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PubMed2005

Intercellular junctions in Ewing sarcoma/primitive neuroectodermal tumor: additional evidence of epithelial differentiation.

Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) has recently been shown to frequently express cytokeratins, suggesting partial epithelial differentiation. Older ultrastructural studies have documented primitive cell-cell junctions in ES/PNET, reportedly resembling poorly formed desmosomes. Recently, paraffin-reactive antibodies have become available to proteins found in a variety of intercellular junctions indicative of epithelial differentiation, including tight junctions, desmosomes and adherens junctions. We examined intercellular junction protein expression in a large number of genetically confirmed ES/PNET. Formalin-fixed, paraffin-embedded sections from 23 primary and seven recurrent or metastatic cases of genetically confirmed ES/PNET were immunostained for claudin-1 and occludin (tight junction structural proteins), zonula occludens-1 (ZO-1, tight junction linker protein), desmoglein 1/2 (desmosomal adherens protein), desmoplakin (desmosomal structural protein) and E-cadherin (epithelial adherens junction protein), using steam heat-induced epitope retrieval and the Dako Envision system. Cases with >5% positive cells were scored as 'positive'. Normal colonic epithelium and skin served as external positive controls. Claudin-1 was expressed by 19 of 30 specimens (63%), ZO-1 was expressed by 15 of 29 specimens (51%), and occludin was expressed by three of 28 specimens (11%). In 28 specimens all three tight junction markers were evaluable. In all, 15 samples (54%) expressed only one tight junction marker, and 10 samples (36%) expressed two tight junction markers. No case expressed all three tight junction markers. Desmoglein was expressed in one of 30 (3%) samples. Desmoplakin was expressed in two of 28 (7%) samples. E-cadherin was negative in all cases. Our data suggest that many of the previously described cell-cell junctions in ES/PNET are poorly formed tight junctions, given the high frequency of claudin-1 and ZO-1 expression. This may underestimate the true frequency of tight junction protein expression in ES/PNET, as there are at least 20 different claudins and other ZO proteins. These tight junctions are almost certainly abnormal, given the absence of occludin expression in most cases. Desmosomal and adherens junction protein expression was rare to absent. Our findings provide additional evidence that ES/PNET frequently show partial epithelial differentiation.

Bone Neoplasms↗
PubMed2000

Capacity for epithelial differentiation in synovial sarcoma: analysis of a new human cell line.

AIM: To analyse the capacity for epithelial differentiation in synovial sarcoma using a new human cell line. METHODS: A new human cell line, KU-SS-1, was established from a monophasic, spindle cell type of synovial sarcoma by grafting those cells on to severe combined immunodeficient (SCID) mice and then transferring them to in vitro culture systems. The KU-SS-1 cells were characterised by light and electron microscopy, and by immunohistochemical, flow cytometric, and cytogenetic analysis. RESULTS: Primary tumour and cultured cells at passage 20 showed a positive reaction for vimentin, which is a mesenchymal marker. After 40 passages, subcultured cells were injected into SCID mice to induce further tumours. These advanced subcultured cells and the tumour cells that they induced were positive for cytokeratin, an epithelial marker, and exhibited epithelial ultrastructural features such as intermediate junctions. Furthermore, two colour immunofluorescent analysis for proliferating nuclear cell antigen (PCNA) and intermediate filaments showed that a large number of PCNA expressing cells were positive for vimentin, and that part of this fraction also expressed cytokeratin. The existence of cells with reactivity for these three markers indicated that, in this cell line, a fraction with high proliferating capacity had both mesenchymal and epithelial markers. In addition, cytogenetically, this cell line expressed the SYT-SSX chimaeric transcript as a result of the t(X;18) (p11;q11) translocation. CONCLUSIONS: A human synovial sarcoma cell line was established and stably maintained in cell culture for more than 70 passages. In addition, this cell line showed epithelial differentiation, which supports the hypothesis that synovial sarcoma is a carcinosarcoma like tumour with true epithelial differentiation. This cell line will be a useful tool for investigating the nature of this tumour and will contribute to clinical studies.

Adult↗
PubMed2003

A tumor-associated beta 1 integrin mutation that abrogates epithelial differentiation control.

