Abstract
Phosphorus MRS offers a non‐invasive tool for monitoring cell energy and phospholipid metabolism and can be of additional value in diagnosing cancer and monitoring cancer therapy. In this study, we determined the transverse relaxation times of a number of phosphorous metabolites in a group of breast cancer patients by adiabatic multi‐echo spectroscopic imaging at 7 T. The transverse relaxation times of phosphoethanolamine, phosphocholine, inorganic phosphate (Pi), glycerophosphocholine and glycerophosphatidylcholine were 184 ± 8 ms, 203 ± 17 ms, 87 ± 8 ms, 240 ± 56 ms and 20 ± 10 ms, respectively. The transverse relaxation time of Pi in breast cancer tissue was less than half that of healthy fibroglandular tissue. This effect is most likely caused by an up‐regulation of glycolysis in breast cancer tissue that leads to interaction of Pi with the GAPDH enzyme, which forms part of the reversible pathway of exchange of Pi with gamma‐adenosine tri‐phosphate, thus shortening its apparent transverse relaxation time. As healthy breast tissue shows very little glycolytic activity, the apparent T 2 shortening of Pi due to malignant transformation could possibly be used as a biomarker for cancer.
Highlights
The PDE metabolites in these spectra display a short T2 component that we subscribe to mobile phospholipids[10] in the form of GPtC and GPtE, as these signals disappear in the noise after the second echo
The phantom measurements of T2 (Figure 5A and 5B) of inorganic phosphate (Pi) indicate that the shorter T2 of Pi in breast cancer tissue is probably not caused by a general pH effect on the T2 of Pi and/or a pH dependent general Pi−protein interaction, as the influence of pH and general protein interaction on the T2 of Pi is only minor (Figure 5A and 5B)
The exchange rate of Pi ↔ γ‐adenosine tri‐phosphate (ATP) in the brain is 0.2 s−1,15,16 and in resting muscle it is 0.06 s−1.17 It is the reversible interaction with the glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) enzyme, which forms part of the pathway of Pi exchange with γ‐ATP (Figure 1), that causes the apparent T2 shortening of Pi
Summary
Wybe J.M. van der Kemp | Tijl A. van der Velden | Alexander M. Metabolite ratios of PMEs to phosphodiesters (PDEs, namely glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE),[2] PMEs to inorganic phosphate (Pi)[3,4] and PMEs to gamma‐adenosine tri‐phosphate (γ‐ATP)[2] have been proposed as biomarkers to assess response to cancer therapy Another metabolic hallmark of cancer is up‐regulated aerobic glycolysis,[5] known as the Warburg effect. While in vivo metabolite ratios measured by MRS should be interpreted carefully, because of their dependence on the combination of flip‐ angle, repetition time and intrinsic longitudinal relaxation time of the metabolites, measured apparent T2 values of metabolites can be compared readily and can provide information about the mobility of metabolites It is well known, for instance, that the large PDE peaks observed at low field in the human breast are mainly from mobile phospholipids and not from aqueous GPC and GPE. To rule out pH dependence or the effect of general Pi‐protein interactions on the transverse relaxation time of Pi, we quantify these influences on the T2 of Pi solutions in phantom measurements
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