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PubMed1989

Retinoic acid regulation of the expression of retinoic acid receptors in wild-type and mutant embryonal carcinoma cells.

The embryonal carcinoma cell line P19 undergoes terminal differentiation upon induction by retinoic acid (RA). The effects of RA on the retinoic acid receptor (RAR) mRNA level were investigated in P19 cells and an RA non-responsive mutant RAC65. RA induced a rapid accumulation of RAR alpha within 2 h and this was followed by an increase in the RAR beta mRNA. RAC65 cells differed from P19 cells in that the accumulation of RAR alpha mRNA was delayed and that an aberrant pattern of RAR alpha transcript was observed.

Animals↗

PubMed1990

Characteristics of embryonic stem cell differentiation: a comparison with two embryonal carcinoma cell lines.

Embryonic stem (ES) cells isolated from late blastocysts can now be maintained in culture in an undifferentiated state provided they are grown in the presence of a specific differentiation inhibitor, known variously as leukaemia inhibiting factor (LIF) or differentiation inhibiting activity (DIA), found at high concentrations in medium conditioned by Buffalo rat liver (BRL) cells. ES cells acquired a differentiated phenotype in monolayer, either when in the absence of LIF/DIA or in the presence of retinoic acid (RA). We have now characterized this bipotential differentiation of ES cells in terms of a series of extracellular matrix and cell surface proteins as well as cytokeratin expression, and compared it with the changes observed during the differentiation of two embryonal carcinoma (EC) cell lines, P19 and F9. ES cells exposed to RA in the presence of LIF/DIA largely resembled F9 EC + RA after 5 days, while ES cells deprived of LIF/DIA formed a culture with mixed phenotype resembling P19 EC + RA. This study therefore establishes the predominantly parietal endoderm-like phenotype of cells derived from ES by RA induction, and suggests that a mixed population of endoderm- and ill-defined mesoderm-like cells are formed after removal of specific inhibitor(s) of differentiation.

Animals↗

PubMed2003

Renal cell carcinoma antigen is expressed by yolk sac tumors and yolk sac elements of embryonal carcinomas.

Renal cell carcinoma antigen is a rather specific marker for normal and neoplastic renal tissue. We investigated the expression of this antigen in 34 gonadal and extragonadal germ cell tumors, including 8 pure yolk sac carcinomas and 26 embryonal carcinomas, 15 of which were combined with teratomas, seminomas, and dysgerminomas. Renal cell carcinoma antigen was demonstrated in all 8 yolk sac tumors and 21 of 26 embryonal carcinomas (81%). In yolk sac tumors, renal cell carcinoma antigen reactivity was diffusely present throughout the tumors. In embryonal carcinomas, this marker was identified only in yolk sac components. Both intracytoplasmic and membranous staining patterns were present. No reactivity was noticed in embryonal carcinoma cells, seminoma, dysgerminoma, and other components of teratomas. The study suggests an antigenic similarity between renal tubules and yolk sac tumors. Furthermore, the renal cell carcinoma antigen may be used as an addition to the panel of immunocytochemical markers for yolk sac carcinomas.

Adolescent↗

PubMed1989

A transfected H-ras oncogene does not inhibit differentiation of cardiac and skeletal muscle from embryonal carcinoma cells.

P19 embryonal carcinoma (EC) cells can be induced to differentiate in vitro into a variety of cell types, including cardiac and skeletal myocytes. We have isolated P19 cells stably transformed with either the activated human H-ras oncogene or with a chimeric gene in which the H-ras oncogene was controlled by a muscle-specific promoter. These P19 lines exhibited ubiquitous and muscle-specific expression of the activated H-ras protein, respectively. In both lines of P19 cells, normal cardiac and skeletal muscle differentiation was observed. Since the activated H-ras prevents differentiation of myoblast cell lines, our results suggest that the EC-derived muscle progenitor cell differs from continuous myoblast cell lines, perhaps by lacking a complementing oncogene responsible for myoblast immortalization.

Actins↗

PubMed1999

The expression and function of cadherin-mediated cell-to-cell adhesion in human embryonal carcinoma cells.