SCC4 human keratinocytes are derived from a squamous cell carcinoma of the tongue and undergo very little spontaneous differentiation. Introduction of a wild-type beta 1 integrin subunit into SCC4 cells stimulates differentiation, suggesting either that the cells have a defect in the integrin signaling pathways that control differentiation or that the beta1 subunit itself is defective. Here we describe a heterozygous mutation in the SCC4 beta 1 subunit. The mutation, T188I, maps to the I-like domain. It results in constitutive activation of ligand binding, irrespective of the partner alpha subunit, in solid phase assays with recombinant protein and in living cells. The mutation promotes cell spreading, but not proliferation, motility, or invasiveness. It results in sustained activation of Erk MAPK independent of cell spreading. When introduced into SCC4 keratinocytes, the wild-type beta1 integrin stimulates differentiation, whereas the mutant is inactive. Activation of beta 1 integrins in normal keratinocytes also suppresses differentiation. These results establish, for the first time, mutation as a mechanism by which integrins can contribute to neoplasia, because the degree of differentiation in epithelial cancers is inversely correlated with prognosis. They also provide new insights into how integrins regulate keratinocyte differentiation.

Amino Acid Sequence↗
PubMed1995

Transcriptional regulation of the ezrin gene during rat intestinal development and epithelial differentiation.

Polarized intestinal epithelial cells are characterized by the presence of a brush border at their apical surface. The brush border cytoskeleton is assembled during cell differentiation and is composed of parallel actin bundles, held together by specific actin-binding proteins. Using specific cDNA probes we have studied the expression of the mRNAs encoding ezrin and moesin, two members of a class of proteins that connect the microvillar cytoskeleton to the plasma membrane, during the process of enterocyte maturation that occurs both in the embryonic and in the adult small intestine, along the crypt-villus axis. The steady state levels of ezrin mRNA were found to increase in the fetal gut epithelium between day 15 and day 20 of gestation and during the first week after birth, in parallel with the morphogenetic process that leads to cell polarization and brush border assembly. On the contrary, moesin mRNA is expressed at very low levels in the mature small intestine, with a sudden drop in transcription occurring at birth. In the continuously renewing epithelium of adult animals, ezrin mRNA levels are higher in the differentiated villus cells of the distal portions of the gastrointestinal tract and very low in undifferentiated crypt cells. These data demonstrate that the expression of the ezrin gene is regulated at the level of mRNA abundance during development and differentiation of the intestinal epithelium.

Amino Acid Sequence↗
PubMed1991

Modulation of xanthine dehydrogenase and oxidase activities during the hormonal induction of vaginal epithelial differentiation in ovariectomized mice.

The modulation of xanthine dehydrogenase/oxidase (XD/XO) activities in vaginal epithelium as a function of estrogen- and progesterone-induced differentiation was investigated in ovariectomized SENCAR mice. The vaginal epithelium of ovariectomized mice consisted of one or two cell layers. Intraperitoneal administration of 20 micrograms 17 beta-estradiol stimulated vaginal hyperplasia, and orthokeratinization. In contrast, although i.p. administration of 2.5 mg progesterone induced hyperplasia, it caused mucification of surface cells. Relative to ovariectomized control mice, vaginal XO specific activities were significantly elevated within 48 h of estradiol treatment and reached a maximum (285%-330% of control) 24-48 h later. The changes in XO specific activity correlated with the appearance of granular and horny layers in the epithelium, and reflected increases in both tissue XD content and the conversion of XD to XO. Approximately 45% of total XD + XO activity was XO in control mice. In contrast, 80% of total activity was contributed by XO in mice 72 h or 96 h after 17 beta-estradiol treatment. In marked contrast, vaginal XO + XD and XO specific activities, and XO/XD + XO ratios were unaffected in ovariectomized mice treated with progesterone. Collectively, these studies suggest that the expression of XD, and the conversion of XD to XO in vaginal epithelium are differentiation-specific, and characteristic of the orthokeratinization pathway of differentiation.

Animals↗
PubMed1976

Evaluation of vitamin A analogs in modulating epithelial differentiation of 13-day chick embryo metatarsal skin explants.

Seventeen vitamin A compounds were evaluated in organ culture for activity in altering epithelial differentiation of metatarsal skin explants from 13-day-old chick embryos. The explants keratinized in 6 to 8 days and, when cultured in the presence of beta-retinoic acid (RA), inhibition of keratinization occurred and a mucous metaplasia developed. A cyclopentenyl analog of retinoic acid was approximately 10-fold more effective than RA in producing mucous metaplasia. Six other analogs exhibited about the same activity as RA: trimethylmethoxyphenyl analog of retinoic acids, alpha-retinoic acid, 13-cis-retinoic acid, methyl retinoate, ethyl retinoate, and N-ethylretinamide. The following 5 vitamin A compounds were about one-fourth as effective as RA: the trimethylmethoxyphenyl analog of ethylretinamide, the phenyl analog of retinoic acid, the trimethylmethoxyphenyl analog of ethyl retinoate, beta-retinyl acetate, and retinol. The furyl analog of retinoic acid and N,N-diethylretinamide were approximately one-tenth and one-fifteenth less effective than RA in inhibiting keratinization. The analog, alpha-retinyl acetate, was about one-hundredth as effective as RA and the pyridyl analog of retinoic acid (2.5 X 10(-5) M) did not inhibit keratinization. Since the property of altering epithelial differentiation may be a fundamental requirement for the prophylaxis and/or treatment of malignant epithelial lesions, this system can be used to determine whether the new synthetic analogs of vitamin A are active in modulating epithelial differentiation.

