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PubMed1979

Junctional modulation in mouse embryonal carcinoma cells by Fab fragments of rabbit anti-embryonal carcinoma cell serum.

Mouse embryonal carcinoma PCC4 cells are connected by extensive gap and tight junctions. When the cells are incubated in a medium containing Fab fragments against embryonal carcinoma F9 cells, they round up and a process of junctional removal is initiated. In particular, gap junctions are internalized and after 30 hr of incubation with the anti-F9 Fab fragments both tight and gap junctions are no longer present at the cell surface; however, the cells are still in contact by means of small attachment sites.

Animals↗

PubMed1988

Characterization of neurotransmitter phenotype during neuronal differentiation of embryonal carcinoma cells.

Embryonal carcinoma cells are useful in the study of embryogenesis and development, and their differentiation into neurons serves as a model of neuronal development. Retinoic acid was used to differentiate P19S18O1A1 embryonal carcinoma cells into neuronal, glial, and fibroblast-like cells and the phenotype of the neuronal population was examined. Neuron-specific enolase was present in the neuronal cells, suggesting that these neurons had reached some degree of maturity. A population (approximately 70%) of the neurons showed positive immunocytochemistry for tyrosine hydroxylase, dopamine beta-hydroxylase and phenylethanolamine N-methyltransferase, three enzymes in the pathway of catecholamine synthesis. Therefore a population of the neurons appeared to be adrenergic. These neurons also showed a low level of histofluorescence for endogenous catecholamines and exhibited an exogenous catecholamine reuptake system. In order to determine the phenotype of other neuron-like cells found to be negative for the adrenergic properties examined, immunocytochemistry for neuropeptides and neurotransmitters known to coexist within central neurons was performed. Serotonin, vasoactive intestinal peptide, glutamic acid decarboxylase, and choline acetyltransferase were all absent from retinoic acid-treated P19S18O1A1 neuronal cultures. These studies, along with those that compare the effects of retinoic acid and other growth modulators on neuronal differentiation of embryonal carcinoma cells, should aid in the understanding of neuronal induction and development in vivo.

Animals↗

PubMed1994

Expression of retinoid X receptors in P19 embryonal carcinoma cells and embryonic stem cells.

The pluripotent mouse embryonal carcinoma cell line P19 provides an excellent model system to study the mechanisms by which retinoic acid (RA) exerts its biological effects. When aggregated and exposed to low concentrations of RA, P19 cells differentiate into neuron- and glial-like cells. The diverse biological effects of RA are mediated by two families of receptors localized in the cell nucleus, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Each family consists of three members designated alpha, beta and gamma. While the patterns of expression of the RARs have been studied in P19 cells, similar data for the RXRs have not been available. We demonstrate here that these receptors are expressed in P19 and are regulated during RA-induced differentiation. We also show that pluripotent mouse embryonic stem cells express the RXRs as well.

Animals↗

PubMed1986

Negative regulation of early polyomavirus expression in mouse embryonal carcinoma cells.

Embryonal carcinoma cells are resistant to infection by polyomavirus (Py). We showed that this block was partially removed by inhibiting protein synthesis temporarily. The block was also partially removed when Py was coinfected with simian virus 40. Cycloheximide treatment of cells infected with Py mutants able to grow on PCC4 embryonal carcinoma cells led to 3- to 10-fold increases in the production of T-antigen-positive cells. At 31 degrees C, Py T-antigen expression was enhanced when the cells were treated with cycloheximide. We suggest that a negative labile regulatory protein(s) is synthesized in PCC4 cells, preventing the initiation of early Py transcription by binding to the noncoding sequence, especially the enhancer element B and perhaps also element A, and that the Py mutants retained a binding site(s).

Animals↗

PubMed1998

Up-regulated expression of murine Mcl1/EAT, a bcl-2 related gene, in the early stage of differentiation of murine embryonal carcinoma cells and embryonic stem cells.

We have cloned a murine homologue of the human Mcl1/EAT gene, a Bcl-2 related gene. Sequence analysis revealed that murine Mcl1/EAT (mMcl1/EAT) has three Bcl-2 homology domains, two PEST sequences, and immediate response boxes (IRB). The presence of IRB indicates that mMcl1/EAT is an immediate-early gene. mMcl1/EAT increases dramatically with exposure to retinoic acid in murine embryonal carcinoma cell lines (F9 and PCC3) as well as embryonic stem cells, both of which are models of early embryogenesis.

