Alterations in arginine and energy metabolism, structural and signalling lipids in metastatic breast cancer in mice detected in plasma by targeted metabolomics and lipidomics

Abstract

BackgroundThe early detection of metastasis based on biomarkers in plasma may improve cancer prognosis and guide treatment. The aim of this work was to characterize alterations in metabolites of the arginine pathway, energy metabolism, and structural and signalling lipids in plasma in the early and late stages of murine breast cancer metastasis.MethodsMice were orthotopically inoculated with 4T1 metastatic breast cancer cells, and plasma was analysed along the pulmonary metastasis progression using LC-MS/MS-based targeted metabolomics and lipidomics.ResultsBased on primary tumour growth and pulmonary metastases, 1–2 weeks after 4T1 cancer cell inoculation was defined as an early metastatic stage, and 3–4 weeks after 4T1 cancer cell inoculation was defined as a late metastatic stage. Early metastasis was featured in plasma by a shift of L-arginine metabolism towards arginase (increased ornithine/arginine ratio) and polyamine synthesis (increased putrescine). Late metastasis was reflected in plasma by further progression of changes in the arginine pathway with an additional increase in asymmetric dimethylarginine plasma concentration, as well as by a profound energy metabolism reprogramming towards glycolysis, an accelerated pentose phosphate pathway and a concomitant decrease in tricarboxylic cycle rate (“Warburg effect”). The late but not the early phase of metastasis was also characterized by a different lipid profile pattern in plasma, including a decrease in total phosphatidylcholines, a decrease in diester-bound phospholipid fraction and an increase in lysophospholipids associated with an increase in total sphingomyelins.ConclusionsThe early phase of metastasis in murine 4T1 metastatic breast cancer was associated with plasma metabolome changes characteristic of arginase activation and polyamine synthesis. The late metastasis was reflected in plasma not only by the alterations in arginine pathways but also by a shift towards glycolysis and the pentose pathway, remodelling of structural lipids and activation of lipid signalling, all of which coincided with metastasis progression.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1075-y) contains supplementary material, which is available to authorized users.

Isothermal Microcalorimetry of Tumor Cells: Enhanced Thermogenesis by Metastatic Cells

“…It is conceivable that the role of lipid metabolism in metastasis involves not only energy production but also that of a building block supplier for membrane biogenesis. Metabolic pathways involving fatty acid can also generate signaling lipids (45,46). Our own results, using high-resolution oxygen, confirmed the implication of lipid metabolism in metastasis.…”

Early and late endothelial response in breast cancer metastasis in mice: simultaneous quantification of endothelial biomarkers using mass spectrometry-based method

“…The robust increase in WBC count of 4T1 tumour-bearing mice was also reported previously (Wang et al, 2015), and was linked to medullary and extramedullary haematopoiesis (Younos et al, 2011, 2012), with expansion of myeloid-derived suppressor cells (MDSCs) promoting metastases development (Younos et al, 2011; Cao et al, 2014; Kus et al, 2018). The increased leukocytosis underlines robust cancer-associated systemic inflammation as evidenced also by increased plasma concentration of pro-inflammatory cytokines, e.g.…”

Fourier transform infrared spectroscopic signature of blood plasma in the progression of breast cancer with simultaneous metastasis to lungs

“…But slight variations among numerous spectra per each group collected in this work and also negative results of water vapor test, we rather exclude a strong effect of some of these factors on our analysis. Moreover, the comparison of our spectroscopic results with the targeted lipidomic analysis performed on the same animal 4T1 cancer model suggests that a fast and reagent‐free FTIR‐based screening of a small plasma volume properly corresponds to structural remodeling of lipids.…”

“…Figure IIIB shows that integral intensities of band at 1031 and 1153 cm −1 increase remarkably in the last stage of the breast cancer progression. LC/MS/MS measurements performed on plasma of the investigated here murine model has showed that concentrations of glycolytic intermediates hexoses‐phosphates, fructose‐1,6‐bi‐phosphate, and pentose‐phosphates are elevated only at the late metastatic phase , what suggests that spectral changes shown for the 1031 and 1153 cm −1 bands might be associated with this group of sugars. In turn, a graph in Figure IIIC shows a gradual decrease of other saccharides (1012/1054 cm −1 ) which is not unambiguously assigned to a specific group of these biomolecules.…”

“…We also find that ratio of bands at 1638 and 1652 cm −1 assigned to β-sheet and α-helical conformations of proteins, respectively, exhibits a slight increase in the early phase of the breast cancer on week 2 when the mean breast tumor sizes represented ca. 1% of body weight and single clusters of cancer cells were found in a few animals ( Figure 4IIC) [20]. Amyloid-β peptides secreted to blood vessels have been well recognized in plasma IR spectra by the increase of the 1638 cm −1 absorbance in Alzheimer's disease as well as in type 2 diabetes [21,37].…”