Animals↗
PubMed1997

Human oral buccal mucosa reconstructed on dermal substrates: a model for oral epithelial differentiation.

To develop a model for the study of oral epithelial differentiation, we reconstructed artificial buccal mucosa equivalents using keratinocytes and fibroblasts or de-epidermized dermis derived from non-cornifying buccal mucosa. The buccal mucosa equivalents reconstructed in this way showed a morphology closely mimicking that of their in vivo counterparts. There was no formation of horny layers and granular layers. The expression of various differentiation markers such as K13, involucrin and loricrin was consistent with that of the in vivo state, and indicative of the hyperproliferative state. We also demonstrated that the differentiation of oral epithelial cells was influenced by the de-epidermized dermis and subepithelial fibroblasts. The epidermis of buccal mucosa equivalents seemed to be less sensitive to retinoic acid than that of the skin. The effects of calcipotriol on the buccal mucosa equivalent and the skin epidermis were different. These results suggest that the pharmacological effects of retinoic acid and calcipotriol on the buccal mucosa are different from those on the skin. A useful model system for studies of oral keratinocyte differentiation and pharmacological research could be based on these artificial buccal mucosa equivalents.

Calcitriol↗
PubMed2004

Expression of enamel proteins and LEF1 in adamantinomatous craniopharyngioma: evidence for its odontogenic epithelial differentiation.

AIMS: Adamantinomatous craniopharyngioma (ACP) resembles histologically some odontogenic tumours, such as ameloblastoma and calcifying odontogenic cyst. However, there has been no evidence that ACP differentiates also functionally as odontogenic epithelium. The aim of this study was to gain evidence of odontogenic epithelial differentiation in ACP by means of immunohistochemistry. Among normal human tissues, enamel proteins are expressed exclusively in teeth, and lymphoid enhancer factor 1 (LEF1), in co-operation with beta-catenin, play an important role in tooth development. The expression of these proteins is therefore indicative of odontogenic epithelial differentiation. METHODS AND RESULTS: The expression of enamel proteins and LEF1 was examined in 10 adamantinomatous and six papillary craniopharyngiomas. All the ACPs showed a variable degree of enamel protein expression, including amelogenin, enamelin and enamelysin, mainly in ghost cells. LEF1 was also heterogeneously expressed in ACPs; remarkably, its expression pattern was identical to that of nuclear beta-catenin accumulation. In contrast, none of the papillary craniopharyngiomas expressed enamel proteins or LEF1. CONCLUSIONS: These results suggest that ACP consistently shows odontogenic epithelial differentiation. Since ACPs harbour beta-catenin mutation, the inappropriate activation of beta-catenin/LEF1 complex-dependent transcription may play a critical role in ACP tumorigenesis.

Adult↗
PubMedDate not supplied

Malignant fibrous histiocytoma with epithelial differentiation?

A case of recurrent soft part sarcoma with focal areas showing epithelial differentiation in the right thigh in a 78-year-old woman is reported. The primary tumor consisted of myxoid areas and solid areas, in which relatively uniform epithelioid tumor cells were arranged in sheets, whereas pleomorphism and a storiform pattern appeared in the recurrent tumors. Thus this tumor was suspected to be a malignant fibrous histiocytoma. However, further studies showed unexpected ultrastructural and immunohistochemical features. Cytokeratin immunoreactivity and tonofilamentlike structures probably indicated epithelial differentiation of some tumor cells. From the clinical and histological findings, this tumor should be identified as a malignant fibrous histiocytoma with phenotypic expressions of epithelial cell.

Aged↗
PubMed2000

Type 1 vasoactive intestinal peptide receptor expression in PC3/AR cells is evidence of prostate epithelial differentiation.

