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PubMed1994

Exemption of satellite DNA from demethylation in immortalized differentiated derivatives of F9 mouse embryonal carcinoma cells.

DNA methylation in F9 embryonal carcinoma cells at various stages of retinoic acid-induced differentiation was compared to that in immortalized differentiated derivatives of this cell line. Different repetitive sequences, such as L1 LINE, GAPDH pseudogenes, and major and minor satellite DNA, lost their methylation to similar extents during F9 differentiation into parietal endoderm cells. In the immortalized derivatives 8a and P1, which phenotypically resemble F9 cells at intermediate stages of differentiation, methylation patterns diverged: Methylation of L1 and GAPDH sequences was strongly and moderately diminished, respectively, whereas methylation of satellite DNA was almost as high as that in stem cells. P19 embryonal carcinoma cells and D3 embryonic stem cells possessed methylation patterns similar to those of F9 stem cells. In immortalized cell lines with differentiated phenotypes derived from P19, methylation was diminished uniformly throughout the genome, but the overall level of methylation remained higher than that in terminally differentiated F9 cells. Treatment with the methylation inhibitor deoxyazacytidine halted the proliferation of 8a, P1, and F9 cells and elicited marked changes in morphology. However, markers of differentiation were not induced in F9 cells. The finding that all immortalized differentiated derivatives of embryonal carcinoma cells retained a higher level of DNA methylation--at least in parts of their genomes--than did terminally differentiated cells may indicate a function of demethylation of DNA and of satellite sequences in particular in terminal differentiation of extraembryonic tissues.

Animals↗

PubMed1985

Effects of pulsed electromagnetic field on growth and differentiation of embryonal carcinoma cells.

A murine embryonal carcinoma cell line (F9) was used to examine the effect of a pulsed electromagnetic field on the growth and differentiation of malignant cells. The cells can be induced to differentiate into parietal endodermal cells by treatment with retinoic acid. The pulsed electromagnetic field (1 Gauss and 10 Gauss) promoted the growth of embryonal carcinoma cells in both the presence and absence of retinoic acid. The pulsed electromagnetic field was also found to inhibit retinoic acid-induced differentiation, when the degree of differentiation was based on morphological criteria or on the production of plasminogen activator.

Animals↗

PubMed1992

Expression of Pax-3- and neuroectoderm-inducing activities during differentiation of P19 embryonal carcinoma cells.

A P19 embryonal carcinoma stem cell line carrying an insertion of the E. coli LacZ gene in an endogenous copy of the Pax-3 gene was identified. Expression of the Pax-3/LacZ fusion gene in neuroectodermal and mesodermal lineages following induction of differentiation by chemical treatments (retinoic acid and dimethylsulfoxide) was characterized using this line and is consistent with the previous localization of Pax-3 expression in the embryo to mitotically active cells of the dorsal neuroectoderm and the adjacent segmented dermomyotome. Pax-3/LacZ marked stem cells were also utilized as target cells in mixing experiments with unmarked P19 cells that had been differentiated by pretreatment with chemical inducers. Induction of beta-galactosidase and neuroectodermal markers in the target cells demonstrates that: (1) some differentiated P19 cell derivatives transiently express endogenous Pax-3- and neuroectoderm-inducing activities, (2) undifferentiated target stem cells respond to these activities even in the presence of leukemia inhibitory factor and (3) the endogenous activities can be distinguished from, and are more potent than, retinoic acid treatment in inducing neuroectoderm. These observations demonstrate that P19 embryonal carcinoma cells provide a useful in vitro system for analysis of the cellular interactions responsible for neuroectoderm induction in mammals.

Animals↗

PubMed1990

Cell density and cell cycle effects on retinoic acid-induced embryonal carcinoma cell differentiation.

P19 embryonal carcinoma cells can be induced to differentiate with a pulse of only 4 hr in retinoic acid (RA). The efficiency of RA-induced differentiation is independent of the position of P19 cells in the cell cycle but is critically dependent on the ratio between the number of cells and the number of moles of RA in the culture medium. P19 cultures at lower cell density are more efficiently induced to differentiate than cultures containing cells at higher cell densities. This effect is not mediated by cell-to-cell contact but may be related to the rapid metabolism of RA by the cells. Individual clones of differentiating P19 cells can develop into at least three different cell types suggesting that each cell in the population of embryonal carcinoma cells retains pluripotency.

