MR‐visible lipids and the tumor microenvironment

Abstract

MR-visible lipids or mobile lipids are defined as lipids that are observable using proton magnetic resonance spectroscopy in cells and in tissues. These MR-visible lipids are composed of triglycerides and cholesterol esters that accumulate in intracellular neutral lipid droplets, where their MR visibility is conferred as a result of the increased molecular motion available in this unique physical environment. This review will discuss factors that lead to the biogenesis of MR-visible lipids in cancer cells and in other cell types such as immune cells and fibroblasts. We focus on the accumulations of mobile lipids that are inducible in cultured cells by a number of stresses, including culture conditions and in response to activating stimuli or apoptotic cell death induced by anticancer drugs. This is compared with animal tumor models, where increases in mobile lipids are observed in response to chemo and radiotherapy, and to human tumors where mobile lipids are observed predominantly in high-grade brain tumors and in regions of necrosis. Conducive conditions for mobile lipid formation in the tumor microenvironment will be discussed including low pH, oxygen availability and the presence of inflammatory cells. It is concluded that MR-visible lipids appear in cancer cells and human tumors as a stress response. Mobile lipids stored as neutral lipid droplets may play a role in detoxification of the cell or act as an alternate energy source, especially in cancer cells, which often grow in ischemic/hypoxic environments. The role of MR-visible lipids in cancer diagnosis and assessment of treatment response both in animal models of cancer as well as human brain tumors will also be discussed. Although technical limitations exist in the accurate detection of intratumoral mobile lipids, early increases in mobile lipids after therapeutic interventions may be used as a potential biomarker for assessing treatment response in cancer.

Investigation of lipid composition of dissected sentinel lymph nodes of breast cancer patients by 7T proton MR spectroscopy

“…Six groups of lipid peaks were identified in the acquired spectra: methine protons at 5.4 ppm and at 5.2 ppm, protons from the methylene glycerol backbone at 4.3 and 4.1 ppm, a small PUFA peak at 2.8 ppm, methylene protons between 2.0 and 2.3 ppm and at 1.6 and 1.3 ppm, and methyl protons at 0.9 ppm. The lipid resonances at 5.4-5.2, at 2.8 and at 2.3-2 ppm exclusively include proton spins that are connected to at least one carbon double bond, -CH¼CH-, ¼CH-CH 2 -CH¼, and -CH 2 -CH¼CH-CH 2 -, respectively, and thus originate from UFAs (25). The other lipid resonances (4.3-4.1, 1.6-1.3, and 0.9) originate from both saturated and unsaturated fatty acids and the glycerol backbone.…”

“…Mobile lipid composition, detectable by proton MRS, has been associated with cancer and can thus serve as a potential biomarker (25,26). Lipids, among others, consist of fatty acids, which can be divided into fatty acids containing a carbon double bond (C¼C; unsaturated fatty acids [UFAs]) and fatty acids containing no carbon double bonds (saturated fatty acids).…”

“…The prior group contains monounsaturated fatty acids (MUFAs), ie, fatty acids containing a single C¼C, and polyunsaturated fatty acids (PUFAs), ie, fatty acids containing several carbon double bonds. PUFAs are, among others, involved in the regulation of tumor p53 signal, telomere shortening, and tumor angiogenesis (21,24,25,27). A review by Das (27) showed that PUFAs, by inhibiting superoxide dismutase, increase oxygen radicals in tumor cells, which causes apoptosis, and that lower levels of UFAs in tumor cells were observed.…”

“…A review by Das (27) showed that PUFAs, by inhibiting superoxide dismutase, increase oxygen radicals in tumor cells, which causes apoptosis, and that lower levels of UFAs in tumor cells were observed. Previous research demonstrates that fat composition, including PUFAs, may be a potential marker for differentiating benign from malignant tissue (21,22,25,28). These studies have been performed by HR-MAS, C13 spectroscopy, or using a large single voxel in proton MRS.…”

CARS based label‐free assay for assessment of drugs by monitoring lipid droplets in tumour cells

“…1 H NMR detection of the mobile lipids in these droplets has been used as a non-invasive method for detecting tumour cell death in vivo [31][32][33]. A recent study suggested that this LD accumulation is due to inhibition of fatty acid oxidation in the mitochondria, as a result of an increase in intra-mitochondrial reactive oxygen species (ROS), which diverts fatty acids away from oxidation and towards the synthesis of triacylglycerols which are the major lipid constituent of the LDs [3].…”