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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2002 Apr 29;357(1420):405–417. doi: 10.1098/rstb.2002.1058

From teratocarcinomas to embryonic stem cells.

Peter W Andrews 1
PMCID: PMC1692959  PMID: 12028783

Abstract

The recent derivation of human embryonic stem (ES) cell lines, together with results suggesting an unexpected degree of plasticity in later, seemingly more restricted, stem cells (so-called adult stem cells), have combined to focus attention on new opportunities for regenerative medicine, as well as for understanding basic aspects of embryonic development and diseases such as cancer. Many of the ideas that are now discussed have a long history and much has been underpinned by the earlier studies of teratocarcinomas, and their embryonal carcinoma (EC) stem cells, which present a malignant surrogate for the normal stem cells of the early embryo. Nevertheless, although the potential of EC and ES cells to differentiate into a wide range of tissues is now well attested, little is understood of the key regulatory mechanisms that control their differentiation. Apart from the intrinsic biological interest in elucidating these mechanisms, a clear understanding of the molecular process involved will be essential if the clinical potential of these cells is to be realized. The recent observations of stem-cell plasticity suggest that perhaps our current concepts about the operation of cell regulatory pathways are inadequate, and that new approaches for analysing complex regulatory networks will be essential.

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Selected References

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  1. Alison M. R., Poulsom R., Jeffery R., Dhillon A. P., Quaglia A., Jacob J., Novelli M., Prentice G., Williamson J., Wright N. A. Hepatocytes from non-hepatic adult stem cells. Nature. 2000 Jul 20;406(6793):257–257. doi: 10.1038/35018642. [DOI] [PubMed] [Google Scholar]
  2. Amit M., Carpenter M. K., Inokuma M. S., Chiu C. P., Harris C. P., Waknitz M. A., Itskovitz-Eldor J., Thomson J. A. Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev Biol. 2000 Nov 15;227(2):271–278. doi: 10.1006/dbio.2000.9912. [DOI] [PubMed] [Google Scholar]
  3. Andrews P. W., Banting G., Damjanov I., Arnaud D., Avner P. Three monoclonal antibodies defining distinct differentiation antigens associated with different high molecular weight polypeptides on the surface of human embryonal carcinoma cells. Hybridoma. 1984 Winter;3(4):347–361. doi: 10.1089/hyb.1984.3.347. [DOI] [PubMed] [Google Scholar]
  4. Andrews P. W., Bronson D. L., Benham F., Strickland S., Knowles B. B. A comparative study of eight cell lines derived from human testicular teratocarcinoma. Int J Cancer. 1980 Sep 15;26(3):269–280. doi: 10.1002/ijc.2910260304. [DOI] [PubMed] [Google Scholar]
  5. Andrews P. W., Casper J., Damjanov I., Duggan-Keen M., Giwercman A., Hata J., von Keitz A., Looijenga L. H., Millán J. L., Oosterhuis J. W. Comparative analysis of cell surface antigens expressed by cell lines derived from human germ cell tumours. Int J Cancer. 1996 Jun 11;66(6):806–816. doi: 10.1002/(SICI)1097-0215(19960611)66:6<806::AID-IJC17>3.0.CO;2-0. [DOI] [PubMed] [Google Scholar]
  6. Andrews P. W., Damjanov I., Berends J., Kumpf S., Zappavigna V., Mavilio F., Sampath K. Inhibition of proliferation and induction of differentiation of pluripotent human embryonal carcinoma cells by osteogenic protein-1 (or bone morphogenetic protein-7). Lab Invest. 1994 Aug;71(2):243–251. [PubMed] [Google Scholar]
