Glycerophosphocholine and Glycerophosphoethanolamine Are Not the Main Sources of the In Vivo ³¹P MRS Phosphodiester Signals from Healthy Fibroglandular Breast Tissue at 7 T

Transduction of mitogenic signals in cells can be mediated by molecules derived from the synthesis and breakdown of the major membrane phospholipid, phosphotidylcholine. Studies were performed on human mammary epithelial cells in culture to understand the impact of malignant transformation and progression on membrane phospholipid metabolism. In the model system used here, phosphocholine levels and total choline-containing phospholipid metabolite levels increased with progression from normal to immortalized to oncogene-transformed to tumor-derived cells. These changes occurred independently of cell doubling time. A "glycerophosphocholine to phosphocholine switch" was apparent with immortalization. This alteration in phenotype of increased phosphocholine relative to glycerophosphocholine was observed in oncogene-transformed and for all human breast tumor cell lines analyzed. The results demonstrate that progression of human mammary epithelial cells from normal to malignant phenotype is associated with altered membrane choline phospholipid metabolism.

Following the impetus of early clinical and experimental investigations, in vivo and in vitro MRS studies of tumours pointed in the eighties to the possible significance of signals arising from phospholipid (PL) precursors and catabolites as novel biochemical indicators of in vivo tumour progression and response to therapy. In the present decade, MRS analyses of individual components contributing to the 31P PME (phosphomonoester) and PDE (phosphodiester) resonances, as well as to the 1H 'choline peak', have reinforced some of these expectations. Moreover, the absolute quantification of these signals provided the basis for addressing more specific (although still open) questions on the biochemical mechanisms responsible for the formation of intracellular pools of PL derivatives in tumours, under different conditions of cell proliferative status and/or malignancy level. This article is aimed at providing an overview on: (a) quantitative MRS measurements on the contents of phosphocholine (PCho), phosphoethanolamine (PEtn) and their glycerol derivatives ģlycerol 3-phosphocholine (GPC) and glycerol 3-phosphoethanolamine (GPE)[ in human tumours and cells (with particular attention to breast and brain cancer and lymphomas), as well as in normal mammalian tissues (including developing organs and rapidly proliferating tissues); (b) possible correlations of MRS parameters like PEtn/PCho and PCho/GPC ratios with in vitro cell growth status and/or cell tumorigenicity; and (c) current and new hypotheses on the role and interplay of biosynthetic and catabolic pathways of the choline and ethanolamine cycles in modulating the intracellular sizes of PCho and PEtn pools, either in response to mitogenic stimuli or in relation to malignant transformation.

Phosphorus ((31)P) T(1) and T(2) relaxation times in the resting human calf muscle were assessed by interleaved, surface coil localized inversion recovery and frequency-selective spin-echo at 3 and 7 T. The obtained T(1) (mean +/- SD) decreased significantly (P < 0.05) from 3 to 7 T for phosphomonoesters (PME) (8.1 +/- 1.7 s to 3.1 +/- 0.9 s), phosphodiesters (PDE) (8.6 +/- 1.2 s to 6.0 +/- 1.1 s), phosphocreatine (PCr) (6.7 +/- 0.4 s to 4.0 +/- 0.2 s), gamma-NTP (nucleotide triphosphate) (5.5 +/- 0.4 s to 3.3 +/- 0.2 s), alpha-NTP (3.4 +/- 0.3 s to 1.8 +/- 0.1 s), and beta-NTP (3.9 +/- 0.4 s to 1.8 +/- 0.1 s), but not for inorganic phosphate (Pi) (6.9 +/- 0.6 s to 6.3 +/- 1.0 s). The decrease in T(2) was significant for Pi (153 +/- 9 ms to 109 +/- 17 ms), PDE (414 +/- 128 ms to 314 +/- 35 ms), PCr (354 +/- 16 ms to 217 +/- 14 ms), and gamma-NTP (61.9 +/- 8.6 ms to 29.0 +/- 3.3 ms). This decrease in T(1) with increasing field strength of up to 62% can be explained by the increasing influence of chemical shift anisotropy on relaxation mechanisms and may allow shorter measurements at higher field strengths or up to 62% additional signal-to-noise ratio (SNR) per unit time. The fully relaxed SNR increased by +96%, while the linewidth increased from 6.5 +/- 1.2 Hz to 11.2 +/- 1.9 Hz or +72%. At 7 T (31)P-MRS in the human calf muscle offers more than twice as much SNR per unit time in reduced measurement time compared to 3 T. This will facilitate in vivo (31)P-MRS of the human muscle at 7 T.