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The rat ventral prostate is a complex gland composed of numerous ducts. The epithelial cells that line the lumen of the ducts are surrounded by stromal cells. The epithelial cells display a characteristic morphology that is dependent on their anatomical location within the ducts; the cells that line the lumen in the region of the ducts close to the urethra (the proximal region) are cuboidal, while those in the distal regions of the ducts are tall columnar cells. We have examined the regional expression of two genes that are expressed in the prostate: prostate steroid-binding protein (PSBP; a marker for androgen-dependent protein synthesis) and TRPM-2 (a marker for programmed cell death). We have demonstrated that the expression of PSBP, in the presence of androgens, and TRPM-2, in the absence of androgens, is restricted to the luminal epithelial cells in the distal regions of the prostatic ducts. Neither of the genes is expressed in the proximal regions of the ducts. In view of the probable effects of the epithelial-stromal interactions in the gland we have also characterized the cytokeratin composition of the epithelial cells lining the prostatic ducts. We have established that the basal epithelial cells of the prostate are primarily localized in the proximal region of the ducts. We propose that these cells may attenuate the influence of the stromal cells on the luminal epithelium and exert a negative influence on the cytodifferentiation of the secretory epithelial cells. The results also suggest that PSBP, which has been considered to be an androgen-dependent gene may, in fact, be a sequence that is constitutively expressed in the luminal cells that die in the absence of androgens. This has significant implications on the mechanism of androgen action in the rat ventral prostate.
Mol Endocrinol 1990 Dec
PMID:Ductal heterogeneity of cytokeratins, gene expression, and cell death in the rat ventral prostate. 170 30

The cellular origin of estrogen-induced kidney tumors in male Syrian hamsters has been repeatedly the subject of controversy. Several authors have proposed that the tumors arise from proximal tubules, from a combination of tubular and interstitial stromal cells, or solely from interstitial cells. Because of the model character of this tumor for hormone-associated cancer, it was further investigated in this study with respect to morphology, enzyme and intermediate filament pattern, the expression of alpha-smooth muscle actin and the extracellular matrix proteins fibronectin and tenascin. These analyses were carried out with early and late tumors as well as metastases to determine possible changes in expression of biochemical parameters during the development and progression of this neoplasm. The enzyme histochemical and intermediate filament patterns were usually the same as those described previously for proliferative foci and early tumors, i.e. highly elevated activities of glucose-6-phosphate dehydrogenase, adenylate cyclase and alkaline phosphatase, a lack of glucose-6-phosphatase and gamma-glutamyltransferase and coexpression of vimentin and desmin, alpha-smooth muscle actin could not be detected in early lesions. In five of 24 advanced tumors inclusions of kidney tubules were found which showed various degrees of alteration in their morphology and enzyme histochemical pattern, but were often directly connected with tubular segments of normal appearance outside the tumor. Like the normal tubules, the enclosed tubular segments were strongly positive for cytokeratin but never expressed vimentin or desmin. Among the 24 tumors studied, two contained cysts which expressed cytokeratin and sometimes also vimentin but not desmin. The enzyme histochemistry of the cells lining the cysts was similar to that of the surrounding tumor mass, except adenylate cyclase was lacking and alkaline phosphatase was not uniformly distributed. In tumors containing cytokeratin-positive cysts, there often were cytokeratin-positive, vimentin-negative and desmin-negative tumor formations in close contact to these cysts. With the exception of cyst formation, the pattern of metastases were identical to that of the primary tumors. All large tumors and the main component of the metastases expressed vimentin, desmin and fibronectin. Mesothelia surrounding metastatic tumor complexes were positive for vimentin, desmin, alpha-smooth muscle actin, fibronectin, cytokeratin and tenascin. It was concluded from these and previous observations on early stages of tumor development that the estrogen-induced hamster kidney tumor originates from mesenchymal interstitial cells (probably pericytes) which may rarely acquire an epithelial phenotype by metaplastic transformation during tumor progression.
Virchows Arch B Cell Pathol Incl Mol Pathol 1991
PMID:Changes in the cellular phenotype and extracellular matrix during progression of estrogen-induced mesenchymal kidney tumors in Syrian hamsters. 171 81

