Metabolic Tumor Imaging Using Magnetic Resonance Spectroscopy

doi:10.1053/j.seminoncol.2010.11.001

Seminars in Oncology

Volume 38, Issue 1, February 2011, Pages 26-41

https://doi.org/10.1053/j.seminoncol.2010.11.001 Get rights and content

The adaptability and the genomic plasticity of cancer cells, and the interaction between the tumor microenvironment and co-opted stromal cells, coupled with the ability of cancer cells to colonize distant organs, contribute to the frequent intractability of cancer. It is becoming increasingly evident that personalized molecular targeting is necessary for the successful treatment of this multifaceted and complex disease. Noninvasive imaging modalities such as magnetic resonance (MR), positron emission tomography (PET), and single-photon emission computed tomography (SPECT) are filling several important niches in this era of targeted molecular medicine, in applications that span from bench to bedside. In this review we focus on noninvasive magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) and their roles in future personalized medicine in cancer. Diagnosis, the identification of the most effective treatment, monitoring treatment delivery, and response to treatment are some of the broad areas into which MRS techniques can be integrated to improve treatment outcomes. The development of novel probes for molecular imaging—in combination with a slew of functional imaging capabilities—makes MRS techniques, especially in combination with other imaging modalities, valuable in cancer drug discovery and basic cancer research.

Section snippets

¹H and ³¹P MRS of Choline Phospholipid Metabolism

Choline phospholipid metabolism is profoundly altered in cancer cells.3, 23, 24, 25 Almost every tumor type investigated has revealed elevated phosphocholine (PC) and increased tCho-containing metabolites.3, 23, 24, 25 Malignant transformation has been found to alter the profile of the choline compounds glycerophosphocholine (GPC) and PC in breast²⁶ and ovarian²⁷ cancer cells. In high-resolution ¹H and ³¹P MR spectra of breast²⁶ and ovarian²⁷ cell extracts, GPC was higher than PC in normal

¹H MRS of Mobile Lipids

In addition to choline metabolites, in vivo single-voxel ¹H MRS and multi-voxel MRSI detect signals from lipid metabolism-related compounds, such as the methylene signal at 1.3 ppm, and the methyl signal at 0.9 ppm (see representative ¹H MR spectra in Figure 1). These methylene and methyl signals originate from CH₂ and CH₃ groups, respectively, in fatty acyl chains of triacylglycerides that form mobile lipid droplets in the cytoplasm of intact cancer cells or in the intercellular space of solid

³¹P MRS of Energy Metabolism and pH

Because ³¹P MRS detects signals from energy metabolites and breakdown products such as nucleoside triphosphates (NTPs), nucleoside diphosphates (NDPs), phosphocreatine (PCr), and inorganic phosphate (Pi) (see Figure 1), it is ideally suited to investigate tumor energy metabolism in vivo. Importantly, tumor pH can be determined from the chemical shift of the Pi resonance as described below. However, its use has declined in recent years, especially for clinical studies, because of poor

¹³C MRS Techniques to Detect Labeled Substrates

¹³C MRS is useful to detect ¹³C-labeled metabolites following administration of suitable ¹³C-labeled substrates in cancer cells and solid tumors. ¹³C MRS has been applied to study glycolysis, choline metabolism,²² or other metabolic pathways. ¹³C MRS is used to detect the incorporation of a ¹³C label, which is introduced into the system as a ¹³C-labeled substrate, within downstream metabolites and products. The flux of substrates through metabolic pathways can be derived by metabolic modeling.

