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This Month in AJP |
A New Method for Measuring Angiogenesis
During the last few years, the mechanisms of angiogenesis have been studied in great detail, in great part because of the recognition that the formation of new blood vessels may constitute a target for tumor therapy. One of the problems of assessing angiogenic responses is the difficulty of obtaining reliable quantitative measurements of the process. Guedez et al (Am J Pathol 2003, 162:1431–1439) describe a method for measuring angiogenesis that can provide reliable quantitative estimates. The technique, named directed-in vivo-angiogenesis assay (DIVAA), consists of the subcutaneous implantation in nude mice of silicone cylinders filled with a very small amount of extracellular matrix. Vascularization in the cylinders (angioreactors) is quantified by injection of FITC-dextran into the mice followed by removal of the angioreactors for spectrofluorometric measurements. The assay has a good range of sensitivity, is reproducible, and proved to be accurate for the analysis of effects of angiogenesis inhibitors. DIVAA may find wide applicability as a quantitative assay to determine the potency of agents that stimulate or inhibit angiogenesis.
Heterogeneity of Endothelial Cells Located at Different Organ Sites
It is not known to what extend endothelial cells from different organ sites may differ in their response to inflammatory stimuli and if they produce a similar spectrum of chemokines, cytokines and adhesion molecules. Lim et al (Am J Pathol 2003, 162:1591–1601) studied the functional capacity of murine heart and lung endothelial cells for chemokine induction, adhesion molecule expression and interactions with T-cells. Only heart endothelial cells showed high constitutive expression of VCAM-1 and produced T-cell arrest, which was mediated by both VCAM-1 and RANTES. In contrast, T-cells exhibited a rolling phenotype on lung endothelial cells. Although both heart and lung endothelial cells stimulated by TNF produced adhesion molecules and chemokines, only heart cells produced high levels of RANTES after stimulation. The results of this study are consistent with the notion that endothelial cells located at different sites are functionally different and may react differently to inflammatory agents.
Repopulation of Human Lung Allografts by Host Cells
Many reports have demonstrated that hemopoietic stem cells injected into mice can differentiate into different lineages and be incorporated into the parenchyma and stromal elements of various organs. Such cells have also been detected, in variable amounts, in gender-mismatched solid organ transplants in humans. Kleeberger et al (Am J Pathol 2003, 162:1487–1494) examined whether host cells may be present in transplanted lungs of human patients. They studied archival tissues from explanted lung allografts, and microdissected cells from these specimens to detect chimerism in the transplants. Kleeberger et al detected cells from the host in the bronchial epithelium, in type II pneumocytes and in sero-mucous glands. The proportion of recipient-derived cells was higher in areas of chronic injury. Although it was expected that the recipient cells present in the transplanted organ originated in the bone marrow of the transplant recipient, this origin could not be confirmed in this study. Nevertheless, the results show that cell chimerism is present in epithelial structures of transplanted lungs.
Mechanisms of HIV-1 Neurotoxicity
Patients with AIDS often develop neurological symptoms involving impairment of motor and cognitive functions. The HIV-1 TAT protein has been thought to be responsible for the neurotoxic effects of viral infection, but most of the work has been performed in cell cultures or by TAT injection into the brain. Kim et al (Am J Pathol 2003, 162:1693–1707) have developed mice in which TAT expression was inducible and driven by the glial fibrillary acidic protein promoter. In these mice, TAT expression was detected only in astrocytes and was dependent on the action of doxycyclin, used as the inducer for the transgene. Induction of TAT expression in astrocytes caused defects in the cortex and cerebellum including neuronal apoptosis, dendrite degeneration, brain edema and astrocytosis. The results demonstrate that TAT expression is highly neurotoxic and causes a similar set of abnormalities as those present in AIDS patients. The mice developed by Kim et al constitute an excellent model to study the pathogenesis of AIDS-related neurological problems.
Microtubule Deficiency in Alzheimer Disease
A major feature of neuronal pathology in Alzheimer disease is cytoskeleton abnormalities consisting of the accumulation of paired helical filaments. It has been proposed that paired helical filaments contain a phosphorylated form of the tau protein, which is defective in its capacity to stabilize microtubules. However there are few quantitative studies of microtubules in Alzheimer disease and in aging patients without the disease, and little information is available on the relationships between a decrease in microtubules and formation of paired helical filaments in patients with the disease. Cash et al (Am J Pathol 2003, 162:1623–1627) show that both the number and length of microtubules is reduced in neurons of patients with Alzheimer disease compared to control cases, and that these changes are unrelated to paired helical filament formation. The authors conclude that reduction of microtubule assembly in aging and in patients with Alzheimer disease is not dependent on tau phosphorylation.
Gene Amplification in Ovarian Cancer
Ovarian carcinoma is the leading cause of death among gynecologic malignancies. The development of diagnostic and prognostic markers for this disease is urgently needed. The method called restriction landmark genome scanning (RLGS) has been used to measure copy numbers of genomic DNA and to detect alterations in DNA methylation in tumors. The techniques used in RGLS are quite elaborate and involve the analysis of thousands of chromosome fragments displayed in 2-dimensional gels. Wu et al (Am J Pathol 2003, 162:1603–1610) combined RLGS with Virtual Genomic Scans (VGS) to analyze gene amplification in ovarian carcinomas. VGS is a computational method that uses genome sequence data bases to identify the fragments obtained by RLGS. Using RLGS coupled with virtual genomic scans, Wu et al show that the L-Myc gene is amplified in a subset of ovarian tumors and that these tumors have high expression of L-Myc mRNA. It remains to be shown whether L-myc can serve as a useful marker for the diagnosis and prognosis of ovarian carcinomas and to identify the role that this gene may have in the pathogenesis of this malignancy.
Related articles in Am J Pathol:
Filament Formation
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