© 2004 by Oxford University Press
© 2004 Oxford University Press
IN THIS ISSUE |
Chronic lymphocytic leukemia (CLL) is caused by an accumulation of malignant lymphocytes that fail to undergo programmed cell death. High expression of the Mcl-1 protein, a member of the Bcl-2 family of apoptosis regulators, is associated with pathogenesis of CLL. To investigate the mechanism of altered Mcl-1 expression in CLL, Moshynska et al. (p. 673) sequenced the MCL-1 gene from peripheral blood lymphocytes of 58 CLL patients and 18 control subjects and analyzed mRNA and protein expression in a subset of patients. Seventeen of the patients but none of the control subjects had a short (6- or 18-nucleotide) insertion in the MCL-1 promoter that was associated with increased mRNA and protein expression. The presence of an insertion was also associated with more rapid disease progression, poorer response to chemotherapy, and shorter survival.
In an editorial (p. 642), Kitada and Reed point out that the promoter insertions were not always associated with high levels of Mcl-1 protein expression, possibly because signals in the microenvironment might combine with the insertions to increase MCL-1 expression or because Mcl-1 may turn over rapidly. Ultimately, they note, the discovery of the insertions will be important in developing improved prognostic information about CLL as well as in better understanding the molecular mechanism of aberrant apoptosis in this disease.
DNAzyme Targeting of c-Jun
Little is known about the role of the transcription factor c-Jun in angiogenesis. Zhang et al. (p. 683) used microvascular endothelial cells transfected with a DNA enzyme (DNAzyme) that inactivates the c-Jun mRNA (Dz13) or related oligonucleotides to examine the role of c-Jun in determining the phenotypes of these cells in vitro and in rodent models of corneal neovascularization, solid tumor growth, and vascular endothelial growth factor (VEGF)–induced angiogenesis. They found that Dz13-transfected cells expressed less c-Jun protein than mock-transfected cells or cells transfected with a scrambled version of Dz13. Dz13 blocked endothelial cell proliferation, migration, chemoinvasion, and tubule formation, and it inhibited VEGF-induced neovascularization in the rat cornea and solid melanoma growth in mice. The authors conclude that DNAzymes targeting c-Jun may have therapeutic potential as inhibitors of tumor angiogenesis and growth.
In an accompanying editorial, Folkman (p. 644) discusses the implications of these results for the field of angiogenesis research. He notes that these findings suggest an additional pathway by which endostatin inhibits angiogenesis.
Nano-Sized Contrast Agent for Visualizing Lymphatic Drainage
A breast cancer patient’s prognosis and treatment often depends on the precise detection of metastatic lesions in the corresponding sentinel lymph node. Kobayashi et al. (p. 703) have developed a four-dimensional method of micro-magnetic resonance lymphangiography with the nano-sized contrast agent G6 to detect sentinel lymph node drainage in normal mice and in mouse models of breast cancer. Using this method, regions of sentinel lymph nodes containing metastatic mammary tumors were visualized as black spots, and regions without tumors that had normal lymphatic drainage were white, as they were in the normal mice. The authors conclude that this new imaging method may have potential prognostic applications in human breast cancer.
Selenium and Prostate Cancer Risk
Epidemiologic studies suggest that low selenium levels are associated with an increased incidence of prostate cancer, although results are conflicting. In a nested case–control study, Li et al. (p. 696) examined the association between pre-diagnostic plasma selenium levels and risk of prostate cancer in men enrolled in the Physicians’ Health Study. The authors found that pre-diagnostic plasma selenium levels were inversely associated with risk of advanced prostate cancer, even among men diagnosed after 8 years of follow-up. Among subjects diagnosed in the pre- (before October 1990) and post- (after October 1990) prostate-specific antigen (PSA) screening eras, the inverse association with prostate cancer risk was observed only for case subjects with elevated baseline PSA levels. The authors conclude that the association between baseline plasma selenium levels and risk of advanced prostate cancer suggests that higher levels of selenium may slow prostate cancer tumor progression.
In the accompanying editorial, Taylor et al. (p. 645) show how science has recently deepened the understanding of selenium and prostate cancer, layer by layer. Integrating the results of several selenium epidemiology trials with understanding of the molecular and cellular bases of selenium activity, they show that selenium has tremendous potential as a cancer prevention agent.
Skin Cancer, Non-Hodgkin Lymphoma, and Use of Systemic Glucocorticoids
Because patients treated with glucocorticoids, a common immunosuppressive therapy, may have an increased risk of skin cancer, Sørensen et al. (p. 709) analyzed data from the population-based North Jutland Prescription Database and the Danish Cancer Registry to determine whether use of glucocorticoids was associated with skin cancer or non-Hodgkin lymphoma. They found increased overall risks for squamous cell and basal cell carcinomas, particularly among persons who had received 15 or more prescriptions for glucocorticoids during the 8-year study, and also found an elevated risk for non-Hodgkin lymphoma among those receiving 10–14 prescriptions. They conclude that use of glucocorticoids may be a shared risk factor for certain skin cancers and lymphomas.
Apoptosis as a Target for Chemoprevention
Cancer chemopreventive agents are typically natural products or their synthetic analogs that inhibit the transition of normal cells to premalignant cells or of premalignant cells to malignant cells. Because an increasing number of these compounds have been shown to stimulate apoptosis in premalignant and malignant cells in vitro and in vivo, Sun et al. (p. 662) have constructed a paradigm supporting apoptosis-inducing pathways as novel targets for cancer chemoprevention by highlighting recent studies of several chemopreventive agents that target these pathways.
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