Antigens, Differentiation↗

PubMed1987

Amplification and enhanced expression of the c-Ki-ras2 protooncogene in human embryonal carcinomas.

Two cell lines of human embryonal carcinoma, Tera-1 and Tera-2, have been found to exhibit a 4- to 6-fold amplification of protooncogene c-Ki-ras2. The polyadenylic acid selected RNA also showed 8-fold or greater enhancement, showing marked elevation in the level of two major mRNAs, 5.7 and 4.0 kilobases, and two additional minor mRNAs, 2.3 and 1.2 kilobases, as compared with those of a normal human embryonic fibroblast cell line, MRC-5. More than one-half of the number of tumor samples obtained from metastatic human embryonal carcinomas also showed c-Ki-ras2 gene amplification and enhanced mRNA expression. However, the c-Ki-ras2 gene amplification did not always lead to enhanced mRNA expression, and some embryonal carcinomas showed mRNA overexpression without apparent c-Ki-ras2 gene amplification. These results suggest that human embryonal carcinomas may have c-Ki-ras2 amplification and/or overexpression before in vitro culture. Among various chromosomal changes observed in Tera-1 and Tera-2 cells, there were anomalies in chromosome 12 in which c-Ki-ras2 is located although these karyological changes alone could not account for the amplification observed. It is suggested that the genomic instability and active DNA replication during the early developmental period may give rise to changes involving c-Ki-ras2 which may contribute to oncogenic processes.

Aneuploidy↗

PubMed1999

Cardiac and skeletal muscle development in P19 embryonal carcinoma cells.

Mouse P19 embryonal carcinoma cells are pluripotent stem cells that can be maintained in culture in an undifferentiated state or can be induced to differentiate in vitro into multiple cell types. P19 cells aggregated in the presence of dimethylsulfoxide differentiate into spontaneously beating cardiomyocytes and bipolar skeletal myocytes that exhibit the biochemical and physiologic properties of their embryonic equivalents. P19 cells can be readily manipulated genetically, resulting in the loss or over-expression of a gene of interest. Because of this versatility, the P19 system is suited for examining the molecular mechanisms controlling the developmental decisions of stem cells differentiating into the skeletal or cardiac muscle lineage.

Animals↗

PubMed1985

Derivation of a nondifferentiating clone from multipotential PSA1 embryonal carcinoma cells.

The ability of PSA1 embryonal carcinoma cells to differentiate when grown as clones on a monolayer of feeder cells was assessed using morphological criteria. The first appearance of a differentiated phenotype within a clone occurred at different times for individual clones after 10 days of culture, this being apparently unrelated to clone size or cell density. Those clones which showed no morphological evidence of differentiation after several weeks (about 5% of the clones observed) were selected and recloned with the aim of finding variant lines which were stably deficient in their differentiating ability. Undifferentiated clones - identified and selected after about 3 weeks of growth - were of three different types after recloning: those similar to control cultures of PSA1, those having delayed and reduced differentiation frequency, and those having variable frequencies of differentiation in replicate reclonings. The isolation of a variant with a more complete differentiation deficiency was accomplished by selecting ten nondifferentiating clones growing isolated in individual culture wells after 5 weeks of culture. One of these, T2H9, proved to be a stable, differentiation-deficient variant subline with less than 3% of its clones showing any morphological evidence of differentiation in five repeated reclonings. It was also determined that the frequency of undifferentiated clones in embryonal carcinoma cultures increased from 0.3% to 54% after 11 months of in vitro aging, i.e., approximately 200 cell doublings. The isolation of clonal embryonal carcinoma cell derivatives which are stable, heritable differentiation variants provides resources for somatic-cell genetic analysis of stem-cell pluripotency.

Animals↗

PubMed2002

Expression profiling of lineage differentiation in pluripotential human embryonal carcinoma cells.

Pluripotential human embryonal carcinoma (EC) cell linesundergo differentiation programs resembling those occurring in embryonal stem cells during development. Expression profiling was performed during the terminal differentiation of the EC cell line, NTera2/Clone D1 by all-trans-retinoic acid. Time-response analysis via clustering of >12,000 human transcripts revealed distinct stages in the transition from an EC cell to neuronal progenitor cells expressing patterning markers compatible with posterior hindbrain fates followed by the appearance of immature postmitotic neurons with an evolving synaptic apparatus. Global analysis of gene expression allows monitoring cell fate and differentiation of EC cells in vitro and may provide insight into human embryonal stem cell development.

