The Tumor Microenvironment Modulates Choline and Lipid Metabolism

Abstract

An increase of cellular phosphocholine (PC) and total choline (tCho)-containing compounds as well as alterations in lipids have been consistently observed in cancer cells and tissue. These metabolic changes are closely related to malignant transformation, invasion, and metastasis. The study of cancer cells in culture plays an important role in understanding mechanisms leading to altered choline (Cho) and lipid metabolism in cancer, as it provides a carefully controlled environment. However, a solid tumor is a complex system with a unique tumor microenvironment frequently containing hypoxic and acidic regions and areas of nutrient deprivation and necrosis. Cancer cell–stromal cell interactions and the extracellular matrix may also alter Cho and lipid metabolism. Human tumor xenograft models in mice are useful to mimic the growth of human cancers and provide insights into the influence of in vivo conditions on metabolism. Here, we have compared metabolites, obtained with high resolution 1H MRS of extracts from human breast and prostate cancer cells in a 2-dimensional (2D) monolayer culture and from solid tumor xenografts derived from these cells, as well as the protein expression of enzymes that regulate Cho and lipid metabolism. Our data demonstrate significant differences in Cho and lipid metabolism and protein expression patterns between human breast and prostate cancer cells in culture and in tumors derived from these cells. These data highlight the influence of the tumor microenvironment on Cho and lipid metabolism.

1H NMR metabolomics reveals increased glutaminolysis upon overexpression of NSD3s or Pdp3 in Saccharomyces cerevisiae

“…Aliphatic (A) and aromatic (B) regions. 31 Tumor cells display an altered metabolism of choline and lipids, 31 with an increase in the levels of PC and total choline (PC, glycerophosphocholine, and choline). PCA score plots show a strong class discrimination between control (WT) replicates (red) and NSD3s overexpression (green) (A), and between control (WT) replicates (red) and Pdp3 overexpression (green) (B).…”

“…DSS, 4,4-dimethyl-4-silapentane-1-sulfonic acid; NMR, nuclear magnetic resonance; PC, phosphocholine F I G U R E 2 NMR metabolomics shows similar metabolic profile on NSD3s or Pdp3 overexpression. [31][32][33][34][35][36] The synthesis of PC is performed from choline by the action of choline kinase ( Figure 4). PCA loading plots highlight important metabolites for class discrimination between NSD3s + and WT, such as glutamate, aspartate, and alanine (C), and between Pdp3 + and WT, such as phosphocholine, aspartate, and alanine (D).…”

“…PCA loading plots highlight important metabolites for class discrimination between NSD3s + and WT, such as glutamate, aspartate, and alanine (C), and between Pdp3 + and WT, such as phosphocholine, aspartate, and alanine (D). 31,33,35,36 Increased PC levels can also be explained by the higher rate of choline transport. 29 Endogenous synthesis of arginine is not sufficient to meet the needs of proliferating tumor cells 28 ; therefore, arginine is required by cancer cells, and it has been associated with the development of tumors.…”

Advanced Imaging of Brain Metastases: From Augmenting Visualization and Improving Diagnosis to Evaluating Treatment Response

“…Magnetic resonance spectroscopy (MRS) detects tissue metabolites by their characteristic resonant frequencies (17). In oncologic applications, the metabolites of interest are products or byproducts of malignancy-related pathways (17,18). The most common metabolites are N-acetylaspartate (NAA), choline (Cho), lipid (Lp), and creatine (Cr).…”

Metabolism: A New Frontier in Cancer Research

“…These cellular alterations are energy demanding and require an increased synthesis of cellular metabolites, and often the metabolism is altered to keep up with these changes [1]. Therefore, it was expected that the enzymes responsible for the control of the metabolism should be up or down regulated.…”