Squamous cell metaplasia (SCM) is a frequent epithelial alteration of the human tracheobronchial mucosa. This review pays particular attention to the fact that SCM can mimic esophageal, and in some instances even skin-type differentiation, showing striking similarities not only in morphology but also in terms of gene expression. Therefore, characterization of this dynamic process lends insight into the process of stratification, squamous cell formation, and "keratinization" in a pathologically relevant in vivo situation in man. First, the concept of metaplasia is presented with certain historical viewpoints on histogenesis. Then, the morphological characteristics of normal bronchial epithelium are compared with the altered phenotype of cells in SCM. These changes are described as a disturbance of the finely tuned balance of differentiation and proliferation through the action of a variety of extrinsic and intrinsic factors. Molecular aspects of altered cell/cell and cell/extracellular matrix interactions in stratified compared with single-layered epithelia are discussed with reference to SCM in the lung. Intracellular organizational and compositional changes are then summarized with special emphasis on the differential distribution of the cytokeratin (CK) polypeptides. Finally, the still unresolved problems of the histogenetic relationships between normal bronchial mucosa, SCM, and pulmonary neoplasms are addressed. As these questions remain open, examples for detection of well defined "markers" are provided that may be employed as objective criteria for determining clinically important cellular differentiation features.
Virchows Arch B Cell Pathol Incl Mol Pathol 1991
PMID:Squamous cell metaplasia in the human lung: molecular characteristics of epithelial stratification. 172 55

The regulation of pulmonary alveolar type II cell proliferation and differentiation is poorly understood and has been difficult to study, in part due to lack of proliferation, cellular heterogeneity, and phenotypic instability of type II cells in primary culture. To develop a stable population of homogeneous cells capable of proliferation, we transfected type II cells isolated from the lungs of neonatal rats with an immortalizing oncogene, adenovirus 12SE1A, using a retroviral vector. Individual clones were isolated, screened for cytokeratin expression, and further characterized. One of the 12SE1A expressing clones, E1A-T2, has epithelial features such as cytokeratin expression and tight junctions, and coexpresses vimentin. E1A-T2 rapidly proliferate when grown in 10% fetal bovine serum, and slow their growth at confluence. A labeling index of greater than 90% during a 24-h pulse of [3H]thymidine reflects a uniform population of proliferating cells. E1A-T2 can be grown and passed in 0.4% fetal bovine serum, suggesting the production of an autocrine growth factor(s). The type II cell Maclura pomifera agglutinin (MPA)-binding glycoprotein, MPA-gp200, appears to be expressed in an incompletely glycosylated form, whereas other features of differentiated type II cells, such as lamellar bodies, surfactant protein A, and a high percentage of saturated phosphatidylcholine, are absent. Homogeneous, clonally derived type II cell lines, such as E1A-T2 may retain sufficient type II cell features of interest to test new hypotheses relating to cell proliferation and differentiation otherwise not feasible using primary cultures of type II cells.
Am J Respir Cell Mol Biol 1992 Jan
PMID:A rat alveolar type II cell line developed by adenovirus 12SE1A gene transfer. 172 94

Highly purified follicular dendritic cells (FDC) were isolated from human tonsils and cultivated for up to 150 days. The cell separation method employed produced pure aggregates (FDC-clusters) composed of FDC and germinal center lymphoid cells, useful for the analysis of the relationship between these two cell types and of the behavior of FDC in culture. During the first few days of culture, lymphoid cells located between FDC extensions survived better than those which were free or partly covered by FDC. After 6 days, the lymphoid population degenerated and only the FDC survived. The unique antigenic pattern of FDC (positive for HLA-DR. DRC-1, CD14b, CD21, CD23, CD35) disappeared within a few days of culture. Recombinant interferon-gamma exerted a positive effect either on retaining HLA-DR expression or on the reexpression of these antigens by FDC. HLA-ABC antigens were traced until the 10th day and desmosomal junctions until the 14th day. Subsequently, FDC presented peculiar features, including oval and rhomboid shapes, one to ten nuclei, fine amoeboid extensions, stress fibers and a radical dense zone in their cytoplasm. FDC possessed actin, tubulin and vimentin, but neither desmin nor cytokeratin. After 40 days of culture, FDC enlarged and were covered with abundant membrane extensions. Even when kept as long as 150 days in vitro. FDC did not proliferate in any of the culture conditions employed.
Virchows Arch B Cell Pathol Incl Mol Pathol 1990
PMID:Isolation and long-term cultivation of human tonsil follicular dendritic cells. 197 38