¹³C MRS of ¹³C-Labeled Glucose/Lactate

Since a high glycolytic activity is a common feature of many cancers, ¹³C MRS of ¹³C-labeled glucose has been used to study glycolysis in tumors. Cancer cells undergo glycolysis even in the presence of oxygen,44, 68 referred to as the “Warburg effect” after Otto Warburg who observed this phenomenon in 1930. Glycolysis is regulated by multiple oncogenes and signaling pathways.⁴⁴ Glycolysis in cancer cells occurs under well-oxygenated conditions, in part, through the stabilization of

Hyperpolarized ¹³C MRS

The use of hyperpolarized ¹³C-labeled substrates has revitalized ¹³C MRS studies because of the large increase in ¹³C detection sensitivity achieved by hyperpolarization.76, 77 Dynamic nuclear polarization (DNP) for solution-state MRS (DNP-MRS) can, in theory, increase the ¹³C detection sensitivity of hyperpolarized ¹³C-labeled substrates and their metabolites by up to 10,000-fold.76, 77 To achieve DNP, homogeneously distributed organic free radicals are added to the sample before cooling it,

¹H MRS in Clinical Diagnosis

Most clinical MR scanners have routine sequences for ¹H MRS/I measurements.11, 12, 81, 82, 83 Quantitative ¹H MRS and ¹H MRSI measurements of tCho and tissue-specific metabolites are frequently implemented in the clinic, in addition to standard dynamic contrast-enhanced (DCE) MR imaging (MRI), to diagnose primary malignant tumors in brain,7, 8, 9, 10 prostate,¹¹ and breast.12, 13, 14, 84 The addition of MRS to standard MRI techniques can significantly increase the sensitivity up to 88%, the

¹H MRS Monitoring of Cancer Therapy: Clinical and Preclinical Examples

The identification, and effective neutralization, of targets and pathways that present a molecular Achilles heel of cancer cells form the basis of finding effective treatments against cancer. Factors complicating this endeavor arise because each cancer represents an individual disease with a unique molecular makeup and a genomic instability that facilitates adaptation and survival following anticancer treatments. As more critical targets in cancer cells are revealed, a transition is occurring

Conclusion

The major strengths of MRS are the ability to provide a wide range of metabolic and functional information, and to seamlessly integrate with complementary MRI applications. MRS can fulfill important requirements in cancer discovery and treatment in the current era of personalized and targeted molecular medicine. MRS methods may provide an understanding of the effects of downregulating specific targets on downstream changes in physiology and metabolism, which are a rich source to mine for

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: Financial disclosures: The authors have nothing to disclose.

: Supported in part by National Institutes of Health Grants No. R01 CA134695, P50 CA103175, R01 CA73850, R01 CA82337, R01 CA136576, R01 CA138515, R21 CA140904, and R21 CA133600.

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Molecular imaging in oncologyMetabolic Tumor Imaging Using Magnetic Resonance Spectroscopy

Section snippets

1H and 31P MRS of Choline Phospholipid Metabolism

1H MRS of Mobile Lipids

31P MRS of Energy Metabolism and pH

13C MRS Techniques to Detect Labeled Substrates

13C MRS of 13C-Labeled Glucose/Lactate

Hyperpolarized 13C MRS

1H MRS in Clinical Diagnosis

1H MRS Monitoring of Cancer Therapy: Clinical and Preclinical Examples

Conclusion

Radiol Clin North Am

Cancer Lett

J Magn Reson Series B

Int J Radiat Oncol Biol Phys

J Biol Chem

Neoplasia

Bioorg Med Chem

Magn Reson Imaging

Neoplasia

Magn Reson Imaging

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Cancer statistics, 2009

CA Cancer J Clin

Tumour metabolomics in animal models of human cancer

J Proteome Res

Therapeutic targets and biomarkers identified in cancer choline phospholipid metabolism

Pharmacogenomics

'Why do tumour cells glycolyse?': from glycolysis through citrate to lipogenesis

Mol Cell Biochem

A metabolomics perspective of human brain tumours

FEBS J

Quantitative analysis of prostate metabolites using 1H HR-MAS spectroscopy

Magn Reson Med

Clinical applications of magnetic resonance spectroscopy

Magn Reson Q

Analysis of volume MRI and MR spectroscopic imaging data for the evaluation of patients with brain tumors

Magn Reson Med

Metabolic profiles of human brain tumors using quantitative in vivo 1H magnetic resonance spectroscopy

