An immortalized interleukin‐3 (IL‐3)‐dependent progenitor cell line, BAF‐3, undergoes programmed cell death (apoptosis) when deprived of IL‐3. This program is characterized by an early degradation of DNA into oligonucleosome‐length fragments that precedes by several hours the loss of cell viability. In the absence of IL‐3, DNA fragmentation and cell death can be prevented by the calcium ionophores A23187 (1 microM) and ionomycin (0.5 microM). This addition of calcium ionophore maintains cell viability while reversibly arresting the cell cycle. Apoptosis by growth factor deprivation is also a mechanism of cell elimination in bone marrow cells removed from the stromal micro‐environment, as DNA fragmentation and cell death was shown to take place in primary cultures of IL‐3‐responsive bone marrow cells after IL‐3 removal.
We investigate the profile of choline metabolites and the expression of the genes of the Kennedy pathway in biopsies of human gliomas (n = 23) using 1H High Resolution Magic Angle Spinning (HR‐MAS, 11.7 Tesla, 277 K, 4000 Hz) and individual genetic assays. 1H HR‐MAS spectra allowed the resolution and relative quantification by the LCModel of the resonances from choline (Cho), phosphocholine (PC) and glycerophosphorylcholine (GPC), the three main components of the combined tCho peak observed in gliomas by in vivo 1H NMR spectroscopy. All glioma biopsies depicted a prominent tCho peak. However, the relative contributions of Cho, PC, and GPC to tCho were different for low and high grade gliomas. Whereas GPC is the main component in low grade gliomas, the high grade gliomas show a dominant contribution of PC. This circumstance allowed the discrimination of high and low grade gliomas by 1H HR‐MAS, a result that could not be obtained using the tCho/Cr ratio commonly used by in vivo 1H NMR spectroscopy. The expression of the genes involved in choline metabolism has been investigated in the same biopsies. High grade gliomas depict an upregulation of the β gene of choline kinase and phospholipase C, as well as a downregulation of the cytidyltransferase B gene, the balance of these being consistent with the accumulation of PC. In the low grade gliomas, phospholipase A1 and lysophospholypase are upregulated and phospholipase D is downregulated, supporting the accumulation of GPC. The present findings offer a promising procedure that will potentially help to accurately grade glioma tumors using 1H HR‐MAS, providing in addition the genetic background for the alterations of choline metabolism observed in high and low grade gliomas. Copyright © 2009 John Wiley & Sons, Ltd.
SummaryApoptosis is now widely recognized as a common form of cell death and represents a mechanism of cell clearance in many physiological situations where deletion of cells is required. Peptide growth factors, initially characterised as stimulators of cell proliferation, have now been shown to inhibit death in many cell types. Deprivation of growth factors leads to the induction of apoptosis, i.e. condensation of chromatin and degradation in oligonucleosomesized fragments, formation of plasma and nuclear membrane blebs and cell fragmentation into apoptotic bodies which can be taken up by neighbouring cells. Here we discuss the mechanism(s) by which growth factors may inhibit apoptosis. Apoptosis: an overviewOften referred to as programmed cell death, apoptosis has been extensively reported in the scientific literature through morphological studies in many tissues where death was taking place as a consequence of a physiological phenomenon (reviewed in ref. 1). In these studies the presence of scattered single cells with highly condensed chromatin has been one of the parameters indicating the presence of apoptotic cell death(2). In a later phase the chromatin appears to be distributed into sub-cellular structures called apoptotic bodied3).However, apoptosis is not only observed in the balanced situation of physiological tissue turnover but also in the elimination of specific cell subsets that occurs in embryogenesis, for instance in the embryonic development of the intestine and nervous system and in the regression of female sexual organs in the male(4). Apoptosis has also been implicated as the mechanism of cell elimination during tissue regression in metamorph~sis(~). Apoptotic cells have also been observed during tumour growth and regression. Thus, for example, apoptotic bodies of epithelial cell origin were described during development of squamous cell carcinoma(6) and kinetics studies have demonstrated waves of apoptosis during sarcoma growth(7). Therefore, during tumour growth some cells, perhaps those deprived of growth factors, undergo apoptosis. When tumours are treated with chemotherapy, apoptosis is responsible for at least some of the cell deaths which ensue(*).There are further experimental modulations of tissues where cell death is induced and apoptosis is observed. Regression of hyperplastic organs such as the liver or kidneys after lead poisoning is accompanied by the appearance of apoptotic celld9). Apoptosis is observed in the rat prostate after repeated withdrawal of testosterone stimulation(10), in rat liver after removal of tumour promoters(l]), in keratinocytes after UV irradiation(12) and in neuronal cells following glutamate treatment(13).Because apoptotic cells are rapidly, and specifically, engulfed in vivo by neighbouring cells(14) in order to keep cell debris to a minimum and to allow shrinkage of a tissue without disruption of its basic architecture, these morphological tissue studies probably greatly underestimate the number of deaths occurring. Indeed, it has been proposed that man...
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