Intracellular cyclic AMP (cAMP) regulates many critical differentiated functions of tracheal epithelial cells. An in vitro model system for reliable study of cAMP metabolism in these cells has been developed. Viable tracheal epithelial cells could be recovered from greater than 50% of necropsy specimens. Culture success rate was not significantly affected by age of subject, endotracheal intubation, or time between death and autopsy, although most specimens were obtained within 24 h of death. Human tracheal epithelial cells grown in primary culture displayed a typical histologic epithelial appearance, and the ultrastructure showed microvilli, junctional complexes, and tonofilaments. The cells uniformly stained with fluorescent antibody to cytokeratin, and expressed receptors for isoproterenol and vasoactive intestinal peptide. Human tracheal epithelial cells grown serum-free in an equal volume mix of Ham's F12 medium and Dulbecco's minimal essential medium containing growth supplements (Medium A) and cholera toxin (CT) had higher basal cAMP levels and greater increase in intracellular cAMP in response to phosphodiesterase inhibition than cells grown in Medium A without CT. Cells grown in Medium A without CT had similar morphology and grew at a comparable rate but attached to the culture substratum less readily than cells grown in Medium A with CT. Cells grown in Medium A without CT had less cAMP response to phosphodiesterase inhibition, less rapid accumulation of cAMP, and greater proportional response to receptor-mediated stimulation of cAMP production compared to cells grown with CT, though the final cAMP levels achieved were comparable.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1990 Jan
PMID:Adenosine 3:5' cyclic monophosphate synthesis by human tracheal epithelial cells. 215 12

Endothelin, synthesized by endothelial cells, is the most potent vasoconstrictor and bronchoconstrictor agent known. We investigated endothelin release from human bronchial epithelial cells and the binding of the peptide to autologous bronchial smooth muscle cells in culture. Epithelial and smooth muscle cells were isolated by enzymatic digestion of bronchial tissue obtained on surgery, and cultured to confluency by standard methods. Epithelial cells stained positively for cytokeratin filaments. Smooth muscle cells stained uniformly for alpha-smooth muscle actin. Immunoreactive endothelin contents in the supernatants of epithelial cells extracted on C8 Amprep columns were evaluated by radioimmunoassay. Epithelial cells released appreciable amounts of immunoreactive endothelin into the culture medium (from 0.65 to 2.1 pmol/ml). A single specific binding site for [125I]endothelin 1 was identified on bronchial smooth muscle cells with an apparent Kd of 113 pM and a maximal binding capacity of 22.1 fmol/10(6) cells. At room temperature the binding was saturable, reached equilibrium at 120 min (25 pM endothelin 1), and was slowly and incompletely reversed by unlabeled endothelin over a period of 8 h. Conditioned medium from epithelial cells inhibited the [125I]endothelin 1 binding, dose dependently, and the effect was antagonized by monospecific antiserum. Thus, human bronchial smooth muscle cells possess specific binding sites for endothelin 1 and human bronchial epithelial cells secrete an endothelin-like material. This may have a role in the pathogenesis of asthma.
Am J Respir Cell Mol Biol 1990 Aug
PMID:Specific binding of endothelin on human bronchial smooth muscle cells in culture and secretion of endothelin-like material from bronchial epithelial cells. 219 95

