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¹H nuclear magnetic resonance spectroscopy characterisation of metabolic phenotypes in the medulloblastoma of the SMO transgenic mice.

Hekmatyar SK, Wilson M, Jerome N, Salek RM, Griffin JL, Peet A, Kauppinen RA - Br. J. Cancer (2010)

Bottom Line: These tumours showed low concentrations of N-acetyl aspartate and high concentrations of choline-containing metabolites (CCMs), glycine, and taurine relative to the cerebellar parenchyma in the wild-type (WT) C57BL/6 mice.Taurine, glycine, and CCM are potential metabolite biomarkers for the SMO medulloblastomas.The MRS data from the medulloblastomas with defined molecular pathology is discussed in the light of metabolite profiles reported from human tumours.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Biomedical NMR Research Center, Dartmouth College, 706 Vail, Hanover, NH 03755, USA.

ABSTRACT

Background: Human medulloblastomas exhibit diverse molecular pathology. Aberrant hedgehog signalling is found in 20-30% of human medulloblastomas with largely unknown metabolic consequences.

Methods: Transgenic mice over-expressing smoothened (SMO) receptor in granule cell precursors with high incidence of exophytic medulloblastomas were sequentially followed up by magnetic resonance imaging (MRI) and characterised for metabolite phenotypes by ¹H MR spectroscopy (MRS) in vivo and ex vivo using high-resolution magic angle spinning (HR-MAS) ¹H MRS.

Results: Medulloblastomas in the SMO mice presented as T₂ hyperintense tumours in MRI. These tumours showed low concentrations of N-acetyl aspartate and high concentrations of choline-containing metabolites (CCMs), glycine, and taurine relative to the cerebellar parenchyma in the wild-type (WT) C57BL/6 mice. In contrast, ¹H MRS metabolite concentrations in normal appearing cerebellum of the SMO mice were not different from those in the WT mice. Macromolecule and lipid ¹H MRS signals in SMO medulloblastomas were not different from those detected in the cerebellum of WT mice. The HR-MAS analysis of SMO medulloblastomas confirmed the in vivo ¹H MRS metabolite profiles, and additionally revealed that phosphocholine was strongly elevated in medulloblastomas accounting for the high in vivo CCM.

Conclusions: These metabolite profiles closely mirror those reported from human medulloblastomas confirming that SMO mice provide a realistic model for investigating metabolic aspects of this disease. Taurine, glycine, and CCM are potential metabolite biomarkers for the SMO medulloblastomas. The MRS data from the medulloblastomas with defined molecular pathology is discussed in the light of metabolite profiles reported from human tumours.

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1H MRS in vivo spectra from and (A) WT mouse cerebellum, (B) SMO mouse cerebellum without T2 hyperintense lesion and (C) SMO mouse cerebellum with a T2 hyperintense tumour. Peak assignments are as follows: (1) lipids and macromolecules at 0.9 p.p.m., (2) lipids and macromolecules at 1.3 p.p.m.+lactate, (3) N-acetyl aspartic acid+N-acetyl aspartylglutamic acid, (4) glutamate+glutamine, (5) creatine, (6) choline containing metabolites, (7) taurine, (8) glycine+myo-inositol.
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fig4: 1H MRS in vivo spectra from and (A) WT mouse cerebellum, (B) SMO mouse cerebellum without T2 hyperintense lesion and (C) SMO mouse cerebellum with a T2 hyperintense tumour. Peak assignments are as follows: (1) lipids and macromolecules at 0.9 p.p.m., (2) lipids and macromolecules at 1.3 p.p.m.+lactate, (3) N-acetyl aspartic acid+N-acetyl aspartylglutamic acid, (4) glutamate+glutamine, (5) creatine, (6) choline containing metabolites, (7) taurine, (8) glycine+myo-inositol.

Mentions: Typical 1H MR spectra from WT cerebellum (a), SMO mouse cerebellum with (b) and without (c) T2 MRI hyperintense tumour are shown (Figure 4). It is evident that the 1H MR spectrum of a tumour in a SMO mouse has a very small resonance associated with N-acetyle aspartate (NAA) and grossly elevated choline-containing metabolite (CCM) and taurine peaks, but normal appearing creatine resonance. Interestingly, the chemical shift region at 1.3 and 0.9 p.p.m. in the spectrum from the SMO medulloblastoma shows only weak signal from lipids, lactate and macromolecules. Quantitative metabolite data are shown in Table 1. It is evident that NAA in medulloblastomas (pooled MRS data from all eight SMO mice with pathological cerebellum in T2 MRI) is severely reduced, whereas taurine, glycine, and CCM are highly elevated. Lactate, macromolecules and lipids in the chemical shift region between 0.9 and 1.4 p.p.m. are similar in medulloblastomas and WT mice. In the cerebella of the SMO mice without MRI abnormality, all metabolites, macromolecules and lipids were within the range determined in the cerebella of the WT mice (Table 1).