  7. Andrews P. W., Damjanov I., Simon D., Banting G. S., Carlin C., Dracopoli N. C., Føgh J. Pluripotent embryonal carcinoma clones derived from the human teratocarcinoma cell line Tera-2. Differentiation in vivo and in vitro. Lab Invest. 1984 Feb;50(2):147–162. [PubMed] [Google Scholar]
  8. Andrews P. W., Goodfellow P. N. Antigen expression by somatic cell hybrids of a murine embryonal carcinoma cell with thymocytes and L cells. Somatic Cell Genet. 1980 Mar;6(2):271–284. doi: 10.1007/BF01538801. [DOI] [PubMed] [Google Scholar]
  9. Andrews P. W., Goodfellow P. N., Shevinsky L. H., Bronson D. L., Knowles B. B. Cell-surface antigens of a clonal human embryonal carcinoma cell line: morphological and antigenic differentiation in culture. Int J Cancer. 1982 May 15;29(5):523–531. doi: 10.1002/ijc.2910290507. [DOI] [PubMed] [Google Scholar]
  10. Andrews P. W., Nudelman E., Hakomori S., Fenderson B. A. Different patterns of glycolipid antigens are expressed following differentiation of TERA-2 human embryonal carcinoma cells induced by retinoic acid, hexamethylene bisacetamide (HMBA) or bromodeoxyuridine (BUdR). Differentiation. 1990 Apr;43(2):131–138. doi: 10.1111/j.1432-0436.1990.tb00439.x. [DOI] [PubMed] [Google Scholar]
  11. Andrews P. W. Retinoic acid induces neuronal differentiation of a cloned human embryonal carcinoma cell line in vitro. Dev Biol. 1984 Jun;103(2):285–293. doi: 10.1016/0012-1606(84)90316-6. [DOI] [PubMed] [Google Scholar]
  12. Artzt K., Dubois P., Bennett D., Condamine H., Babinet C., Jacob F. Surface antigens common to mouse cleavage embryos and primitive teratocarcinoma cells in culture. Proc Natl Acad Sci U S A. 1973 Oct;70(10):2988–2992. doi: 10.1073/pnas.70.10.2988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Assady S., Maor G., Amit M., Itskovitz-Eldor J., Skorecki K. L., Tzukerman M. Insulin production by human embryonic stem cells. Diabetes. 2001 Aug;50(8):1691–1697. doi: 10.2337/diabetes.50.8.1691. [DOI] [PubMed] [Google Scholar]
  14. Badcock G., Pigott C., Goepel J., Andrews P. W. The human embryonal carcinoma marker antigen TRA-1-60 is a sialylated keratan sulfate proteoglycan. Cancer Res. 1999 Sep 15;59(18):4715–4719. [PubMed] [Google Scholar]
  15. Bendel-Stenzel M., Anderson R., Heasman J., Wylie C. The origin and migration of primordial germ cells in the mouse. Semin Cell Dev Biol. 1998 Aug;9(4):393–400. doi: 10.1006/scdb.1998.0204. [DOI] [PubMed] [Google Scholar]
  16. Benham F. J., Andrews P. W., Knowles B. B., Bronson D. L., Harris H. Alkaline phosphatase isozymes as possible markers of differentiation in human testicular teratocarcinoma cell lines. Dev Biol. 1981 Dec;88(2):279–287. doi: 10.1016/0012-1606(81)90171-8. [DOI] [PubMed] [Google Scholar]
  17. Berstine E. G., Hooper M. L., Grandchamp S., Ephrussi B. Alkaline phosphatase activity in mouse teratoma. Proc Natl Acad Sci U S A. 1973 Dec;70(12):3899–3903. doi: 10.1073/pnas.70.12.3899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Bird J. M., Kimber S. J. Oligosaccharides containing fucose linked alpha(1-3) and alpha(1-4) to N-acetylglucosamine cause decompaction of mouse morulae. Dev Biol. 1984 Aug;104(2):449–460. doi: 10.1016/0012-1606(84)90101-5. [DOI] [PubMed] [Google Scholar]
  19. Bjornson C. R., Rietze R. L., Reynolds B. A., Magli M. C., Vescovi A. L. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science. 1999 Jan 22;283(5401):534–537. doi: 10.1126/science.283.5401.534. [DOI] [PubMed] [Google Scholar]