Proliferation of type II cells is important for the recovery of the alveolar epithelium after acute lung injury. However, the factors that regulate the proliferation of human type II cells are unknown. Human alveolar type II cells were isolated from resected lung by dissociation with porcine pancreatic elastase and crystalline trypsin and purified by density-gradient centrifugation and serial differential adherence. The purity of the type II cells in the final adherent preparation was 84.4 +/- 1.1% type II cells by alkaline phosphatase and 87.7 +/- 2.8% by cytokeratin (n = 7). The medium MCDB-151 with 0.4% fetal bovine serum (FBS) was used to demonstrate the stimulatory effect of individual growth factors. Under these conditions, thymidine incorporation was stimulated by insulin, epidermal growth factor, endothelial cell growth supplement (ECGS), and acidic and basic fibroblast growth factors. Cholera toxin did not stimulate thymidine incorporation. The most effective stimulation was by the combination of insulin and ECGS. The incorporation of bromodeoxyuridine was used to identify the proportion of cells that were active in DNA synthesis. Insulin and ECGS increased the percentage of cells that incorporated bromodeoxyuridine from 8.5 +/- 1.3% to 21.3 +/- 2.4% (n = 6). Mitotic figures were seen in smears prepared from cultures incubated with insulin and ECGS. This observation was confirmed by electron microscopy, which demonstrated type II cells in metaphase. Increasing the concentration of FBS or human serum in the culture medium to 10% decreased the stimulatory effect of insulin and ECGS.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1990 Dec
PMID:Human alveolar type II cells: stimulation of DNA synthesis by insulin and endothelial cell growth supplement. 225 83

Three clones coding for carboxy-terminal portions of type II cytokeratins have been isolated from a cDNA library constructed from the epidermis of the frog Xenopus laevis. These clones have been identified by hybridization-selection-translation and Northern blot analysis, and contain sequences complementary to mRNAs of similar size that code for three different polypeptides of the Mr 64,000 group, Ia-c, i.e. the only major type II cytokeratins expressed in this tissue. A comparison of the corresponding nucleotide sequences and the amino acid sequences deduced therefrom shows only minor differences in these polypeptides, most of which occur as isolated point mutations. This indicates that coding sequences of the different type II cytokeratin genes in epidermis of Xenopus are very similar, in contrast to the more extended differences of type II cytokeratin genes expressed in mammalian epidermis, which probably reflects a lower degree of evolutionary divergence of members of this protein family in amphibia. A comparison of the Xenopus sequences with those of mammalian type II cytokeratins reveals the same characteristic features, i.e. an alpha-helical domain ending with the familiar consensus sequence T Y R (X Y) L E G E, followed by a non-helical domain Cl enriched in hydroxyamino acids. Both domains are remarkably conserved in sequence between Xenopus and mammals. The following glycine-rich domain (C2) displays similar oligopeptide repeats (mostly of the type G G G M in the frog keratins), and the terminal C3 domain is characterized by a region exceptionally rich in hydroxyamino acids, which immediately precedes a cluster of basic amino acids at the carboxy terminus. Our results show that the typical features of the domain of type II cytokeratins are already established in amphibia and that these homologies are not restricted to the alpha-helical rod of these proteins but, in principle, extend to the other domains located in the so-called hypervariable tail portion. This suggests that the hypervariable regions are not subject to random variability but contain functionally important domains that have been well conserved during evolution.
J Mol Biol 1985 Aug 20
PMID:Amino acid sequence microheterogeneities of basic (type II) cytokeratins of Xenopus laevis epidermis and evolutionary conservativity of helical and non-helical domains. 241 19

Epithelial cells from various sites and at various stages of differentiation reveal distinct cytokeratin polypeptide patterns. WE have localized these heterogeneous elements at the subcellular level in human salivary glands and in a solid tumor of the breast using a monoclonal and a polyclonal antibody against cytokeratin, and an antibody against tissue polypeptide antigen (TPA) which seems to be related to some cytokeratins. Labeling by the cytokeratin antibodies was more intense in squamous and duct cells than in acinar cells. The TPA:B1 antibody reacted predominantly with duct cells and to a lesser extent with acinar and squamous cells. A precise evaluation of the labeling pattern and a well-preserved cell structure appeared to be important factors in obtaining more detailed information about intermediate filament proteins. The cryoultramicrotomy and the protein A-gold technique are suitable for these studies.
Virchows Arch B Cell Pathol Incl Mol Pathol 1985
PMID:Subcellular localization of tissue polypeptide antigen and cytokeratins in epithelial cells (salivary ad mammary glands). Combined use of the cryoultramicrotomy and the protein A-gold technique. 241 12


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