Amino Acid Sequence↗

PubMed1988

Analysis of cell-differentiation lineage in human teratomas using new monoclonal antibodies to cytostructural antigens of embryonal carcinoma cells.

Human embryonal carcinoma cells sometimes display the developmental potential of early embryonic stem cells. While available data do not clearly identify a counterpart of these tumor cells in normal development, previous comparisons of human embryonal carcinoma and yolk sac carcinomas indicated that these cell types are closely related, and suggested that embryonal carcinoma cells might resemble the progenitors of extraembryonic endoderm. To analyse further cell-differentiation lineage in these tumors, we produced monoclonal antibodies to cytostructurally associated antigens of human embryonal carcinoma cells. Spleen cells from mice immunized with a detergent-insoluble extract of cultured human embryonal carcinoma cells were fused to NS-1 myeloma cells, and hybridoma supernatants were screened by indirect immunofluorescence on the immunizing cell line, then on a panel of cell lines derived from human embryonal carcinomas, yolk sac carcinomas, and a range of neoplastic and normal tissues. Monoclonal antibody GCTM-1 stained the nuclei of all human cells tested and served as a positive control; this antibody immunoprecipitated proteins of 85 and 66 k Da from human embryonal carcinoma cells. GCTM-2 recognized an epitope on a 200-k Da extracellular protein present on the surface of embryonal carcinoma cells, and stained the surface of visceral yolk sac-type carcinoma and colorectal carcinoma cells as well. Enzymatic analysis of carbohydrate residues on the GCTM-2 antigen revealed that it was a keratan sulphate proteoglycan, and suggested that the epitope recognized by the antibody lies on the core protein. In immunoblots, antibody GCTM-3 bound to a 57-k Da cytoskeletal protein expressed in human embryonal carcinoma. This antibody decorated filamentous arrays in cell lines from human embryonal carcinoma, visceral yolk sac carcinoma, parietal yolk sac carcinoma (endodermal sinus tumour), and adenocarcinoma and large cell carcinoma of the lung. Antibody GCTM-4 recognized a determinant present on a 69-k Da polypeptide, associated with a component of the lysosomal compartment, which was expressed in embryonal carcinoma cells, but no other cell type tested. The results with this antibody panel thus allow distinction between human embryonal carcinoma and yolk sac carcinoma, but provide further evidence of a close relationship between these cell types.

Animals↗

PubMed1991

Characterization of a tyrosine kinase signaling pathway in undifferentiated P19 embryonal carcinoma cells.

Embryonal carcinoma (EC) cells are the malignant stem cells of teratocarcinoma and have the capacity to proliferate in the absence of serum growth factors. As yet no receptor protein tyrosine kinases have been identified on undifferentiated EC cells and as a consequence tyrosine kinase signaling pathways could not be studied in these cells. We have used stably transfected P19 embryonal carcinoma cells expressing a well-characterized receptor protein tyrosine kinase, the human epidermal growth factor receptor (hEGF-R) to study protein tyrosine kinase signaling mechanisms in undifferentiated EC cells. Here we report that the ectopically expressed hEGF-R contains EGF-inducible autophosphorylation activity and is rapidly internalized and degraded upon ligand binding. In addition, the exogenous hEGF-R confers EGF-responsiveness to these cells in that inositol phosphate formation and cytoplasmic-free Ca2+ concentration are enhanced in response to EGF. Furthermore, the Na+/H+ exchanger is activated in response to EGF, leading to a sustained rise in intracellular pH. Our results show that undifferentiated P19 EC cells contain the necessary components of protein tyrosine kinase signal transduction machinery.

Adenosine Triphosphate↗

PubMed2002

Intratubular embryonal carcinoma.

Although intratubular embryonal carcinoma has been described adjacent to invasive embryonal carcinoma, to our knowledge it has not been reported as an isolated finding. We present in this report the histologic and immunohistochemical findings of 2 cases of intratubular embryonal carcinoma. One case was exclusively intratubular embryonal carcinoma without an invasive component in the same testis. A malignant mixed germ cell tumor in the contralateral testis had been previously excised. The second case is predominantly composed of intratubular embryonal carcinoma adjacent to a malignant mixed germ cell tumor. In one case, the intratubular embryonal carcinoma was immunoreactive for CD30, AE1/AE3, cytokeratin 7 focally, and p53. It was negative for cytokeratin 20, p21, and alpha-fetoprotein. These findings are strongly supportive of the opinion that intratubular embryonal carcinoma is the precursor of invasive embryonal carcinoma.