  20. Boeuf H., Hauss C., Graeve F. D., Baran N., Kedinger C. Leukemia inhibitory factor-dependent transcriptional activation in embryonic stem cells. J Cell Biol. 1997 Sep 22;138(6):1207–1217. doi: 10.1083/jcb.138.6.1207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Borlongan C. V., Tajima Y., Trojanowski J. Q., Lee V. M., Sanberg P. R. Transplantation of cryopreserved human embryonal carcinoma-derived neurons (NT2N cells) promotes functional recovery in ischemic rats. Exp Neurol. 1998 Feb;149(2):310–321. doi: 10.1006/exnr.1997.6730. [DOI] [PubMed] [Google Scholar]
  22. Briggs R., King T. J. Transplantation of Living Nuclei From Blastula Cells into Enucleated Frogs' Eggs. Proc Natl Acad Sci U S A. 1952 May;38(5):455–463. doi: 10.1073/pnas.38.5.455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Brinster R. L. The effect of cells transferred into the mouse blastocyst on subsequent development. J Exp Med. 1974 Oct 1;140(4):1049–1056. doi: 10.1084/jem.140.4.1049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Burdon T., Stracey C., Chambers I., Nichols J., Smith A. Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells. Dev Biol. 1999 Jun 1;210(1):30–43. doi: 10.1006/dbio.1999.9265. [DOI] [PubMed] [Google Scholar]
  25. Cairns J. Mutation selection and the natural history of cancer. Nature. 1975 May 15;255(5505):197–200. doi: 10.1038/255197a0. [DOI] [PubMed] [Google Scholar]
  26. Campbell K. H., McWhir J., Ritchie W. A., Wilmut I. Sheep cloned by nuclear transfer from a cultured cell line. Nature. 1996 Mar 7;380(6569):64–66. doi: 10.1038/380064a0. [DOI] [PubMed] [Google Scholar]
  27. Cibelli J. B., Stice S. L., Golueke P. J., Kane J. J., Jerry J., Blackwell C., Ponce de León F. A., Robl J. M. Cloned transgenic calves produced from nonquiescent fetal fibroblasts. Science. 1998 May 22;280(5367):1256–1258. doi: 10.1126/science.280.5367.1256. [DOI] [PubMed] [Google Scholar]
  28. Clarke D. L., Johansson C. B., Wilbertz J., Veress B., Nilsson E., Karlström H., Lendahl U., Frisén J. Generalized potential of adult neural stem cells. Science. 2000 Jun 2;288(5471):1660–1663. doi: 10.1126/science.288.5471.1660. [DOI] [PubMed] [Google Scholar]
  29. Damjanov I., Andrews P. W. Ultrastructural differentiation of a clonal human embryonal carcinoma cell line in vitro. Cancer Res. 1983 May;43(5):2190–2198. [PubMed] [Google Scholar]
  30. Damjanov I., Horvat B., Gibas Z. Retinoic acid-induced differentiation of the developmentally pluripotent human germ cell tumor-derived cell line, NCCIT. Lab Invest. 1993 Feb;68(2):220–232. [PubMed] [Google Scholar]
  31. Damjanov I. Pathogenesis of testicular germ cell tumours. Eur Urol. 1993;23(1):2–7. doi: 10.1159/000474563. [DOI] [PubMed] [Google Scholar]
  32. Damjanov I., Solter D. Experimental teratoma. Curr Top Pathol. 1974;59:69–130. doi: 10.1007/978-3-642-65857-0_2. [DOI] [PubMed] [Google Scholar]
  33. Damjanov I. Teratocarcinoma stem cells. Cancer Surv. 1990;9(2):303–319. [PubMed] [Google Scholar]
  34. Duran C., Talley P. J., Walsh J., Pigott C., Morton I. E., Andrews P. W. Hybrids of pluripotent and nullipotent human embryonal carcinoma cells: partial retention of a pluripotent phenotype. Int J Cancer. 2001 Aug 1;93(3):324–332. doi: 10.1002/ijc.1355. [DOI] [PubMed] [Google Scholar]
  35. Einhorn L. H. Treatment strategies of testicular cancer in the United States. Int J Androl. 1987 Feb;10(1):399–405. doi: 10.1111/j.1365-2605.1987.tb00210.x. [DOI] [PubMed] [Google Scholar]
