Histology and histopathology Vol.17, nº 2 (2002)
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- PublicationOpen AccessTumor-associated fibroblasts (Part I): active stromal participants in tumor development and progression?(Murcia: F. Hernández, 2002) Kunz-Schughart, L.A.; Knuechel, R.Phenotypic and functional characteristics of tumor associated fibroblasts (TAF) in contrast to normal fibroblasts are re v i e wed in this first synopsis (part I). Terms as tumor stroma, desmo-plasia, T A F , myofibroblast, and fetal-type fibroblast are defined, and experimental systems to study heterologous cell interactions are presented. While we only start to gather information on the genotype of T A F , a broad range of data deals with the e xpression profile of these cells, co v ering e.g. ECM and ECM-modulating molecules, growth factors and cytokines. Summarizing the recent state of kno w l e d g e indicates that TAF provide sources for tumor diagnosis and therap y , that ha v e to be further defined in an or g an- s p e c i f ic approach in terms of the functional impact on the tumor cell and its environment (see part II).
- PublicationOpen AccessImmunogold localization of mitochondrial aspartate aminotransferase in mitochondria and on the cell surface in normal rat tissues(Murcia : F. Hernández, 2002) Cechetto, J.D.; Sadacharan, S.K.; Berk, P.D.; Gupta, R.S.Mitochondrial aspartate aminotransferase (mAspAT) (E.C. 2.6.1.1), an important enzyme in amino acid metabolism, is identical to a fatty acid-binding protein (FA B Pp m) isolated from plasma membranes of several cell types. Employing a monospecific polyclonal antibody to rat mAspAT, we have used immunogold electron microscopy to study the subcellular distribution of mAspAT in various mammalian tissues. Immunogold labeling of rat tissue sections embedded in LR Gold resin showed strong labeling of mitochondria in all tissues examined (viz. live r, pancreas, pituitary, spleen, heart, kidney, submandibular gland). In addition, strong and specific labeling was also observed at a number of non-mitochondrial sites including various locations in k i d n ey, such as on cell surface in distal tubules and cortical collecting ducts, in condensing vacuoles, along cell boundaries between adjoining cells, and in endothelial cells lining capillaries in the glomerulus. S u r face labeling due to mAspAT was also seen in arteriolar endothelial cells and in lymphocytes. These findings support the previous identification of mAspAT as both a mitochondrial enzyme and a plasma membrane protein. It is suggested that in accordance with its established role in other cells and tissues, the surfa c e - located mAspAT in kidney and endothelial cells is i nvo l ved in the fatty acid transport process. The duallocalization of mAspAT, as well as a large number of other mitochondrial proteins (viz. Hsp60, Hsp10, Cytochrome c, TRAP-1 and P32 (gC1q-R)) in recent studies, within both mitochondria and at various specific extramitochondrial sites raises fundamental questions about the role of mitochondria in cell structure and function, and about the mechanisms that exist in normal cells for protein translocation from mitochondria to other compartments. These results have implications for the role of mitochondria in apoptosis and different diseases.
- PublicationOpen AccessLow density lipoproteins and mitogenic signal transduction processes: Role in the pathogenesis of renal disease(Murcia : F. Hernández, 2002) Kamanna, V.S.Abnormalities in lipid and lipoprotein metabolism are commonly observed in patients with chronic renal disease. Specifi c a l l y, hyperlipidemia and the glomerular deposition of atherogenic lipoproteins (e.g., Low density lipoprotein, LDL; and its oxidized variants) are implicated in key pathobiological processes i nvo l ved in the development of glomerular disease, including stimulation of monocyte infiltration into the mesangial space, mesangial cell hy p e r c e l l u l a r i t y, and mesangial extracellular matrix deposition. This rev i ew discusses recent understanding of glomerular mitogenic responses, intracellular signaling events associated with mesangial hypercellularity in renal diseases, and the participation of cholesterol and atherogenic lipoproteins in intracellular signaling pathways involved in mesangial cell proliferation. G e n e r a l l y, the mitogenic intracellular signaling p a t h ways are regulated by the activation of series of transmembrane and cytoplasmic protein tyrosine kinases that converge into the activation of Ras and down-stream m i t o g e n - a c t ivated protein kinase (MAP kinase). A c t ivated MAP kinase, through translocating into the nucleus and the activation of various transcription factors and protooncogenes, regulate cell proliferation. The importance of mitogenic intracellular signaling in mesangial proliferative disease has only recently been recognized and showed that the activation of MAP kinase and/or cy c l i n / cyclin-dependent kinases play crucial role in different phases of cell growth cycle and hypercellularity of glomerular cells in va r i o u s experimental renal diseases. Using glomerular mesangial cells as an in-vitro model system, studies from our laboratory indicated that the accumulation of LDL and more potently its oxidized forms within the glomerulus, through the activation of membrane receptor tyrosine kinases (e.g., EGF receptor), activate Ras and MAP kinase signaling cascade leading to DNA synthesis and subsequent mesangial cell proliferation. These data suggest that atherogenic lipoproteins may act as one of the major endogenous modulators for mitogenic signaling response and cell proliferation within the glomerulus. It is reasonable to speculate that the correction or reduction of hy p e r l i p i d e m i a , glomerular lipid deposition, and the pro-oxidative milieu within the glomerulus, through the inhibition of mitogenic signaling events, may provide protective e nvironment against mesangial hypercellularity and subsequent matrix deposition, and the progression of renal disease.