Human embryonal carcinoma (EC) cells typically require high cell densities to maintain their characteristic phenotype; they are generally subject to differentiation when cultured at low cell densities, marked by changes in morphology and expression of the surface antigen, SSEA-1. To test whether cadherin mediated cell-to-cell adhesion may be responsible for maintaining an EC phenotype we ascertained that human EC cells generally express E- and P-cadherins, and are subject to cadherin mediated, Ca2+ dependent aggregation. However, in the NTERA2 human EC cell line, inhibition of cadherin mediated adhesion by culture in low levels of Ca2+ did not result in the changes typically seen under low cell density conditions. Low Ca2+ levels also did not affect the pattern of differentiation in these cells following induction with retinoic acid. Therefore, cadherin-mediated cell adhesion does not appear to play a role in maintaining an EC phenotype. On the other hand, culture at both low cell density and in the absence of Ca2+ did result in changes in the patterns of cadherin expression suggesting a feedback regulatory effect of cell-to-cell adhesion. Further, lithium which inhibits the cytoplasmic kinase GSK3beta and hence influences beta-catenin levels did cause differentiation of NTERA2 cells. However, consideration of the phenotype of the resultant cells suggested that this effect may be because of lithium mimicking activation of a Wnt signalling pathway, rather than an effect on signalling consequent upon cadherin mediated cell to cell adhesion.

Cadherins↗

PubMed1989

Control of beta-interferon expression in murine embryonal carcinoma F9 cells.

Murine embryonal carcinoma F9 cells, a tissue culture model for early embryonic development, do not produce interferon (IFN) in response to poly(I-C), as determined by an antiviral assay. RNase protection analyses were used to examine total RNA extracted from the cells for the presence of beta-IFN RNA. Whereas F9 cells differentiated in vitro with retinoic acid produced a biologically active protein as well as beta-IFN RNA in response to poly(I-C), undifferentiated F9 cells produced no detectable beta-IFN RNA even in the presence of cycloheximide, an IFN-superinducing agent. These results show that undifferentiated embryonal carcinoma cells do not accumulate beta-IFN RNA in response to an IFN-inducing agent, suggesting a transcriptional regulatory mechanism. However, this control mechanism is altered upon differentiation, since the gene can be transcriptionally activated in retinoic acid-differentiated cells.

Animals↗

PubMed1986

The differentiation of carcinomas of teratomatous origin from embryonal carcinoma. A light and electron microscopic study.

Carcinomas derived from teratomatous epithelium occur rarely in the metastases of patients with testicular cancer. These carcinomas of teratomatous origin (CTO) are easily confused with residual embryonal carcinoma (EC). For that reason, we compared the light and electron microscopic appearances of 6 CTOs with those of 12 ECs. As seen by light microscopy, the CTOs formed glands and more frequently had well-defined cytoplasmic borders, eosinophilic cytoplasm, and nonoverlapping, regular nuclei with small or absent nucleoli and little chromatin clumping and clearing, compared with the ECs. Mucin was present in the cells or glandular lumina of three CTOs but was absent in all the ECs. The demonstration of cytoplasmic glycogen was of no differential aid. The most useful differentiating ultrastructural features were long tight junctions and telolysosomes, which occurred in all of the EC but which were absent in the six cases of CTO. Desmosomes with inserting tonofilaments were present in three cases of CTO but were much less developed in EC. Two cases of CTO had microvilli with anchoring rootlets; such anchoring rootlets were not observed among EC. The distinction of CTO from residual EC is important, because CTO will likely need to be treated in a different manner.

Cell Transformation, Neoplastic↗

PubMed1982

Control of muscle and neuronal differentiation in a cultured embryonal carcinoma cell line.

Pluripotent murine embryonal carcinoma cells can differentiate in culture into many tissue types similar to those normally found in early embryos and may be useful in investigating some developmental events. Central to our understanding of embryonic development are explanations of cellular determination, that is, the commitment of early embryonic cells to form divergent cell types. Of relevance is recent work with the F9 line of embryonal carcinoma cells which suggests that certain extra-embryonic cell types are specifically formed following treatment of undifferentiated cells with drugs and the manipulation of culture conditions. We report here that the P19 line of embryonic carcinoma cells may provide and analogous system in which drugs can be used to manipulate the formation of tissues which normally comprise the fetus. In the presence of dimethyl sulphoxide (DMSO) aggregates of P19 cells differentiate rapidly to form large amounts of cardiac and skeletal muscle but no neurones or glia. We have previously shown that in the presence of high concentrations of retinoic acid (greater than 5 x 10(-7) M), aggregates of these same cells develop into neuronal and glial tissues but not muscle. Thus, drugs can be used to generate two quite different spectra of embryonic tissue types from the same population of embryonal carcinoma cells.