  36. Evans M. J., Kaufman M. H. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981 Jul 9;292(5819):154–156. doi: 10.1038/292154a0. [DOI] [PubMed] [Google Scholar]
  37. Evans M. J. The isolation and properties of a clonal tissue culture strain of pluripotent mouse teratoma cells. J Embryol Exp Morphol. 1972 Aug;28(1):163–176. [PubMed] [Google Scholar]
  38. Fenderson B. A., Andrews P. W., Nudelman E., Clausen H., Hakomori S. Glycolipid core structure switching from globo- to lacto- and ganglio-series during retinoic acid-induced differentiation of TERA-2-derived human embryonal carcinoma cells. Dev Biol. 1987 Jul;122(1):21–34. doi: 10.1016/0012-1606(87)90328-9. [DOI] [PubMed] [Google Scholar]
  39. Fenderson B. A., Zehavi U., Hakomori S. A multivalent lacto-N-fucopentaose III-lysyllysine conjugate decompacts preimplantation mouse embryos, while the free oligosaccharide is ineffective. J Exp Med. 1984 Nov 1;160(5):1591–1596. doi: 10.1084/jem.160.5.1591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Finch B. W., Ephrussi B. RETENTION OF MULTIPLE DEVELOPMENTAL POTENTIALITIES BY CELLS OF A MOUSE TESTICULAR TERATOCARCINOMA DURING PROLONGED CULTURE in vitro AND THEIR EXTINCTION UPON HYBRIDIZATION WITH CELLS OF PERMANENT LINES. Proc Natl Acad Sci U S A. 1967 Mar;57(3):615–621. doi: 10.1073/pnas.57.3.615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. GURDON J. B. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J Embryol Exp Morphol. 1962 Dec;10:622–640. [PubMed] [Google Scholar]
  42. Galli R., Borello U., Gritti A., Minasi M. G., Bjornson C., Coletta M., Mora M., De Angelis M. G., Fiocco R., Cossu G. Skeletal myogenic potential of human and mouse neural stem cells. Nat Neurosci. 2000 Oct;3(10):986–991. doi: 10.1038/79924. [DOI] [PubMed] [Google Scholar]
  43. Gmür R., Solter D., Knowles B. B. Independent regulation of H-2K and H-2D gene expression in murine teratocarcinoma somatic cell hybrids. J Exp Med. 1980 Jun 1;151(6):1349–1359. doi: 10.1084/jem.151.6.1349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Goodell M. A., Jackson K. A., Majka S. M., Mi T., Wang H., Pocius J., Hartley C. J., Majesky M. W., Entman M. L., Michael L. H. Stem cell plasticity in muscle and bone marrow. Ann N Y Acad Sci. 2001 Jun;938:208–220. doi: 10.1111/j.1749-6632.2001.tb03591.x. [DOI] [PubMed] [Google Scholar]
  45. Gooi H. C., Feizi T., Kapadia A., Knowles B. B., Solter D., Evans M. J. Stage-specific embryonic antigen involves alpha 1 goes to 3 fucosylated type 2 blood group chains. Nature. 1981 Jul 9;292(5819):156–158. doi: 10.1038/292156a0. [DOI] [PubMed] [Google Scholar]
  46. Greaves M. F. "Target" cells, cellular phenotypes, and lineage fidelity in human leukaemia. J Cell Physiol Suppl. 1982;1:113–125. doi: 10.1002/jcp.1041130418. [DOI] [PubMed] [Google Scholar]
  47. Gönczöl E., Andrews P. W., Plotkin S. A. Cytomegalovirus replicates in differentiated but not in undifferentiated human embryonal carcinoma cells. Science. 1984 Apr 13;224(4645):159–161. doi: 10.1126/science.6322309. [DOI] [PubMed] [Google Scholar]
  48. Hadorn E. Transdetermination in cells. Sci Am. 1968 Nov;219(5):110–passim. doi: 10.1038/scientificamerican1168-110. [DOI] [PubMed] [Google Scholar]
  49. Hata J., Fujita H., Ikeda E., Matsubayashi Y., Kokai Y., Fujimoto J. [Differentiation of human germ cell tumor cells]. Hum Cell. 1989 Dec;2(4):382–387. [PubMed] [Google Scholar]