- PublicationOpen AccessTumor-associated fibroblasts (Part II): functional impact on tumor tissue(Murcia : F. Hernández, 2002) Kunz-Schughart, L.A.; Knuechel, R.The article focuses on the functional impact of tumor-associated fibroblasts (TAF) on its surrounding cells. It intends to cover the recent knowledge on TAF, the phenotype, and expression profile of which have been described in the first part of the rev i ew series ( Kunz-Schughart and Knuechel, 2002). The present r ev i ew is subdivided into two main chapters: (1) functional impact of TAF on tumor cells and (2) fibroblast-host cell interactions in tumor tissue. In the first paragraph of chapter (1) about the role of fibroblasts in tumor cell growth and differentiation it is reve a l e d , h ow strongly cellular interaction is dependent on fibroblast and tumor cell type as well as the spatial ratio between the cells. The variation of cellular behav i o r depending on quantity of molecules holds also true for the group of ECM molecules, e.g. the balance between MMPs and TIMPs, which provide an interesting therapeutic target in tumor tissue. This is one of the topics addressed in the second paragraph which focuses on tumor cell dissemination. Chapter (2) addresses the relation of TAF to other intra- or peritumoral host cells. The hypoxia-related angiogenesis induction of fibroblasts via growth factor secretion (e.g. VEGF) is considered as important as the immune modulatory properties of fibroblasts on immune cells, such as m o n o cytes/macrophages. These cellular properties can be tested under controlled conditions in threedimensional heterologous cultures of human cells, p r oviding the chance for systematic modification to assess therapeutic effects in an in vivo like environment.
- PublicationOpen AccessAbnormalities in dendritic cell and macrophage accumulation in the pancreas of nonobese diabetic (NOD) mice during the early neonatal period(Murcia : F. Hernández, 2002) Charré, S.; Rosmalen, J.G.M.; Pelegri, C.; Alves, V.; Leenen, P.J.M.; Drexhage, H.A.; Homo-Delarche, F.Dendritic cell (DC), macrophage (Mø) and l y m p h o cyte infiltrations have been observed in normal human perinatal pancreata, but have never been investigated so early in control mice. In type 1 diabetesprone NOD mice, these cells are thought to infiltrate first the periphery of the islets of Langerhans around weaning before further islet infiltration and ß-cell destruction. We quantified, during the first month of life, the numbers of DC (characterized by CD11c positivity and dendritic morphology), histiocyte-like Mø (characterized by ER-MP23 positivity) and Mø with scave n g i n g potential (characterized by BM8 positivity) in C57BL/6, DBA/2 and BALB/c control, and NOD and lymphocytedeficient NODscid mouse pancreata. First, CD11c+ DC were present at low densities from birth onwards in control pancreata, while densities were higher in NOD and NODscid. Second, high numbers of BM8+ and ER-MP23+ Mø were observed at birth in all strains investigated. After birth, particularly BM8+ cells disappeared progressively in control strains, but not in NOD and NODs c i d. Third, NOD mice also had more E R - M P 2 3+ Mø at birth compared to controls. Finally, DC and Mø localizations were similar in all strains, i.e., mostly as dispersed cells in periva s c u l a r, periductular, peri-islet areas and interlobular septa. The most remarkable finding was that particularly BM8+ Mø, were seen at sites of islet neogenesis and predominantly at the duct-islet interface. Our data showed that different types of APC were present in the pancreas during postnatal development in various control mouse strains and some differences were o b s e r ved in NOD and NOD s c i d mice from birth onwards.