Magnetic Resonance Spectroscopy in Metabolic and Molecular Imaging and Diagnosis of Cancer

Since its discovery in the 1940's, magnetic resonance (MR) spectroscopy (MRS) has developed into a major technique used by chemists to elucidate molecular structures. The underlying principle of MRS is the generation of radiofrequency (RF) signals by magnetic nuclear spins that are excited with a specific RF to precess in an external magnetic field B0. The magnetic resonance frequency ω0 is linearly dependent on B0 and the gyromagnetic ratio of the nucleus γ, as ω0 = γB0. The MR signal intensity depends on the concentration of nuclear spins, the magnetic field strength B0, and the gyromagnetic ratio γ of these spins. The magnetization signal in MRS is characterized by two rate constants, the spin-lattice (or longitudinal relaxation time) T1, and the spin-spin (or tranverse relaxation time) T2. Since the resonance frequency of a particular nucleus is dependent upon its molecular structure, an important aspect of MRS is the ability to distinguish a nucleus with respect to its environment in the molecule. Because the molecular structure-based frequency shift and the resonance frequency are directly proportional to the strength of the magnetic field, the frequency shift is converted into a field-independent dimensionless value known as the chemical shift. Since the frequency shifts are extremely small in comparison to the resonance frequency, the chemical shift is expressed in parts per million (ppm). The chemical shift is typically reported relative to a reference resonance frequency. MRS therefore provides information about the chemical environment of the nuclear spin such as number of chemical bonds, neighboring nuclei, and overall chemical structure. As a result, each peak in an MR spectrum has a characteristic chemical shift that is dependent upon the chemical structure of the metabolite or compound, and a peak area that is proportional to the concentration of the compound. Scalar spin-spin interactions, or J-couplings, produce fine multiplet structures that can be used to further analyze the chemical structure of a given molecule. Within the past two decades, the same principles of chemical shifts, magnetic moments, relaxation rates, and deriving concentrations from peak integrals have been applied in several preclinical and clinical studies to advance cancer discovery, diagnosis, and treatment. Incorporating imaging techniques with MRS has resulted in the development of MR spectroscopic imaging (MRSI) where the chemical information is spatially phase encoded,1–3 providing images of specific chemical compounds such as metabolites, reporter probes, labeled substrates, or drugs. The purpose of this article is to review recent developments and examples of the use of multi-nuclear MRS in cancer, and its integration with multi-modality imaging in cancer discovery and treatment. The ability of cancer cells to adapt and survive treatments, and the collateral damage to normal cells as a result of several cancer treatments, continue to make the successful treatment of cancer a major challenge for the twenty first century. Tumor recurrence and metastasis are the leading causes of morbidity and mortality from cancer and, despite major advances in cancer research and treatment, cancer continues to evade cure. This is not surprising given the complexities of a tumor, and the genomic plasticity of cancer cells and stromal cells that are co-opted within the tumor. A schematic of the different components of a tumor is shown in Figure 1. Figure 1 Schematic of the components of a tumor. Cancer cells are embedded within the extracellular matrix (ECM). The ECM consists of a complex meshwork of structural extracellular proteins. The tumor microenvironment (TME) contains the ECM and stromal cells such ... Physiological conditions such as hypoxia and acidic extracellular pH (pHe) that exist in the tumor microenvironment, the interactions between cancer cells and stromal cells such as endothelial cells, fibroblasts and macrophages, the extracellular matrix, and the numerous secreted factors and cytokines cumulatively influence progression, aggressiveness, and response of the disease to treatment. Hypoxia, in particular, is a major cause of radio- and chemo-resistance in cancer cells. Because of the remarkable ability of cancer cells to adapt and survive, finding effective treatments against cancer depends upon identifying and attacking targets and pathways critically important for the cancer cell. Multi-nuclear MRS provides unique opportunities for molecular and functional imaging of cancer in preclinical and clinical studies, and for imaging interactions between cancer cells and stromal cells. Some of these applications of MRS, the nuclei commonly studied, and the information that can be obtained are summarized in Table 1. From this table it is apparent that multi-nuclear noninvasive MRS methods have wide-ranging applications in cancer that can translate from bench to beside. The chemical structures of various compounds referred to in this review article are summarized in Tables 2 and ​and3.3. Table 3 also provides details regarding administration and dose of the contrast agents described here. Table 1 Nuclei commonly studied in order of sensitivity of detection and some of their preclinical (+) and clinical (*) applications in cancer. The intensity of the MR signal depends on the concentration of nuclear spins, and the gyromagnetic ratio γ ... Table 2 Chemical structures of metabolites referred to in this review article. Table 3 Chemical structures of reporter molecules referred to in this review article. The past decade has seen major advances in sequence design, development of novel reporter probes, and technological advances that have significantly increased the uses of MRS in molecular and functional imaging applications in oncology. Some of the recent applications of 1H, 13C, 31P, and 19F MRS in preclinical models of cancer are reviewed, and examples of biomedical MRS applications for each nucleus are shown in Figure 2. New developments, such as hyperpolarization of spins to increase the sensitivity of detection of the MR signal of 13C-labeled substrates are discussed. Advantages and limitations of the spectroscopic techniques and challenges for the future are outlined. Figure 2 Examples of multi-nuclear MRS applications. From top to bottom: Representative in vivo single-voxel 1H MRS of an MDA-MB-231 breast tumor xenograft model obtained at 4.7T, and ex vivo high-resolution 1H MRS of a water-soluble MDA-MB-231 cell extract obtained ... The use of MR biomarkers such as the total choline (tCho) signal and perfusion are already being explored clinically for characterizing tumors and following treatment response.4–7 The elevation of choline compounds presents a unique target to exploit for molecular targeting; such targeting can be imaged noninvasively with MRS.8,9 Both pharmacological and molecular approaches are being developed to target choline metabolism, specifically choline kinase activity, which is the first step in choline phospholipid biosynthesis. The interaction between cancer cells and the tumor microenvironment is providing new insights into the etiology and progression of cancer. For example, oxygen partial pressure (pO2) in tumors can be imaged by both 1H and 19F MRSI.10,11 Oxygen is sensed by administration of reporter molecules through changes in the spin-lattice relaxation rate. Integrating MRSI with MRI and other imaging modalities such as optical and nuclear imaging is providing useful insights into the dynamics between hypoxia and the tumor extracellular matrix (ECM), vascularization, extracellular pH, interstitial fluid transport, and metabolism in preclinical models.12–14 These insights can be exploited to find effective treatment strategies.