¹H nuclear magnetic resonance spectroscopy characterisation of metabolic phenotypes in the medulloblastoma of the SMO transgenic mice.

Hekmatyar SK, Wilson M, Jerome N, Salek RM, Griffin JL, Peet A, Kauppinen RA - Br. J. Cancer (2010)

1H MRS in vivo spectra from and (A) WT mouse cerebellum, (B) SMO mouse cerebellum without T2 hyperintense lesion and (C) SMO mouse cerebellum with a T2 hyperintense tumour. Peak assignments are as follows: (1) lipids and macromolecules at 0.9 p.p.m., (2) lipids and macromolecules at 1.3 p.p.m.+lactate, (3) N-acetyl aspartic acid+N-acetyl aspartylglutamic acid, (4) glutamate+glutamine, (5) creatine, (6) choline containing metabolites, (7) taurine, (8) glycine+myo-inositol.
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Related In: Results  -  Collection

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fig4: 1H MRS in vivo spectra from and (A) WT mouse cerebellum, (B) SMO mouse cerebellum without T2 hyperintense lesion and (C) SMO mouse cerebellum with a T2 hyperintense tumour. Peak assignments are as follows: (1) lipids and macromolecules at 0.9 p.p.m., (2) lipids and macromolecules at 1.3 p.p.m.+lactate, (3) N-acetyl aspartic acid+N-acetyl aspartylglutamic acid, (4) glutamate+glutamine, (5) creatine, (6) choline containing metabolites, (7) taurine, (8) glycine+myo-inositol.
Mentions: Typical 1H MR spectra from WT cerebellum (a), SMO mouse cerebellum with (b) and without (c) T2 MRI hyperintense tumour are shown (Figure 4). It is evident that the 1H MR spectrum of a tumour in a SMO mouse has a very small resonance associated with N-acetyle aspartate (NAA) and grossly elevated choline-containing metabolite (CCM) and taurine peaks, but normal appearing creatine resonance. Interestingly, the chemical shift region at 1.3 and 0.9 p.p.m. in the spectrum from the SMO medulloblastoma shows only weak signal from lipids, lactate and macromolecules. Quantitative metabolite data are shown in Table 1. It is evident that NAA in medulloblastomas (pooled MRS data from all eight SMO mice with pathological cerebellum in T2 MRI) is severely reduced, whereas taurine, glycine, and CCM are highly elevated. Lactate, macromolecules and lipids in the chemical shift region between 0.9 and 1.4 p.p.m. are similar in medulloblastomas and WT mice. In the cerebella of the SMO mice without MRI abnormality, all metabolites, macromolecules and lipids were within the range determined in the cerebella of the WT mice (Table 1).

Bottom Line: These tumours showed low concentrations of N-acetyl aspartate and high concentrations of choline-containing metabolites (CCMs), glycine, and taurine relative to the cerebellar parenchyma in the wild-type (WT) C57BL/6 mice.Taurine, glycine, and CCM are potential metabolite biomarkers for the SMO medulloblastomas.The MRS data from the medulloblastomas with defined molecular pathology is discussed in the light of metabolite profiles reported from human tumours.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Biomedical NMR Research Center, Dartmouth College, 706 Vail, Hanover, NH 03755, USA.

ABSTRACT

Background: Human medulloblastomas exhibit diverse molecular pathology. Aberrant hedgehog signalling is found in 20-30% of human medulloblastomas with largely unknown metabolic consequences.

Methods: Transgenic mice over-expressing smoothened (SMO) receptor in granule cell precursors with high incidence of exophytic medulloblastomas were sequentially followed up by magnetic resonance imaging (MRI) and characterised for metabolite phenotypes by ¹H MR spectroscopy (MRS) in vivo and ex vivo using high-resolution magic angle spinning (HR-MAS) ¹H MRS.

Results: Medulloblastomas in the SMO mice presented as T₂ hyperintense tumours in MRI. These tumours showed low concentrations of N-acetyl aspartate and high concentrations of choline-containing metabolites (CCMs), glycine, and taurine relative to the cerebellar parenchyma in the wild-type (WT) C57BL/6 mice. In contrast, ¹H MRS metabolite concentrations in normal appearing cerebellum of the SMO mice were not different from those in the WT mice. Macromolecule and lipid ¹H MRS signals in SMO medulloblastomas were not different from those detected in the cerebellum of WT mice. The HR-MAS analysis of SMO medulloblastomas confirmed the in vivo ¹H MRS metabolite profiles, and additionally revealed that phosphocholine was strongly elevated in medulloblastomas accounting for the high in vivo CCM.

Conclusions: These metabolite profiles closely mirror those reported from human medulloblastomas confirming that SMO mice provide a realistic model for investigating metabolic aspects of this disease. Taurine, glycine, and CCM are potential metabolite biomarkers for the SMO medulloblastomas. The MRS data from the medulloblastomas with defined molecular pathology is discussed in the light of metabolite profiles reported from human tumours.

Show MeSH
Related in: MedlinePlus