Adult↗

PubMed1986

Murine lymphocyte and embryonal carcinoma cell surface antigens recognised by rabbit anti-murine embryonal carcinoma serum.

Some recent studies have suggested that murine embryonal carcinoma (EC) cells which lack classical H-2 molecules must express some novel class-I-MHC (major histocompatibility complex) type antigens. We have investigated whether rabbit anti-EC sera may recognize such components. Molecules of 40 and 48 kd were immunoprecipitated from EC cells and lymphocytes. The possibility that these molecules may be coded for by genes in the Qa-Tla locus which contains many MHC class-I genes or pseudogenes was investigated. The 40 and 48 kd molecules were not associated with beta 2-microglobulin on EC cells, nor with each other or other molecules through S-S bonds, although they appeared to have intradisulphide structures. Peptide map analysis suggested that the lymphocyte 40 and 48 kd molecules were related to the EC cell 40 and 48 kd molecules. However, these molecules were different from H-2, Ia or Qa-2 molecules from the same mouse strain.

Animals↗

PubMed1976

Embryonal carcinoma of the ovary: a clinicopathologic entity distinct from endodermal sinus tumor resembling embryonal carcinoma of the adult testis.

The clinical and pathologic features of 15 examples of a hitherto undescribed germ cell tumor of the ovary are delineated. This tumor resembles the embryonal carcinoma of the adult testis and may be distinguished from the endodermal sinus tumor on the basis of its histologic and immunohistochemical characteristics. An indirect immunoperoxidase method for the localization of human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) was done on formalin-fixed paraffin-embedded tissue from 10 neoplasms; HCG was present in all 10 neoplasms, and AFP was found in seven. HCG was indentified only in cells resembling syncytiotrophoblast, whereas AFP was present only in mononuclear embryonal cells, indicating that the two protein antigens were localized in different cell types. Abnormal hormonal manifestations, consisting of precocious puberty, irregular bleeding, amenorrhea, or hirsutism, were present in nine (60%) of the patients. The actuarial survival for the entire group was 39%; for those with stage I tumors, 50%. We are proposing the term "embryonal carcinoma" for this neoplasm in order to distinuish it from the more common endodermal sinus tumor of the ovary and to emphasize the histologic similarity to embryonal carcinoma of the adult testis.

Adolescent↗

PubMed2004

Nuclear cloning of embryonal carcinoma cells.

Embryonal carcinoma (EC) cells have served as a model to study the relationship between cancer and cellular differentiation given their potential to produce tumors and, to varying degrees, participate in embryonic development. Here, nuclear transplantation was used to assess the extent to which the tumorigenic and developmental potential of EC cells is governed by epigenetic as opposed to genetic alterations. Nuclei from three independent mouse EC cell lines (F9, P19, and METT-1) with differing developmental and tumorigenic potentials all were able to direct early embryo development, producing morphologically normal blastocysts that gave rise to nuclear transfer (NT)-derived embryonic stem (ES) cell lines at a high efficiency. However, when tested for tumor or chimera formation, the resulting NT ES cells displayed an identical potential as their respective donor EC cells, in stark contrast to previously reported NT ES cells derived from transfer of untransformed cells. Consistent with this finding, comparative genomic hybridization identified previously undescribed genetic lesions in the EC cell lines. Therefore, nonreprogrammable genetic modifications within EC nuclei define the developmental and tumorigenic potential of resulting NT ES cells. Our findings support the notion that cancer results from the deregulation of stem cells and further suggest that the genetics of ECs will reveal genes involved in stem cell self-renewal and pluripotency.

Animals↗

PubMed1980

H1 histone and nucleosome repeat length alterations associated with the in vitro differentiation of murine embryonal carcinoma cells to extra-embryonic endoderm.