Actins↗

PubMed1987

The characteristics of embryonal carcinoma cells in teratocarcinomas.

The orchiectomy specimens and the respective lymphadenectomies of 33 teratocarcinomas (teratoma and embryonal carcinoma) and 30 embryonal carcinomas were identified in a series of 457 consecutive germ cell tumors of the testis. Although teratocarcinomas were larger tumors the retroperitoneal lymphadenectomies revealed metastases in only 10 of 33 (30%) teratocarcinomas as compared to 19 of 30 (63%) embryonal carcinomas. Even after subtracting the teratoma component and stratifying for size of the embryonal carcinoma component, the teratocarcinomas were still less likely to metastasize than comparably sized pure embryonal carcinomas. Statistical significance was found between the differences in size and the differences in the rates of metastases, before and after stratifying for size of the embryonal carcinoma component of the teratocarcinomas. Further, all embryonal carcinomas metastasized as embryonal carcinoma while only 5 teratocarcinomas metastasized as embryonal carcinoma. This study supports experimental evidence that the embryonal carcinoma cells in teratocarcinomas are not necessarily identical to embryonal carcinoma cells in embryonal carcinomas.

Adult↗

PubMed1992

Expression pattern of SR alpha promoter in human embryonal carcinoma and transgenic tissues in mice.

Human embryonal carcinoma is thought to be a counterpart of mouse embryonal carcinoma, which has provided useful information for studying early molecular events in murine embryogenesis. A major practical problem in the use of human embryonal carcinoma for molecular pathological studies is the lack of an efficient expression system for foreign genes. The SR alpha promoter is a fusion promoter containing the SV 40 early promoter and the R segment and part of the U5 sequence of the long terminal repeat derived from human T-cell leukemia virus type I. We analyzed the expression pattern of the SR alpha promoter in human and mouse embryonal carcinoma lines and transgenic mouse tissues. Efficient and stable expression was detected in all cell lines tested, and tissues from all mice of four independent transgenic lines carrying the SR alpha-CAT vector showed a detectable level of CAT expression. These data suggest that the SR alpha promoter is useful for studies of both human embryonal carcinoma and transgenic mouse tissue. Using this expression system, we are now able to label human embryonal carcinomas with various genes, for example beta galactosidase, and follow their fate at the single-cell level in nude mice, where xenotransplanted human embryonal carcinoma expresses differentiation capability.

Animals↗

PubMed1991

Lectin histochemistry of embryonal carcinoma.

Histological tissue sections of human testicular embryonal carcinoma from 13 patients and of a xenograft tumour in nude mice, as well as cell lines of human embryonal carcinoma, were investigated with eight different lectins to characterize the distribution of glycoconjugates in embryonal carcinoma. In all cases the malignant cells showed binding with Con A, WGA and RCA I conjugates, whereas other lectins were bound to some, but never to all, tumour cells in each group, revealing the heterogeneity of the malignant cells. A polarization of cancer cells was shown particularly with WGA and RCA I labelling, which was most intense on the luminal borders of the carcinoma cells, where pseudotubular structures were formed. The sugar staining properties were retained in cell culture and in the xenograft tumour. Regardless of the germ cell origin, embryonal carcinoma cells differed from normal germ cells. The distribution of glycoconjugates was also different from that of testicular carcinoma-in-situ germ cells, which share morphological features and the pattern of glycosylation with seminoma cells. However, the similarities in lectin binding pattern of seminomas and embryonal carcinomas suggest the close relationship between the two types of testicular malignancy, without excluding the possibility that embryonal carcinomas were derived from seminomas. Although lectins seem to be less important for differential diagnostic use in testicular cancer, our findings showed the usefulness of lectin histochemistry for characterization of embryonal carcinoma.

Animals↗

PubMed1990

Expression of a parathyroid hormone-like protein and its receptor during differentiation of embryonal carcinoma cells.

