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Microarray Analyses of Gene Expression in Cancers and Premalignant Conditions: Molecular Genetic Studies of Extraskeletal Myxoid Chondrosarcoma and Microarray Analysis of Nodules in Cirrhotic Livers
Global analyses of gene expression in tumors are now widely performed. These studies have multiple goals including overall analysis of gene expression, the identification of new markers, and the establishment of new classifications that can provide more reliable prognostic information. Two papers in this issue illustrate the application if microarray technology to different aspects of the molecular pathogenesis of tumors. Sjögren et al (Am J Pathol 2003, 162:781–792) analyzed the pathogenesis of extraskeletal myxoid chondrosarcomas (EMCs) using cytogenetic and molecular analysis in conjunction with microarrays. They detected clonal chromosome abnormalities in 9 of 10 tumors. These included translocations, trisomies, and gene fusions. Despite histological and expression of different gene fusion transcripts, the gene expression profile of EMCs was quite uniform and distinct from that of other soft tissue sarcomas. In the other study, Anders et al (Am J Pathol 2003, 162:991–1000) performed microarray expression analysis in macroregenerative and dysplastic nodules from livers of patients with advanced cirrhosis induced by hepatitis C virus. Compared to gene expression in the surrounding cirrhotic liver, a total of 53 genes were found to be over- or underexpressed in the nodules and six genes were validated by PCR and immunohistochemistry. The down-regulated genes included FMS-like tyrosine kinase 3 ligand (Flt-3 ligand). Other genes such as semaphorin E and caveolin-1 were up-regulated. The work of Sjögren et al on EMCs focused on established tumors while Anders et al studied early lesions that may be cancer precursors. These different approaches highlight the multiple application of microarray analysis of gene expression in cancer research.
Full-Length hTERT mRNA as a Prognostic Marker for Neuroblastomas
Neuroblastomas are highly heterogeneous tumors in their morphology and biological behavior. Recent data indicate that telomerase activity (TA) may be a good prognostic predictor for neuroblastomas and is capable of discriminating between subtypes of varying aggressiveness. Shortening of telomeres is a well-recognized mechanism that limits cell division. TA present in many tumors overcomes this limitation by synthesizing telomeric DNA sequences at chromosomal tips. Measurement of TA in clinical samples is difficult and has been often substituted by PCR analysis of hTERT, the human telomerase reverse transcriptase, one of the telomerase components. Krams et al (Am J Pathol 2003, 162:1019–1026) determined whether hTERT mRNA expression can serve as a prognostic marker for neuroblastomas. hTERT transcripts in general showed no correlation with disease prognosis. However, because hTERT RNA undergoes alternative splicing, the authors examined the potential prognostic value of truncated and full-length hTERT mRNA. In a multivariate analysis, expression of full-length hTERT transcripts emerged as a very strong predictor of long-term survival. The work shows that measurements of hTERT mRNA may be of great value for assessing prognosis in patients with neuroblastomas.
Cell Cycle Entry of Motor Neurons Is Associated with Cell Death in Amyotrophic Lateral Sclerosis
Recent data indicate that cell cycle proteins may participate in neuronal cell death. It has been proposed that the re-entry of terminally differentiated neurons into the cell cycle may deregulate the phase-specific expression of cell cycle genes, eventually causing cell death. In amyotrophic lateral sclerosis (ALS) there is extensive neural loss in the cortex, brainstem, and spinal cord. Ranganathan and Bowser (Am J Pathol 2003, 162:823–835) investigated whether alterations in the expression of cell cycle proteins may be associated with neuronal cell death in ALS. In tissues from ALS patients there was hyperphosphorylation of the retinoblastoma protein, increased levels of cyclin D, and cytoplasmic redistribution of E2F. The data support the notion that in ALS patients, motor neurons may be stimulated to enter the cell cycle but do so in such an anomalous way that they trigger E2F-mediated cell death.
A Novel Marker for Pericytes and Vascular Smooth Muscle Cells
Pericytes are perivascular cells located in microvessels. There appears to be structural and biochemical diversity among pericytes, which is complicated by the lack of specific markers to identify these cells. Null mutants for TGFß, among other proteins, fail to develop vascular layers and die during development with cardiovascular defects. Most importantly, in double knockout mice for platelet-derived growth factor-B (PDGF-B) and PDGF receptor ß, recruitment of pericytes is impaired leading to perinatal death caused by microaneurysm rupture and edema. Based on these observations, Bondjers et al (Am J Pathol 2003, 162:721–729) compared gene expression profiles from the heads of PDGF-B-deficient mice with those of littermate controls to search for genes that may be down-regulated in the null strain. Expression of RGS5, a gene that encodes a member of the RGS family of regulators of G protein signaling was significantly decreased in PDGF-B null mice. RGS5 was detected in brain pericytes by in situ hybridization and in pericytes and vascular smooth muscle cells within some other tissues. In lung and gut, RGS5 expression was localized in visceral rather than vascular smooth muscle cells. This work identifies a new marker for pericytes and vascular smooth muscle cells in embryonic development that should greatly facilitate the study of the mechanisms of angiogenesis.
New Clues to the Pathogenesis of Congenital Myotonic Dystrophy
Myotonic dystrophy (DM1) is the most common adult-onset neuromuscular disease. It is an autosomal-dominant disorder caused by the expression of a CTG repeat sequence in the 3' untranslated region of the gene for the cAMP-dependent protein kinase DMPK. In DM1 patients there appears to be a correlation between the size of the CTG repeat and the severity of the disease. The length of the repeat may vary among tissues of individual patients. Various hypotheses have been proposed linking the expansion of the CTG repeats with disease pathogenesis. One hypothesis is that DM1 mutant transcripts are retained in the nucleus and have dominant-negative effects on RNA transcription. Furling et al (Am J Pathol 162:1001–1009) examined whether nuclear retention of DMPK mRNA actually results in a reduction in the levels of the enzyme. DM1 fetuses had impaired skeletal muscle development with persistence of embryonic and fetal myosin heavy chain and a 43% decrease in DMPK expression. The data demonstrate that nuclear retention of DMPK mRNA in fetuses with congenital DM1 causes both reduction in DMPK expression and delayed slow fiber maturation.
Proteoglycan Modification in Myofibroblasts May Determine Their Responsiveness to Growth Factors
Extracellular matrix synthesis, deposition, and turnover are regulated by growth factors and cytokines, including platelet-derived growth factor (PDGF) and fibroblast growth factor 2 (FGF2). Myofibroblasts are one of the cell types involved in fibrosis and much work has been done in attempting to establish differences between the properties of fibroblasts and myofibroblasts. Thomas et al (Am J Pathol 2003, 162:977–989) show that both cell types respond to PDGF but only fibroblasts proliferate in response to FGF2. Responsiveness to FGF2 in myofibroblasts can be acquired by incubation of these cells with heparin sulfate and heparin. The work suggests that the myofibroblast phenotype is associated with a different proteoglycan profile than that of fibroblasts, accounting for the differential responsiveness to FGF2.
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