The histone compositions and average distance between nucleosomes have been determined for F9.22 and PSA1 murine embryonal carcinoma cell lines, for primary extra-embryonic endoderm derived from the in vitro differentiation of PSA1 embryonal carcinoma cells, and for two long-term extra-embryonic endodermal cell lines. A change in the relative proportions of two forms of the H1 histones (H1A and H1B) was found to correlate with the extra-embryonic endodermal differentiated phenotype. The embryonal carcinoma cells had a ratio of H1A/H1B of 1.49 or greater. In contrast, extra-embryonic endoderm from either cell lines or freshly isolated from differentiating embryonal carcinoma cell cultures had a ratio of H1A/H1B of less than 0.9. Partial peptide mapping of gel purified H1A and H1B suggest the two proteins differ in primary structure. The nucleosome repeat length of the embryonal carcinoma cell lines was 196 bp of DNA. Primary extra-embryonic endoderm was found to have a value of 205 bp, but the long-term extra-embryonic endodermal cell lines had an average nucleosome repeat length of 187 bp. Since both freshly isolated primary endoderm and the long-term endodermal cell lines express differentiated functions (basement membrane glycoproteins and plasminogen activator activity), there appears to be no simple correlation between the nucleosome repeat length and the expression of these differentiated functions.

Animals↗

PubMed1995

The function of inducible promoter systems in F9 embryonal carcinoma cells.

Embryonal carcinoma (EC) cells represent an important model for studying the regulation of cellular differentiation during embryonic development and tumor formation. The differentiation of EC cells is associated with changes in the expression of a number of cellular genes, some of which have been implicated directly in the regulation of differentiation. To facilitate further studies of the possible roles of cellular gene products during the differentiation of EC cells, we have used transient transfection assays to compare the function of three promoter systems that direct the conditional expression of recombinant gene constructs. One system employs the mouse mammary tumor virus (MMTV) promoter, which is induced by glucocorticoid hormones. The other two systems are based on chimeric transactivator proteins consisting of the bacterial lac repressor or tet repressor, respectively, fused with a viral transactivation domain. The chimeric proteins function in mammalian cells as sequence-specific activators of transcription that are regulated by either lactose analogs or tetracycline. Transient transfections of mouse F9 EC cells and their differentiated cells with an MMTV promoter-reporter gene construct and a second plasmid encoding the rat glucocorticoid receptor resulted in a dramatic induction of reporter gene expression by glucocorticoid hormone of approximately 200-fold. The conditional expression system based on the tetracycline-responsive transactivator exhibited a similar range of reporter gene expression in response to tetracycline. In contrast, the system based on the lac repressor exhibited a much more limited range of conditional reporter gene expression in our studies. These findings and others discussed in this report suggest that the tetracycline-responsive promoter system may be useful for the conditional expression of recombinant gene constructs in F9 EC cells. Furthermore, data are presented indicating that the human beta-actin promoter should be suitable for stable expression of conditional transactivators, such as the tetracycline-responsive transactivator, in F9 cells before and after differentiation.

Actins↗

PubMed1991

Changes in surface glycoconjugates in adhesion-defective variants of P19 embryonal carcinoma cells.

Embryonal carcinoma cells defective in their ability to adhere to tissue culture dishes were isolated from mutagenized P19X1 and P19S1801A1 cells. Three independently isolated variants were analyzed for their morphology, surface properties and ability to differentiate in vitro. Two of the mutant cell lines expressed similar amounts of stage-specific embryonic antigens TEC-1, TEC-4 and Thy-1 as parental cells, whereas all three showed significant reduction in the expression of uvomorulin as determined by a direct radioantibody binding assay. Variant cells exhibited a decrease in their ability to aggregate in media with or without CA2+ and were unable to form compact aggregates when cultured for two days in complete culture media. In the presence of retinoic acid variant cells formed aggregates which exhibited significantly lower frequency neuron formation after transfer to tissue culture dishes. The combined data indicate that the adhesion-defective phenotype of P19-derived cells is in part the result of a reduced surface expression of uvomorulin.

Animals↗

PubMed1989

Regulation and patterns of endogenous and exogenous gene expression during differentiation of embryonal carcinoma cells.

Embryonal carcinoma (EC) cells offer an interesting model system for evaluating differentiation because the cells are pluripotent, thus resembling germ cells and embryonic stem cells, and because a number of agents have been defined that are capable of promoting the differentiation of these cells. This chapter examines how EC cells might be triggered to differentiate, with emphasis on retinoic acid because this compound is a potent, naturally occurring inducer that has been studied extensively in this system. The nature of alterations in gene expression during EC cell differentiation is reviewed from the perspective of evaluating whether these changes are likely to be responsible for, or a result of, the differentiation event. Finally, we consider in molecular terms why EC cells, but not their differentiated derivatives, are refractory to the expression of many viral genomes following infection. Based upon these studies, we propose that fundamental changes in gene expression that are observed when differentiation is triggered in EC cells are likely to be due to the disappearance or neutralization of strong repressor elements.

