© 2004 by Oxford University Press
© 2004 Oxford University Press
IN THIS ISSUE |
In This Issue
Ceramide Pathway of Apoptosis in NeuroblastomaThe lipid second messenger ceramide, which is generated by both acidic and neutral sphingomyelinases or by ceramide synthases, is a common intermediate of many apoptotic pathways. Metabolism of ceramide involves several enzymes, including glucosylceramide synthase and GD3 synthase, and results in the formation of gangliosides (GM3, GD3, and GT3), which in turn promote the generation of reactive oxygen species (ROS) and apoptosis. Lovat et al. (p. 1288) explored how fenretinide, a retinoic acid derivative, induces apoptosis via increases in ceramide levels in neuroblastoma cells. The authors identified a novel pathway of fenretinide-induced ROS generation and apoptosis that is mediated by acidic sphingomyelinase, glucosylceramide synthase, and GD3 synthase. They also identified GD3 as a key signaling intermediate leading to apoptosis via the activation of 12-lipoxygenase. The authors conclude that the components of this novel pathway may be suitable molecular targets for treating neuroblastoma.
In an editorial, Dmitrovsky (p. 1264) discusses how the discovery of a specific fenretinide-mediated apoptotic pathway involving GD3 in neuroblastoma indicates that this ganglioside is more than just a neuronal marker of differentiation.
Blocking Tumor Response to Glucose Deprivation
Cells in solid tumors are often exposed to glucose deprivation, a stress condition that leads to the accumulation of unfolded proteins in the endoplasmic reticulum. This accumulation in turn activates the unfolded protein response (UPR), an adaptive stress signaling pathway that involves the increased expression of genes encoding chaperones and other proteins that protect cells from the effects of unfolded proteins. Disruption of the UPR might enable the selective targeting of glucose-deprived solid tumors. In this issue, Park et al. (p. 1300) show that a novel macrocyclic compound from a microorganism, versipelostatin (VST), inhibited expression of UPR pathway genes in cancer cells exposed to glucose stress but not in cells treated with other kinds of chemical stressors that induce the UPR. VST treatment also led to the selective death of glucose-deprived cells. Finally, xenograft tumor growth was inhibited in mice treated with VST.
In a related editorial, Sausville (p. 1266) notes that the work is important because new ways to activate cell death pathways that are selective for the tumor environment, as opposed to the host, are needed. He also points out that the findings emphasize the importance of natural products in drug discovery.
Probabilities of Death From Breast Cancer and Other Causes
Among cancer patients, probabilities of death from that cancer and other causes in the presence of competing risks are optimal measures of prognosis and of mortality across demographic groups. Schairer et al. (p. 1311) used data on breast cancer patients from the Surveillance, Epidemiology, and End Results Program in a competing risk model for such an analysis. They found that the probability of death from breast cancer after nearly 28 years of follow-up ranged from 0.03 to 0.10 for patients with in situ disease to 0.70 to 0.85 for patients with distant disease, depending on race and age. The probability of death from breast cancer exceeded that from all other causes for patients diagnosed with localized disease before age 50 years, with regional disease before age 60 years, and with distant disease at any age. They conclude that the probability of death from breast cancer varied substantially according to stage of disease, tumor size, estrogen receptor status, and age at diagnosis in all patients.
Burden of Illness in Cancer Survivors
Trends in aging and increased cancer survival likely mean that more people will be facing health burdens related to living with cancer. However, few national estimates of the burden of illness that occurs in addition to the cost of medical care among cancer survivors currently exist. Yabroff et al. (p. 1322) measured components of burden of illness—factors such as utility, lost productivity, and health limitations—in 1823 cancer survivors and 5469 matched control subjects without cancer from the 2000 National Health Interview Survey. The authors found that cancer survivors had higher burden of illness across many of the measured categories compared with similar individuals without cancer. The differences were consistent in survivors of different types of cancer and over multiple time periods after cancer diagnosis. They conclude that improved measurement of long-term burden and lost productivity due to burden of illness is important for future prospective research and that their findings support future research in this area.
Interferon Alfa Immunotherapy and STAT1 Activation
Signal transducer and activator of transcription 1 (STAT1) mediates the
antitumor effects of interferon alfa (IFN 
) by regulating gene
expression within host tissues. Lesinski et al.
(p. 1331) used a flow
cytometry assay to examine phosphorylation-mediated activation of STAT1 within
peripheral blood mononuclear cells (PBMCs). They found that in vitro
IFN -2b treatment of PBMCs resulted in a rapid and dose-dependent
increase in phosphorylated STAT1 (P-STAT1) levels in all major immune cell
subsets, and that relatively low doses of IFN -2b induced maximal STAT1
activation. Compared with melanoma patients, healthy donors had higher basal
levels of P-STAT1 in total PBMCs, natural killer (NK) cells, and T cells.
PSTAT1 was detected in the NK and T cells of two patients who received IFN
-2b immunotherapy. The authors conclude that this flow cytometry method
can be used to monitor STAT1 activation within subsets of immune cells from
patients undergoing IFN immunotherapy.
Diet and Exercise Patterns and Cancer and Disease Prevention
In an effort to reduce obesity and prevent related cancers and chronic diseases in the United States, specific and reliable information about the relationship between these conditions and diet and exercise is needed. In a commentary on the 2003 workshop "Research Strategies for the Study of Nutrition, Physical Activity and Chronic Disease" and discussions that followed, Prentice et al. (p. 1276) recap research strategies and priorities to generate the needed information, with emphasis on study hypothesis development, study design and conduct, methods of measurement and analysis, and reporting standards. The authors conclude with 10 consensus points and detailed research recommendations that can be used to provide reliable advice on diet and exercise to the public.
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