Antineoplastic Agents↗

PubMed1982

Coordinate expression of parietal endodermal functions in hybrids of embryonal carcinoma and endodermal cells.

A derivative, FOT5, of the F9 murine embryonal carcinoma cell line which is resistant to ouabain and thioguanine was fused with a near diploid parietal endodermal cell line, PFHR9, Hybrid clones (ENEC1 to ENEC5) were isolated in HAT Medium containing ouabain at a frequency of approximately 2 x 10(-4). The DNA contents and chromosome number of the ENEC hybrids were approximately the sum of those of the parents. Five hybrid cell lines examined in detail expressed the following parietal endodermal functions: plasminogen activator activity, basement membrane proteins, and endodermal cytoskeletal proteins. Embryonal carcinoma characteristic functions (tumorigenicity, a stage specific embryonic antigen, and high alkaline phosphatase activity) were extinguished in the hybrids. No hybrid clones with embryonal carcinoma morphology were observed among 1,358 hybrid clones examined. Hybrids, propagated for over 100 generations, continued to express endodermal functions and not embryonal carcinoma functions. The coordinate expression of endodermal functions and the extinction of embryonal carcinoma functions in the ENEC hybrids suggest that the parietal endodermal cells contain diffusible activities which extinguish embryonal carcinoma functions and possibly cause the embryonal carcinoma genome to express parietal endodermal characteristics.

Alkaline Phosphatase↗

PubMed1984

Expression of embryonic and MHC antigens in heterokaryons of murine embryonal carcinoma and human melanoma cells.

Mouse embryonal carcinoma cells were fused with human melanoma cells or with cytoplasts of these cells. The expression of embryonic and major histocompatibility complex (MHC) antigens was studied in single heterokaryons and cybrids in the population after fusion. Recognition of heterokaryons by differential staining of mouse and human nuclei was combined with indirect immunofluorescent staining of specific membrane antigens. Complete suppression of embryonic antigen expression was found in heterokaryons within 2 days after fusion. Cybrids, formed by fusion of embryonal carcinoma cells with melanoma cytoplasts, showed a transient decrease in the expression of embryonic antigens. The expression of human MHC antigens, both class I (HLA-A, B, C) and class II (HLA-DR), was only slightly influenced in heterokaryons. No activation of mouse MHC antigens was found. The results indicate that melanoma cells contain trans-acting factors exerting a negative control on the expression of embryonic antigens. In contrast the continued expression of human MHC antigens in heterokaryons suggests that embryonal carcinoma cells either are devoid of or contain only a very limited amount of trans-acting factors controlling the expression of MHC antigens.

Animals↗

PubMed1982

A reproducible colonial morphology formed by individual pluripotent embryonal carcinoma cells in culture and selection of variants.

Embryonal carcinoma cells are stem cells equivalent to those of the early embryo which can be grown in vitro and which under certain conditions can differentiate into many cell types. Events in this differentiation process are numerous and complex, thus a system for the analysis of clonal differentiation is essential. In this paper I report that individual pluripotent embryonal carcinoma cells can each give rise to colonies, in the absence of a feeder layer but in the presence of beta-mercaptoethanol, that show a distinctive and reproducible gross morphology. Embryonal carcinoma cell lines can be derived from the stem cells in these colonies. Furthermore, variant cell lines can be derived from those colonies showing an altered gross morphology. These lines when cloned as above give rise to colonies showing a gross colonial morphology different to that of wild-type. These variant lines have been shown to be embryonal carcinoma cell lines. These findings indicate that genetic and cell lineage analysis of embryonal carcinoma cell differentiation might be possible.

Animals↗

PubMed1984

The embryonal carcinoma of the parotid gland. A rare example of an embryonal tumor.