Differentiation of mouse embryonal carcinoma cells to the parietal endoderm phenotype is associated with expression of PTH-responsive adenylate cyclase. A PTH-like protein (PLP), which binds to PTH receptors and activates adenylate cyclase in classical PTH target cells was recently isolated and cloned. We assessed whether the parietal endoderm phenotype is associated with the expression of PLP or its receptor. A 1.4-kilobase PLP transcript was detected in the mouse parietal endoderm cell line PYS-2. No hybridizing transcripts were evident in undifferentiated mouse embryonal carcinoma cells PSA-1 or F9. However, differentiation of these cells to parietal endoderm, either spontaneously (PSA-1) or by treatment with retinoic acid and dibutyryl cAMP (F9), resulted in expression of the 1.4-kilobase PLP message. Undifferentiated F9 cells displayed negligible specific binding of [125I]PLP-(1-34)amide. When F9 cells were induced to differentiate to parietal endoderm, specific binding sites for [125I]PLP-(1-34)amide were expressed in parallel with PLP-responsive adenylate cyclase. These receptors, like those in classical PTH target tissues, displayed identical affinity (Kd = 5.2 nM) for bPTH-(1-34) and hPLP-(1-34)amide; with binding capacity (Bmax) of 6.6 x 10(4) sites/cell. In the presence of retinoic acid, exogenous PLP substituted for dibutyryl cAMP in a concentration-dependent fashion in promoting the differentiation of F9 cells to parietal endoderm. Thus, both PLP mRNA and PLP receptors coupled to adenylate cyclase are expressed during the differentiation of mouse embryonal carcinoma cells. Increased cAMP levels produced by autocrine stimulation of PLP receptors by PLP may contribute to differentiation of embryonal carcinoma cells into parietal endoderm.

Adenylyl Cyclases↗

PubMed1978

Stimulation of the clonal growth and differentiation of feeder layer dependent mouse embryonal carcinoma cells by beta-mercaptoethanol.

Embryonal carcinoma cells are the undetermined stem cells of teratocarcinomas. Supplementation of culture medium with beta-mercaptoethanol permits the feeder layer independent clonal growth and differentiation of normally feeder layer dependent embryonal carcinoma cell lines. Differentiated cells within the clones appeared less than 6 days after plating and were distinguished from embryonal carcinoma cells by their morphology, lack of histochemically detectable alkaline phosphatase activity, and secretion of plasminogen activator. Over 70% of the colonies secreted plasminogen activator after 6 days. In comparison, a different embryonal carcinoma cell line which has lost the potential for substantial differentiation, either in vitro or in vivo forms very few clones (less than 1%) which secrete plasminogen activator. Embryonal carcinoma cells derived from the rare clones which secrete plasminogen activator have the same frequency of production of plasminogen activator secreting colonies as the parental cell line.

Alkaline Phosphatase↗

PubMed1986

alpha-Difluoromethylornithine induces differentiation of a human embryonal carcinoma cell line in vitro.

Human embryonal carcinoma cells could serve as a useful model system for analysis of early human development. A limited number of human embryonal carcinoma cell lines have been generated from in vivo tumors. We report here that alpha-difluoromethylornithine, a specific enzyme-activated inhibitor of ornithine decarboxylase activity, can induce differentiation in human embryonal carcinoma cells. The differentiated phenotype could be distinguished from undifferentiated cells by altered cellular morphology, biochemical and cell surface antigenic properties. These results suggest that alterations in the intracellular levels of polyamines may play a role in human embryonal carcinoma cell differentiation, and possibly human embryogenesis.

Actins↗

PubMedDate not supplied

Dynamic heterogeneity: metastatic variants to liver are generated spontaneously in mouse embryonal carcinoma cells.

Mouse embryonal carcinoma (EC) cells derived from F9 cells form predominantly liver tumors following the intravenous injection (i.e. experimental metastasis assay) of EC cells into syngeneic 129/J male mice. In this study, EC cells (OTF9) expressing stage-specific embryonic antigen-1 (SSEA-1) are compared with cells (SOTF9) lacking SSEA-1 antigen in the experimental liver metastasis assay. When parallel clones of EC cells were grown to a measured cell number and tested in the experimental metastasis assay, it was observed that the frequency of experimental liver metastases increases with the population size. When the clonal population size is less than the critical number of cells (approximately 2 x 10(5) cells), the frequency of liver tumors is reduced relative to that of the parent EC population. The metastatic ability of clones derived from individual liver metastases did not differ from that of the parental cells. An analysis of the recessive biochemical and immunochemical markers of parental cells and of independent liver metastases suggests that somatic hybridization to host cells by the EC cells is not involved. These results are consistent with predictions from our dynamic heterogeneity model that was formulated by examining the experimental lung metastasis of KHT fibrosarcoma and B16 melanoma cells. Mathematical analysis of the results indicates that the effective rate of generation of the liver metastasizing variant cells is (7 +/- 3) x 10(-6) per cell per generation for both OTF9 and SOTF9 cells.

