feine U, Niethammer D, Muller-Schaumburg W, Meinke J, Eibach E, et al. Scintigraphic imaging of neuroblastoma with [131-I]iodobenzylguanidine. Lancet. 1984;1(8372):333–4.CrossRefPubMedGoogle Scholar
  6. 6.
    Smets LA, Janssen M, Rutgers M, Ritzen K, Buttenhuis C. Pharmacokinetics and intracellular distribution of the tumor-targeted radiopharmaceutical m-iodo-benzylguanidine in SK-N-SH neuroblastoma and PC-12 pheochromocytoma cells. Int J Cancer. 1991;48(4):609–15.CrossRefPubMedGoogle Scholar
  7. 7.
    Smets LA, Loesberg C, Janssen M, Metwally EA, Huiskamp R. Active uptake and extravesicular storage of m-iodobenzylguanidine in human neuroblastoma SK-N-SH cells. Cancer Res. 1989;49(11):2941–4.PubMedGoogle Scholar
  8. 8.
    Smets LA, Rutgers M. Model studies on metaiodobenzylguanidine (MIBG) uptake and storage: relevance for 131I-MIBG therapy of neuroblastoma. J Nucl Biol Med. 1991;35(4):191–4.PubMedGoogle Scholar
  9. 9.
    Carlin S, Mairs RJ, McCluskey AG, Tweddle DA, Sprigg A, Estlin C, et al. Development of a real-time polymerase chain reaction assay for prediction of the uptake of meta-[(131)I]iodobenzylguanidine by neuroblastoma tumors. Clin Cancer Res. 2003;9(9):3338–44.PubMedGoogle Scholar
  10. 10.
    DuBois SG, Geier E, Batra V, Yee SW, Neuhaus J, Segal M, et al. Evaluation of norepinephrine transporter expression and metaiodobenzylguanidine avidity in neuroblastoma: a report from the children’s oncology group. Int J Mol Imaging. 2012;2012:250834.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Mairs RJ, Livingstone A, Gaze MN, Wheldon TE, Barrett A. Prediction of accumulation of 131I-labelled meta-iodobenzylguanidine in neuroblastoma cell lines by means of reverse transcription and polymerase chain reaction. Br J Cancer. 1994;70(1):97–101.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Lawal HO, Krantz DE. SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine. Mol Aspects Med. 2013;34(2-3):360–72.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Guilloteau D, Baulieu JL, Huguet F, Viel C, Chambon C, Valat C, et al. Meta-iodobenzylguanidine adrenal medulla localization: autoradiographic and pharmacologic studies. Eur J Nucl Med. 1984;9(6):278–81.CrossRefPubMedGoogle Scholar
  14. 14.
    Kolby L, Bernhardt P, Levin-Jakobsen AM, Johanson V, Wangberg B, Ahlman H, et al. Uptake of meta-iodobenzylguanidine in neuroendocrine tumours is mediated by vesicular monoamine transporters. Br J Cancer. 2003;89(7):1383–8.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Fottner C, Helisch A, Anlauf M, Rossmann H, Musholt TJ, Kreft A, et al. 6-18F-fluoro-L-dihydroxyphenylalanine positron emission tomography is superior to 123I-metaiodobenzyl-guanidine scintigraphy in the detection of extraadrenal and hereditary pheochromocytomas and paragangliomas: correlation with vesicular monoamine transporter expression. J Clin Endocrinol Metab. 2010;95(6):2800–10.CrossRefPubMedGoogle Scholar
  16. 16.
    Kreissman SG, Seeger RC, Matthay KK, London WB, Sposto R, Grupp SA, et al. Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol. 2013;14(10):999–1008.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Yanik GA, Parisi MT, Shulkin BL, Naranjo A, Kreissman SG, London WB, et al. Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children’s Oncology Group. J Nucl Med. 2013;54(4):541–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Shimada H, Ambros IM, Dehner LP, Hata J, Joshi VV, Roald B, et al. The International Neuroblastoma Pathology Classification (the Shimada system). Cancer. 1999;86(2):364–72.CrossRefPubMedGoogle Scholar
  19. 19.
    Anlauf M, Eissele R, Schafer MK, Eiden LE, Arnold R, Pauser U, et al. Expression of the two isoforms of the vesicular monoamine transporter (VMAT1 and VMAT2) in the endocrine pancreas and pancreatic endocrine tumors. J Histochem Cytochem. 2003;51(8):1027–40.CrossRefPubMedGoogle Scholar
  20. 20.
    Erickson JD, Schafer MK, Bonner TI, Eiden LE, Weihe E. Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter. Proc Natl Acad Sci U S A. 1996;93(10):5166–71.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Peter D, Liu Y, Sternini C, de Giorgio R, Brecha N, Edwards RH. Differential expression of two vesicular monoamine transporters. J Neurosci. 1995;15(9):6179–88.PubMedGoogle Scholar
  22. 22.
    Vo KT, Matthay KK, Neuhaus J, London WB, Hero B, Ambros PF, et al. Clinical, biologic, and prognostic differences on the basis of primary tumor site in neuroblastoma: a report from the International Neuroblastoma Risk Group Project. J Clin Oncol. 2014;32(28):3169–76.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ambros PF, Ambros IM, Brodeur GM, Haber M, Khan J, Nakagawara A, et al. International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Br J Cancer. 2009;100(9):1471–82.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Goto S, Umehara S, Gerbing RB, Stram DO, Brodeur GM, Seeger RC, et al. Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group. Cancer. 2001;92(10):2699–708.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • William Temple
    • 1
    • 4
  • Lori Mendelsohn
    • 1
    • 4
  • Grace E. Kim
    • 2
  • Erin Nekritz
    • 1
    • 4
  • W. Clay Gustafson
    • 1
    • 4
  • Lawrence Lin
    • 3
  • Kathy Giacomini
    • 3
  • Arlene Naranjo
    • 5
  • Collin Van Ryn
    • 5
  • Gregory A. Yanik
    • 6
  • Susan G. Kreissman
    • 7
  • Michael Hogarty
    • 8
  • Katherine K. Matthay
    • 1
    • 4
  • Steven G. DuBois
    • 1
    • 4
    • 9
    Email author
  1. 1.Department of PediatricsUCSF School of MedicineSan FranciscoUSA
  2. 2.Department of PathologyUCSF School of MedicineSan FranciscoUSA
  3. 3.Department of Bioengineering and Therapeutic SciencesUCSF School of PharmacySan FranciscoUSA
  4. 4.UCSF Benioff Children’s HospitalSan FranciscoUSA
  5. 5.Children’s Oncology Group Statistics and Data CenterUniversity of FloridaGainesvilleUSA
  6. 6.CS Mott Children’s HospitalUniversity of MichiganAnn ArborUSA
  7. 7.Duke University Medical CenterDurhamUSA
  8. 8.Children’s Hospital of Philadelphia and Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  9. 9.UCSF School of MedicineSan FranciscoUSA

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