  50. Hirka G., Prakash K., Kawashima H., Plotkin S. A., Andrews P. W., Gönczöl E. Differentiation of human embryonal carcinoma cells induces human immunodeficiency virus permissiveness which is stimulated by human cytomegalovirus coinfection. J Virol. 1991 May;65(5):2732–2735. doi: 10.1128/jvi.65.5.2732-2735.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Hogan B., Fellous M., Avner P., Jacob F. Isolation of a human teratoma cell line which expresses F9 antigen. Nature. 1977 Dec 8;270(5637):515–518. doi: 10.1038/270515a0. [DOI] [PubMed] [Google Scholar]
  52. Hurlbert M. S., Gianani R. I., Hutt C., Freed C. R., Kaddis F. G. Neural transplantation of hNT neurons for Huntington's disease. Cell Transplant. 1999 Jan-Feb;8(1):143–151. doi: 10.1177/096368979900800106. [DOI] [PubMed] [Google Scholar]
  53. Itskovitz-Eldor J., Schuldiner M., Karsenti D., Eden A., Yanuka O., Amit M., Soreq H., Benvenisty N. Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. Mol Med. 2000 Feb;6(2):88–95. [PMC free article] [PubMed] [Google Scholar]
  54. Jacob F. The Leeuwenhoek Lecture, 1977. Mouse teratocarcinoma and mouse embryo. Proc R Soc Lond B Biol Sci. 1978 May 16;201(1144):249–270. doi: 10.1098/rspb.1978.0044. [DOI] [PubMed] [Google Scholar]
  55. Jakob H., Boon T., Gaillard J., Nicolas J., Jacob F. Tératocarcinome de la spuris: isolement, culture et propriétés de cellules a potentialités multiples. Ann Microbiol (Paris) 1973 Oct;124(3):269–282. [PubMed] [Google Scholar]
  56. Jakob H., Dubois P., Eisen H., Jacob F. Effets de l'hexaméthylènebisacétamide sur la différenciation de cellules de carcinome embryonnaire. C R Acad Sci Hebd Seances Acad Sci D. 1978 Jan;286(1):109–111. [PubMed] [Google Scholar]
  57. Jones-Villeneuve E. M., McBurney M. W., Rogers K. A., Kalnins V. I. Retinoic acid induces embryonal carcinoma cells to differentiate into neurons and glial cells. J Cell Biol. 1982 Aug;94(2):253–262. doi: 10.1083/jcb.94.2.253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. KLEINSMITH L. J., PIERCE G. B., Jr MULTIPOTENTIALITY OF SINGLE EMBRYONAL CARCINOMA CELLS. Cancer Res. 1964 Oct;24:1544–1551. [PubMed] [Google Scholar]
  59. Kahan B. W., Ephrussi B. Developmental potentialities of clonal in vitro cultures of mouse testicular teratoma. J Natl Cancer Inst. 1970 May;44(5):1015–1036. [PubMed] [Google Scholar]
  60. Kannagi R., Cochran N. A., Ishigami F., Hakomori S., Andrews P. W., Knowles B. B., Solter D. Stage-specific embryonic antigens (SSEA-3 and -4) are epitopes of a unique globo-series ganglioside isolated from human teratocarcinoma cells. EMBO J. 1983;2(12):2355–2361. doi: 10.1002/j.1460-2075.1983.tb01746.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Kehat I., Kenyagin-Karsenti D., Snir M., Segev H., Amit M., Gepstein A., Livne E., Binah O., Itskovitz-Eldor J., Gepstein L. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest. 2001 Aug;108(3):407–414. doi: 10.1172/JCI12131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Kleppner S. R., Robinson K. A., Trojanowski J. Q., Lee V. M. Transplanted human neurons derived from a teratocarcinoma cell line (NTera-2) mature, integrate, and survive for over 1 year in the nude mouse brain. J Comp Neurol. 1995 Jul 10;357(4):618–632. doi: 10.1002/cne.903570410. [DOI] [PubMed] [Google Scholar]
  63. Kondziolka D., Wechsler L., Goldstein S., Meltzer C., Thulborn K. R., Gebel J., Jannetta P., DeCesare S., Elder E. M., McGrogan M. Transplantation of cultured human neuronal cells for patients with stroke. Neurology. 2000 Aug 22;55(4):565–569. doi: 10.1212/wnl.55.4.565. [DOI] [PubMed] [Google Scholar]