Animals↗

PubMed1983

Two specific markers for neural differentiation of embryonal carcinoma cells.

Two multipotential embryonal carcinoma (EC) cell lines, 1003 and 1009, can be induced to form preferentially neural derivatives in vitro. Synthesis of specific proteins during neural differentiation was followed by two-dimensional gel electrophoresis. The comparison of protein patterns obtained with neural and non-neural derivatives of these EC cell lines indicates that two changes are specific for the neural pathway: (i) the appearance of a new beta-tubulin isoform and (ii) the accumulation of the brain isozyme of creatine phosphokinase already present in small amounts in EC stem cells. These changes were found to take place early in the course of differentiation and to occur even when neurite outgrowth was prevented.

Animals↗

PubMedDate not supplied

Functional expressions of fms and M-CSF during trophoectodermal differentiation of human embryonal carcinoma cells.

A human embryonal carcinoma (EC) cell line, NCR-G3 (G3), is capable of differentiating into a variety of cell types in vitro, including epithelial, muscle, neural and trophoectodermal cells. The production of human chorionic gonadotropin (hCG), a trophoectoderm-specific hormone, begins 7 days after retinoic acid (RR1) treatment and peaks on day 12-13. In this study, we used G3 cells to investigate the biological significance of macrophage colony-stimulating factor (M-CSF), also called colony-stimulating factor-1 (CSF-1), and fms, a receptor tyrosine kinase for M-CSF. The mRNA of c-fms is constitutively expressed in both undifferentiated and differentiated G3 cells. Immunoprecipitation with anti-fms antibodies or flow cytometry revealed that differentiated G3 cells express fms on the cell surface. However, we were unable to demonstrate expression of fms on the surface of undifferentiated G3 cells. Expression of M-CSF mRNA and protein, however, was upregulated by RA treatment prior to hCG production. In order to investigate whether expression of both molecules is biologically functional in G3 cells, we conducted experiments using anti-M-CSF and fms antibodies with neutralizing activity and gene transfer to achieve over-expression of fms in G3 cells. As a result, we observed that hCG production following treatment with both neutralizing antibodies was more than 90 per cent inhibited, and that hCG production increased significantly as a result of over-expression of fms in G3 cells. Our results enabled us to show that M-CSF and fms play important functional roles in the differentiation of G3 cells into trophoectoderm. G3 cells are well suited to serve as an experimental model of human early embryogenesis and of placental differentiation.

Carcinoma, Embryonal↗

PubMedDate not supplied

Effects of taxol on the polymerization and posttranslational modification of class III beta-tubulin in P19 embryonal carcinoma cells.

Undifferentiated P19 embryonal carcinoma cells and P19 cells induced to differentiate along a neuronal pathway by 10(-6) M retinoic acid were treated with taxol to examine the effects of this microtubule-stabilizing drug on the subcellular sorting of class III beta-tubulin and on neurite outgrowth. P19 cells were grown on cover slips and then treated with taxol at concentrations of 10(-6) to 10(-9) M for 24 h. The microtubule cytoskeleton was examined after double-immunofluorescence labelling with a monoclonal antibody to alpha-tubulin (YOL 1/34) and a monoclonal neuron-specific class III beta-tubulin antibody (TuJ1). Treatment of undifferentiated P19 cells with concentrations of taxol greater than 4 x 10(-8) M caused microtubule bundling and multiple aster formation and promoted polymerization of the low levels of class III beta-tubulin found in these cells. In neurons, at 2 x 10(-8) M taxol, bundling of microtubules at the base of the neurite was apparent. At taxol concentrations greater than 1 x 10(-7) M, enhanced assembly of class III beta-tubulin was apparent, although long neurites were not observed. Using isoelectric focusing followed by western blotting, we detected an additional isoform of class III beta-tubulin after treatment with 10(-6) M taxol. The results indicate taxol treatment alters the normal subcellular sorting of tubulin isotypes, promotes the polymerization and posttranslational modification of class III beta-tubulin, and interferes with neurite outgrowth.

Antineoplastic Agents, Phytogenic↗