BACKGROUND: Type 1 vasoactive intestinal peptide receptor (VIP1R) is expressed in many secretory epithelial cells. We investigated VIP1R expression as a marker of prostate secretory epithelial differentiation in normal and malignant prostate tissues and in PC-3 human prostate cancer cells either lacking or expressing a functional androgen receptor. METHODS: VIP1R mRNA in rat prostate was assessed by in situ hybridization. VIP1R mRNA in human prostate tissue was identified by Northern blot hybridization. VIP1R mRNA expression in human prostate cancer cell lines in the presence or absence of androgen was determined by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Human prostate cell lines were treated with VIP, and changes in intracellular cAMP were measured by radioimmunoassay. RESULTS: VIP1R mRNA was expressed only in epithelial cells in normal rat prostate. VIP1R mRNA was present in both normal and malignant human prostate. Well-differentiated LNCaP cells expressed functional VIP receptors, while poorly differentiated PC-3 cells did not. PC-3 cells stably expressing the androgen receptor (PC3/AR) did express functional VIP receptors, but VIP1R mRNA levels were not androgen-regulated. CONCLUSIONS: VIP1R expression indicates epithelial differentiation in normal and malignant prostate. PC3/AR cells and LNCaP cells, both of which express VIP1R and prostate-specific antigen (PSA), are the only prostate cancer cell lines known to express these two markers of prostate epithelial differentiation.

Animals↗
PubMed1999

Neonatal estrogen exposure alters the transforming growth factor-beta signaling system in the developing rat prostate and blocks the transient p21(cip1/waf1) expression associated with epithelial differentiation.

Exposure of male rats to estrogens during the neonatal period retards prostate branching morphogenesis, blocks epithelial differentiation, and predisposes the adult prostate to hyperplasia and dysplasia. The mechanism of neonatal estrogenization is not well understood. The present study evaluated transforming growth factor-beta (TGFbeta) in the neonatally estrogenized ventral prostate to determine whether this paracrine/autocrine factor may in part mediate the effects ofestrogen on the developing prostate gland. Immunocytochemistry using antibodies against active TGFbeta1 and its latency-associated peptide localized this molecule to the periductal smooth muscle cells in the developing prostate. Although neonatal estrogenization increased the accumulation of total and active TGFbeta1 in the smooth muscle layer as early as day 6 of life, it was physically separated from the epithelial ducts by a proliferating layer of fibroblasts surrounding the basement membrane. RT-PCR demonstrated that alterations in TGFbeta1 levels were not due to alterations in TGFbeta1 transcription. TGFbeta2 and TGFbeta3 were primarily immunolocalized to differentiating epithelial cells in developing prostates, and this was markedly dampened between days 10-30 after neonatal estrogen exposure. Immunocytochemistry for TGFbeta signaling components revealed that neonatal estrogenization transiently reduced TGFbeta type I receptor levels in the prostate epithelium, but not in stroma, between days 6-15, whereas there was no effect on TGFbeta type II receptor. Levels of the intracellular signal Smad2 (52 kDa) were detected in epithelial cells but were not altered after estrogenization. To analyze the functional status of the TGFbeta signaling pathway, immunocytochemistry was performed for p21(cip-1/waf-1), a cyclin-dependent kinase inhibitor that is inducible by TGFbeta1 in the prostate. Transient nuclear localization of p21(cip-1/waf-1) was normally observed in epithelial cells between days 6-15 and was associated with entry of cells into a terminal differentiation pathway. Neonatal estrogenization prevented this transient expression of p21(cip-1/waf-1). The present findings demonstrate that the TGFbeta signaling system is perturbed at several levels in the estrogenized prostate, which may in part account for the epithelial cell differentiation blockade as well as the proliferation of periductal fibroblasts in this model.

Animals↗
PubMed1997

Growth factor control of growth and epithelial differentiation in embryonic lungs.

embryonic lung cultures were exposed to either EGF (10 ng/ml) or TGF beta 1 (2 ng/ml) for 72 h, and branching morphogenesis, cell proliferation, and epithelial differentiation (the expression of DSPC synthesis and of surfactant protein C (SP-C) mRNA) were studied. EGF treatment stimulated branching morphogenesis (measured as the number of terminal left lung buds), epithelial differentiation, and cell proliferation. Branching morphogenesis was increased compared to controls after 48 h of culture by 47% and after 72 h by 34% (P < 0.0005). Choline incorporation into DSPC was stimulated by 343% (P = 0.05). SP-C expression was increased sixfold. Thymidine incorporation was stimulated by 49% (P < 0.05). The effects of EGF on thymidine labeling were distributed among epithelial cells of the airway walls and of the branching tips, and also the mesenchyme (P < 0.01 for each area compared to controls). In contrast, TGF beta 1 did not alter the number of terminal left lung buds, inhibited choline incorporation into DSPC by 35% (P < 0.05), and had no effect on thymidine incorporation (87% of control). There was increased thymidine labeling at the branching tips (P < 0.01), while other areas were not different from controls. We conclude that both EGF and TGF beta 1 affect the development of branching morphogenesis and of epithelial differentiation in the embryonic lung.