Embryonal tumors are a neoplastic proliferation of cells of organ rudiments. Morphologically, these tumors are similar to the developmental stages of these organ rudiments. Embryonal tumors of the salivary glands have not been previously described. In the salivary gland register, reviewing the years 1965-1982 (n = 8043), we diagnosed 2,878 tumors of the salivary glands, of these 73 were tumors in children. One case was a malignant epithelial tumor in a 12-year-old boy, which showed the criteria of an embryonal carcinoma in light- and electron microscopy. The tumor revealed solid undifferentiated areas, epidermoid structures with keratinization and acinic structures. Immunhistochemically, the better differentiated epidermoid cells reacted positively with anti-CEA and anti-keratin, the acinic cells were positive with anti-amylase. The ultrastructure was characterized by primitive ductular epithelial cells and acinic cells with their typical morphological features. The embryonal carcinoma has to be distinguished from undifferentiated carcinomas of the salivary glands, which consist of primitive ductular structures only. The failure to detect other tumor markers (lactoferrin, tissue polypeptid antigen) indicates that poorly and well differentiated areas can exist simultaneously in embryonal carcinomas.

Child↗

PubMed2005

Role for up-regulated ganglioside biosynthesis and association of Src family kinases with microdomains in retinoic acid-induced differentiation of F9 embryonal carcinoma cells.

Mouse F9 embryonal carcinoma cells have been widely used as a model for studying the mechanism of embryonic differentiation, because they are similar to the inner cell mass of early mouse embryos and can differentiate into primitive endoderm (PrE) following retinoic acid (RA) treatment. During F9 cell differentiation, the carbohydrate chains of glycoproteins and their corresponding glycosyltransferases are known to undergo rapid changes. However, there have been no corresponding reports on the expression of gangliosides. We have developed a custom cDNA array that is highly sensitive for the genes responsible for sphingolipid (SL) biosynthesis and metabolism. Using this, we found that, of the 28 selected genes, 26 exhibited increased expression during F9 differentiation into PrE. Although neutral glycosphingolipids (GSLs) were expressed at similar levels before and after differentiation, a greater than 20-fold increase in total ganglioside content was evident in PrE. Glucosylceramide synthase inhibitors (d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol [d-PDMP] and its analog) depleted gangliosides and this resulted in delayed expression of Disabled-2 (Dab-2), suggesting the involvement of gangliosides in F9 cell differentiation. Disruption of cholesterol-enriched membrane microdomains by methyl-beta-cyclodextrin (MbetaCD) also delayed differentiation. Both MbetaCD and d-PDMP blocked the accumulation of Src family kinases (SFKs) to microdomains. However, d-PDMP did not block flotillin accumulation, yet MbetaCD did. Additionally, confocal laser microscopy revealed the formation of distinct functional microdomains integrating SFKs with gangliosides and cholesterol during PrE differentiation. Thus, we demonstrate the outstanding up-regulation of ganglioside biosynthesis and its importance in the formation of distinct microdomains incorporating SFKs with gangliosides during RA-induced differentiation of F9 cells.

Animals↗

PubMed1982

[Clinicopathological study of ovarian embryonal carcinoma (Higuchi-Kato)].

Prognoses of embryonal carcinoma (Higuchi-Kato) of the ovary are extremely poor, and new modalities of the treatment are desired. In the present paper, we describe a clinicopathological study of ovarian embryonal carcinoma (Higuchi-Kato) with special references to the treatment and prognosis. 1) The patients examined were 20 in all, 8 belonging to embryonal carcinoma (Higuchi-Kato) Group A, 6 to the Group B, and 6 to the Group C. 2) The median age of patients was 20 years old. 3) The development of tumor was unilateral in all patients but one unsettled. 4) One patient was pregnant when the tumor was discovered. 5) The prognoses of patients in Group C were better than those of others. 6) Serum AFP is a good tumor marker, correlating well with the clinical courses of the patients. 7) To maintain ovarian function of young patients in stage Ia, unilateral adnexectomy with contralateral wedge resection and postoperative intensive chemotherapy are considered to be a choice of treatment method.

Adolescent↗

PubMed1997

Differential expression of gap junctions in neurons and astrocytes derived from P19 embryonal carcinoma cells.

