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Independent Regulation of TGB-ß1 Transcription and Translation by Glucose and PDGF
Increasing scientific evidence supports the notion that a variety of structural cells, including fibroblasts, smooth muscle cells, and epithelial cells can provide effector activity toward an ongoing inflammatory response via the expression of different cytokines. The production of transforming growth factor ß1 (TGF-ß1) is an example of a well-studied cytokine, which is generated by fibroblasts and epithelial cells during inflammation and plays a key role in the progression of inflammation and interstitial fibrosis. Fraser et al (Am J Pathol 2002, 161:1039–1049) provide mechanistic insight into the expression of proximal tubular renal epithelial cell-derived TGF-ß1 during the pathogenesis of renal interstitial fibrosis during diabetes. Their data demonstrate that glucose itself serves an important role via lowering the threshold at which other stimuli, such as platelet-derived growth factor (PDGF), can stimulate renal epithelial cell-derived TGF-ß1. Thus, the role of glucose in diabetic nephropathy may prime the kidney for a subsequent injurious response resulting in interstitial renal fibrosis.
Microarrays of Frozen Cells
Tissue microarrays, generally prepared from cores of paraffin-embedded tissue, have taken the experimental pathology world by storm. Such approaches enable high-throughput immunohistochemistry and molecular cytogenetic analyses, and have already been invaluable in studying genomic mechanisms and disease markers across large numbers of tissue. Stephan et al (Am J Pathol 2002, 161:787–797) report a technique which extends this same paradigm to frozen cells. They use an arrayer to punch 25 wells in a frozen OCT block, then load each well with cell suspensions from various cell lines. They subsequently prepared frozen sections, and evaluated Ep-CAM protein expression by immunofluorescence. The Ep-CAM expression values in the cell array were similar to those obtained by FACS analysis of the corresponding cell lines. The frozen cell array could be particularly useful in assays, including drug target validations, which require maximal preservation of protein function.
Therapeutic Effect of Angiostatin Gene Transfer in a Murine Model of Endometriosis
The growth of ectopic, functional endometrial tissue, which is highly vascularized, is the hallmark of chronic endometriosis. The disease is known to be estrogen-dependent and current therapy consists of hormone treatments aimed at lowering circulating estrogen to postmenopausal levels; however, this therapeutic strategy may promote osteoporosis and increase the risk of heart disease. Dabrosin and co-workers (Am J Pathol 2002, 161:909–918) present a novel experimental therapy for treating this disease by targeting the vascularization aspect of endometriosis. Data from this group demonstrates that the anti-angiogenic agent, angiostatin, delivered in vivo via a replication-deficient adenovirus vector, is an effective treatment for experimental endometriosis. The mechanism of angiostatin’s efficacy appears to involve inhibition of endothelial cell proliferation and augmentation of endothelial cell apoptosis; thus inducing regression and resorption of the endometrial tissue. These studies support the logic for using targeted delivery of angiostatic factors to control endometriosis even in women with preserved estrogen levels.
Molecular Correlates with Histological Subtypes of Renal Cancer
Genetic correlates have been highly informative among renal cell neoplasia, where distinctive cytogenetic and molecular profiles distinguish clear cell, papillary, chromophobe, and oncocytoma tumors. Previous studies have shown a series of characteristic chromosomal trisomies in papillary renal cell carcinoma, whereas a minority of these tumors also contain activating point mutations of the MET receptor tyrosine kinase gene. Sanders et al (Am J Pathol 2002, 161:997–1005) report molecular genetic correlates for the recently proposed "type 1 vs. type 2" histological categories of papillary renal cell carcinoma. Allelic imbalance on chromosome arms 17q and 9p was detected in 78% and 0%, respectively, of type 1 tumors, and in 12% and 37%, respectively, of type 2 tumors. Notably, MET mutations were uncommon overall, being detected in only one of 35 papillary tumors. The authors conclude that allelic imbalance profiles provide a molecular validation of the recently proposed type 1 vs. type 2 histological classification, and suggest that these subtypes of papillary renal carcinoma arise by distinct genetic mechanisms.
Novel Expression of VCAM-1 (CD106) by Squamous Epithelium in Experimental Acute Graft-versus-Host Disease
The ligation of VLA-4 with its receptor VCAM-1 is an important interaction, which governs a variety of inflammatory responses via its adhesive and costimulatory effects. While early studies centered on the expression of VCAM-1 by activated endothelial cells, the investigation by Kim et al (Am J Pathol 2002, 161:763–770) demonstrate that VCAM-1 is also significantly expressed by cutaneous and muscosal epithelial cells during the evolution of graft-versus-host disease. Surface bound VCAM-1 was found on epithelial cells as early as 7 days after transplant in three distinct subpopulations of squamous epithelial cells; those found in the basal cell layer, the follicular infundibulum, and dorsal lingual epithelium. The expression of VCAM-1 was preferentially expressed at sites of early epithelial infiltration by CD4+ T cells, demonstrating that the presence of VCAM-1 on the surface of squamous epithelial cells is of functional consequence. These investigations support the idea that the expression of VCAM-1 by squamous epithelium can facilitate the trafficking of T cells in association with dermal complications of graft-versus-host disease.
Histological Features Reflect Transforming Mechanisms in Transgenic Breast Cancer Models
There is increasing evidence for heterogeneous oncogenic molecular pathways, that serve as alternate transforming mechanisms, in many types of human cancer. One wonders how often these specific biological mechanisms result in subtle differences in tumor morphology, and could therefore be inferred from their characteristic effects on cell architecture. Recent examples where this has proven true include the recognition of tell-tale histological features in colorectal cancers with mismatch repair defects, and in medulloblastomas with inactivation of the PTCH tumor suppressor. Rosner et al (Am J Pathol 2002, 161:1087–1097) now describe characteristic histological features of breast tumors in transgenic mice, depending on whether the predisposing oncogenic mechanism involves activation of the ERBB/RAS versus WNT pathway. Breast tumors in ERBB/RAS pathway transgenics typically formed solid nodules of poorly differentiated cells with abundant cytoplasm. Those in WNT pathway mice more often had myoepithelial and glandular differentiation, with a semblance of ductule-like structures. These observations suggest that molecular cause and histological effect can be exploited in basic and clinical studies of breast cancer.
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