Animals↗
PubMed1986

Disorganization of stroma alters epithelial differentiation of the glandular stomach in adult mice.

The response of adult epithelium in contact with heterologous mesenchymes/stromas was studied in three digestive organs (forestomach, glandular stomach, and duodenum). After various tissues were implanted beneath the epithelial layer of adult mice, the epithelial differentiation was examined after sacrifice of animals at intervals up to 24 weeks. In the forestomach and duodenum, the epithelial differentiation was not affected at all by the tissue implantation. In the glandular stomach, in contrast, epithelial cells exhibited altered differentiation in which chief and parietal cells disappeared and were replaced by columnar epithelial cells with PAS-positive granules. These epithelial cells often formed immature villi. Such differentiation-altered columnar epithelium (DACE) was induced by implanting any type of tissue and even by sham operation, indicating that it was induced by disorganization of the tissue-implanted stroma. The size of DACE was significantly influenced by the stage of implanted tissue; 14.5-day fetal mesenchyme induced the largest DACE, and was followed by 16.5-day fetal mesenchyme, adult stroma, and sham operation. These results suggest the importance of stromal organization in maintaining epithelial differentiation in the glandular stomach.

Animals↗
PubMed2005

Epithelial differentiation of human adipose tissue-derived adult stem cells.

Adult human stem cells are employed in novel treatments and bio-artificial devices. Recent studies have identified an abundant source of stem cells termed adipose-derived adult stem (ADAS)-cells in the subcutaneous adipose tissue. Under appropriate culture conditions ADAS-cells differentiate to various cell types, including chondrocytes, adipocytes, and smooth muscle cells. Aiming at epithelial differentiation this study investigated the effect of all-trans retinoic acid (ATRA) on human ADAS-cells. ATRA-induced cytokeratin 18 expression in ADAS-cells and nearly abolished vimentin expression as shown by Western blot. In immunofluorescence, the formation of keratin fibers in ATRA-treated ADAS-cells could be observed. The percentage of ADAS-cells being able to undergo epithelial differentiation as quantified by FACS-analysis was above 80%. Inhibition of cell growth by ATRA was shown using DAPI- and MTT-assays. ATRA can differentiate ADAS-cells toward the epithelial lineage. This finding, along with a previously described neural differentiation, shows that ADAS-cells have epithelial potential.

Adipose Tissue↗
PubMed1987

Mouse monoclonal antibodies to human epithelial differentiation antigens expressed on the surface of ovarian carcinoma ascites cells.

Four different human epithelial differentiation antigens (MT179, MW162, MW207, and MX35) have been defined by mouse monoclonal antibodies obtained from mice immunized with either an ovarian carcinoma cell line or fresh ovarian carcinoma cells. In an attempt to identify tissue-specific antigens restricted to ovarian epithelial cells, sections of a benign ovarian cyst were used as the initial target for screening hybridoma supernatants. The distribution of the antigens detected by these monoclonal antibodies was determined on frozen sections of 24 normal tissues and on 103 cultured cell lines of various histological types. In spite of the method used to select these monoclonal antibodies, they all reacted to some degree with normal epithelial cells in tissues other than ovary. All antibodies were unreactive with nonepithelial cells in frozen sections. These antibodies also reacted with frozen sections of most or all fresh ovarian carcinomas and benign ovarian cysts. All antibodies were unreactive with ABH, Lewis blood group-related antigens and appeared to be different in specificity from previously described well-characterized antigens of ovarian carcinoma cells. MW162 was characterized as a high-molecular-weight mucin-like molecule, and the determinant recognized is probably carbohydrate in nature. MW207 was identified as a Mr 37,000 protein. These monoclonal antibodies and 24 other previously derived antibodies that react with epithelial differentiation antigens were tested for reactivity with the surface of fresh ovarian carcinoma ascites cells and for nonreactivity with normal mesothelial cells. This assay was designed to select monoclonal antibodies that might be effective agents for i.p. therapy or radioimmunodetection of human ovarian carcinoma. Five antibodies with the desired specificity were selected; these were the four new antibodies described herein and MH99, which was characterized previously and recognizes a glycoprotein having Mr 38,000 and 29,000 subunits. The degree of heterogeneity of antigen expression on ascites carcinoma cell was dependent on the particular antigen being examined and was related to the biochemical nature of the antigen. In particular, most ABH and Lewis blood group-related antigens showed a striking degree of heterogeneity.

Animals↗