The P19 embryonal carcinoma cell line represents a pluripotential stem cell that can differentiate along the neural or muscle cell lineage when exposed to different environments. Exposure to retinoic acid induces P19 cells to differentiate into neurons and astrocytes that express similar developmental markers as their embryonic counterparts. We examined the expression of gap junction genes during differentiation of these stem cells into neurons and astrocytes. Untreated P19 cells express at least two gap junction proteins, connexins 26 and 43. Connexin32 could not be detected in these cells. Treatment for 96 hr with 0.3 mM retinoic acid induced the P19 cells to differentiate first into neurons followed by astrocytes. Retinoic acid produced a decrease in connexin43 mRNA, protein, and functional gap junctions. Connexin26 message was not affected by retinoic acid treatment. The neurons that developed consisted of small round cell bodies extending two to three neurites and expressed MAP2. Connexin26 was detected at sites of cell-cell and cell-neurite contact within 3 days following differentiation with retinoic acid. The astrocytes were examined for production of their intermediate filament marker, glial fibrillary acidic protein (GFAP). GFAP was first detected at 8 days by Western blotting. In culture, astrocytes co-expressed GFAP and connexin43 similar to primary cultures of mouse brain astrocytes. These results suggest that differentiation of neurons and glial cells involves specific connexin expression in each cell type. The P19 cell line will provide a valuable model with which to examine the role gap junctions play during differentiation events of developing neurons and astrocytes.

Animals↗

PubMed1987

Experimental metastasis of mouse embryonal carcinoma cell lines to specific locations.

Embryonal carcinoma cell lines produced tumors in highly specific and unusual sites when injected into mice. The pattern that developed when cells were injected into the left ventricle of the heart involved target organs related either to specific nerve patterns or neuronal outgrowth factors, or to pathways of primordial germ cell migration. Major sites included the ovary, testis, adrenal, iris, whiskers, and male submaxillary gland. Neither local growth responses, determined by direct injection of tumor cells into different organ parenchyma, nor initial attachments, observed upon injection of radiolabeled cells, appeared to sufficiently account for the specificity of tumor metastases occurring after arterial injection. However, tissue from uninjected target sites, but not other tissues, stimulated the in vitro migration of embryonal carcinoma cells. Conditioned medium from only target tissues had a similar effect. These results suggest that the specificity of this tumor pattern may depend on migration responses that are significant in the localization of embryonic germ and neural cells. The specific metastatic pattern observed following i.p. injection of embryonal carcinoma cells, involving only the ovary, appeared to require an additional component of high adhesivity to the target organ.

Animals↗

PubMed1980

Flow cytoenzymology of the early differentiation of mouse embryonal carcinoma cells.

Dual parameter flow cytoenzymology was used to detect biochemical differentiation of embryonal carcinoma cells, the undifferentiated, multipotent stem cells of teratocarcinomas. With the use of fluorogenic substrates, two enzyme systems, alkaline phosphatase (EC 3.1.3.1.) and carboxyl esterase (EC 3.1.1.), were studied. Embryonal carcinoma cells passaged in vitro for several years retained high alkaline phosphatase activities similar to those of embryonal carcinoma cells in embryoid bodies grown in vivo. Similar to the embryonal carcinoma cells in vivo, the in vitro embryonal carcinoma cells were capable of giving rise to progeny with greatly decreased levels of alkaline phosphatase. The embryonal carcinoma cell alkaline phosphatase was inhibited by 1-p-bromotetramisole, suggesting a relationship between this enzyme and somatic, nonintestinal alkaline phosphatase isoenzymes. Determinations of esterase activities in viable teratocarcinoma cells showed that prior to any evidence of morphologic differentiation, the embryonal carcinoma cells are quite heterogeneous with regard to esterase activities.

Alkaline Phosphatase↗

PubMed1980

A cell surface glycoprotein involved in the compaction of embryonal carcinoma cells and cleavage stage embryos.

Fab fragments of rabbit anti-embryonal carcinoma cells IgG dramatically perturb cell-cell interactions between embryonal carcinoma cells and between early mouse embryo blastomeres. These antibodies prevent compaction of preimplantation embryos (or trigger their decompaction) and have similar effects on embryonal carcinoma cells. They probably act through the masking of specific molecules (Fab targets) involved in the mechanisms of recognition between cells during compaction. Fab target molecules have been extracted from embryonal carcinoma cell membranes and purified using their property to inhibit the effects mediated by anti-embryonal carcinoma Fab. The solubilization of the Fab targets could be achieved using both detergent extraction and trypsin treatment of membranes. In the latter case, a glycoprotein of 84,000 daltons could be purified which has all the properties expected from the Fab target and accounts for most of the Fab-inhibiting activity of embryonal carcinoma cell membranes.

Animals↗