Cell Differentiation↗

PubMed1987

Nerve growth factor stimulation of mouse embryonal carcinoma cell migration.

Embryonal carcinoma cells localize to a specific array of target tissues including the male submaxillary gland following intracardiac injection. These target tissues or conditioned medium derived from them have been shown to stimulate the in vitro migration of embryonal carcinoma cells. Here we show that in vitro migration of mouse embryonal carcinoma cells is induced by the simultaneous presence of two different components. One of these is a specific requirement for a fibronectin substrate. The other component is present in male submaxillary conditioned medium and may be nerve growth factor (NGF). Migration of embryonal carcinoma cells on a fibronectin substrate could be induced by purified NGF, but not epidermal growth factor, and submaxillary conditioned medium contained very high levels of nerve outgrowth activity which could be blocked by anti-NGF antibody. Only the high molecular weight 7S NGF complex was active in inducing migration, while the low molecular weight 2.5S NGF inhibited migration. Neither type of NGF or submaxillary conditioned medium stimulated the in vitro growth of embryonal carcinoma cells. 7S NGF thus differentially affects murine embryonal carcinoma cells by inducing cell motility but not cell division. That embryonal carcinoma cells require 7S NGF for their migration in vitro raises the interesting possibility that these cells may respond similarly in vivo, and be stimulated by tissue-specific high molecular weight NGF molecules to migrate or extravasate into the parenchyma of target organs.

Animals↗

PubMed1989

Cell lines with developmental potential restricted to mesodermal lineages isolated from differentiating cultures of pluripotential P19 embryonal carcinoma cells.

Embryonal carcinoma (EC) cells are developmentally pluripotential cells which can be induced to differentiate in cell culture to form a wide variety of cell types. To investigate the lineage relationships between cells of different types, we set out to isolate cell lines with multiple but restricted developmental potentials from differentiating cultures of P19 cells, a line of EC. By selecting for differentiated cells capable of anchorage-independent growth, we isolated cell lines which differentiated in high density cultures to form at least two cell types; myocytes that resembled fetal skeletal muscle cells and loose connective tissue cells that secreted large amounts of type I collagen. These results suggest that skeletal myocytes and connective tissue share a common precursor and that stem cells with limited but multiple developmental potentials can be isolated from differentiating cultures of P19 cells.

Animals↗

PubMed1993

Analysis of transcription factors binding to the duplicated PEA1 and PEA3 sites that are required for polyomavirus mutant expression in PCC4 embryonic carcinoma cells.

Embryonic carcinoma (EC) cell lines, representative of early embryonic undifferentiated cells, are nonpermissive for polyomavirus (PyV) infection as a result of a blockade of viral DNA early transcription and replication. All enhancers of PyV mutants (Py EC-PCC4), selected for the ability to grow on PCC4 EC cells, display a duplication of PEA1 and PEA3 binding sites (sites 1 and 3). However, the Py EC-PCC4 rearrangement is complex and results in variable mutant enhancer activities. We demonstrate here that duplication of sites 1 and 3 is absolutely required for a cooperative cis activation of early Py EC-PCC4 mutant transcription in PCC4 EC cells. In addition, we detect in PCC4 EC cells significant amounts of site 1- and 3-binding proteins, which we characterize as related to the Fos/Jun and Ets protein families, respectively. Wild-type PyV restriction in PCC4 EC cells may be relieved by a cooperation between site 2- and 3-binding proteins that would thereby be activated. Since site 1- or 3-binding factors could be derepressed, we improved the analysis of UV cross-linked DNA-protein complexes and were able to detect a novel factor, called PEA1/2 (for PyV enhancer A site 1- and 2-binding factor). Its DNA binding sequence overlaps sites 1 and 2 (PEA2 binding site) and is not duplicated in the M1 mutant, which exhibits the highest Py EC-PCC4 enhancer activity. he suggest that PEA1/2 is also involved in the regulation of PyV enhancer activity by repressing the site 1-binding activity.

Animals↗