Magn Reson Med

MRS of oligodendroglial tumors: correlation with histopathology and genetic subtypes

Neurology

Three-dimensional H-1 MR spectroscopic imaging of the in situ human prostate with high (0.24-0.7-cm3) spatial resolution

Radiology

Proton magnetic resonance spectroscopic imaging of human breast cancer: a preliminary study

J Magn Reson Imaging

Adding in vivo quantitative 1H MR spectroscopy to improve diagnostic accuracy of breast MR imaging: preliminary results of observer performance study at 4.0 T

Radiology

Specificity of choline metabolites for in vivo diagnosis of breast cancer using 1H MRS at 1.5 T

Eur Radiol

RNA interference-mediated choline kinase suppression in breast cancer cells induces differentiation and reduces proliferation

Cancer Res

Choline kinase is a novel oncogene that potentiates RhoA-induced carcinogenesis

Cancer Res

Increased choline kinase activity in human breast carcinomas: clinical evidence for a potential novel antitumor strategy

Oncogene

Choline kinase inhibition induces the increase in ceramides resulting in a highly specific and selective cytotoxic antitumoral strategy as a potential mechanism of action

Oncogene

Neoadjuvant chemotherapy of locally advanced breast cancer: predicting response with in vivo (1)H MR spectroscopy—a pilot study at 4 T

Radiology

Predicting pathologic response to neoadjuvant chemotherapy in breast cancer by using MR imaging and quantitative 1H MR spectroscopy

Radiology

Molecular causes of the aberrant choline phospholipid metabolism in breast cancer

Cancer Res

Studies of human tumors by MRS: a review

NMR Biomed

Tumour phospholipid metabolism

NMR Biomed

Imaging biochemistry: applications to breast cancer

Breast Cancer Res

Malignant transformation alters membrane choline phospholipid metabolism of human mammary epithelial cells

Cancer Res

Alterations of choline phospholipid metabolism in ovarian tumor progression

Cancer Res

Proton-decoupled 31P MRS in untreated pediatric brain tumors

Magn Reson Med

In vivo 31P MR spectral patterns and reproducibility in cancer patients studied in a multi-institutional trial

NMR Biomed

Molecular imaging in oncology
Metabolic Tumor Imaging Using Magnetic Resonance Spectroscopy

¹H and ³¹P MRS of Choline Phospholipid Metabolism

¹H MRS of Mobile Lipids

³¹P MRS of Energy Metabolism and pH

¹³C MRS Techniques to Detect Labeled Substrates

¹³C MRS of ¹³C-Labeled Glucose/Lactate

Hyperpolarized ¹³C MRS

¹H MRS in Clinical Diagnosis

¹H MRS Monitoring of Cancer Therapy: Clinical and Preclinical Examples

Quantitative analysis of prostate metabolites using ¹H HR-MAS spectroscopy

Metabolic profiles of human brain tumors using quantitative in vivo ¹H magnetic resonance spectroscopy

Three-dimensional H-¹ MR spectroscopic imaging of the in situ human prostate with high (0.24-0.7-cm³) spatial resolution

Adding in vivo quantitative ¹H MR spectroscopy to improve diagnostic accuracy of breast MR imaging: preliminary results of observer performance study at 4.0 T

Specificity of choline metabolites for in vivo diagnosis of breast cancer using ¹H MRS at 1.5 T

Neoadjuvant chemotherapy of locally advanced breast cancer: predicting response with in vivo ⁽¹⁾H MR spectroscopy—a pilot study at 4 T

Predicting pathologic response to neoadjuvant chemotherapy in breast cancer by using MR imaging and quantitative ¹H MR spectroscopy

Proton-decoupled ³¹P MRS in untreated pediatric brain tumors

In vivo ³¹P MR spectral patterns and reproducibility in cancer patients studied in a multi-institutional trial

Efficient ¹H to ³¹P polarization transfer on a clinical 3T MR system

¹H MRS detects polyunsaturated fatty acid accumulation during gene therapy of glioma: implications for the in vivo detection of apoptosis