  64. Lagasse E., Connors H., Al-Dhalimy M., Reitsma M., Dohse M., Osborne L., Wang X., Finegold M., Weissman I. L., Grompe M. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med. 2000 Nov;6(11):1229–1234. doi: 10.1038/81326. [DOI] [PubMed] [Google Scholar]
  65. Lajtha L. G. Stem cell concepts. Differentiation. 1979;14(1-2):23–34. doi: 10.1111/j.1432-0436.1979.tb01007.x. [DOI] [PubMed] [Google Scholar]
  66. Lee V. M., Andrews P. W. Differentiation of NTERA-2 clonal human embryonal carcinoma cells into neurons involves the induction of all three neurofilament proteins. J Neurosci. 1986 Feb;6(2):514–521. doi: 10.1523/JNEUROSCI.06-02-00514.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Martin G. R., Evans M. J. Differentiation of clonal lines of teratocarcinoma cells: formation of embryoid bodies in vitro. Proc Natl Acad Sci U S A. 1975 Apr;72(4):1441–1445. doi: 10.1073/pnas.72.4.1441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Martin G. R., Evans M. J. The morphology and growth of a pluripotent teratocarcinoma cell line and its derivatives in tissue culture. Cell. 1974 Jul;2(3):163–172. doi: 10.1016/0092-8674(74)90090-7. [DOI] [PubMed] [Google Scholar]
  69. Martin G. R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7634–7638. doi: 10.1073/pnas.78.12.7634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Matsui Y., Zsebo K., Hogan B. L. Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture. Cell. 1992 Sep 4;70(5):841–847. doi: 10.1016/0092-8674(92)90317-6. [DOI] [PubMed] [Google Scholar]
  71. McBurney M. W. Hemoglobin synthesis in cell hybrids formed between teratocarcinoma and Friend erythroleukemia cells. Cell. 1977 Nov;12(3):653–662. doi: 10.1016/0092-8674(77)90265-3. [DOI] [PubMed] [Google Scholar]
  72. McBurney M. W., Jones-Villeneuve E. M., Edwards M. K., Anderson P. J. Control of muscle and neuronal differentiation in a cultured embryonal carcinoma cell line. Nature. 1982 Sep 9;299(5879):165–167. doi: 10.1038/299165a0. [DOI] [PubMed] [Google Scholar]
  73. McGrath J., Solter D. Inability of mouse blastomere nuclei transferred to enucleated zygotes to support development in vitro. Science. 1984 Dec 14;226(4680):1317–1319. doi: 10.1126/science.6542249. [DOI] [PubMed] [Google Scholar]
  74. Mezey E., Chandross K. J., Harta G., Maki R. A., McKercher S. R. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science. 2000 Dec 1;290(5497):1779–1782. doi: 10.1126/science.290.5497.1779. [DOI] [PubMed] [Google Scholar]
  75. Miller R. A., Ruddle F. H. Pluripotent teratocarcinoma-thymus somatic cell hybrids. Cell. 1976 Sep;9(1):45–55. doi: 10.1016/0092-8674(76)90051-9. [DOI] [PubMed] [Google Scholar]
  76. Mintz B., Illmensee K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3585–3589. doi: 10.1073/pnas.72.9.3585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Munsie M. J., Michalska A. E., O'Brien C. M., Trounson A. O., Pera M. F., Mountford P. S. Isolation of pluripotent embryonic stem cells from reprogrammed adult mouse somatic cell nuclei. Curr Biol. 2000 Aug 24;10(16):989–992. doi: 10.1016/s0960-9822(00)00648-5. [DOI] [PubMed] [Google Scholar]
  78. Møller H. Clues to the aetiology of testicular germ cell tumours from descriptive epidemiology. Eur Urol. 1993;23(1):8–15. doi: 10.1159/000474564. [DOI] [PubMed] [Google Scholar]
  79. Nicolas J. F., Dubois P., Jakob H., Gaillard J., Jacob F. Tératocarcinome de la souris: différenciation en culture d'une lignée de cellules primitives a potentialités multiples. Ann Microbiol (Paris) 1975 Jan;126(1):3–22. [PubMed] [Google Scholar]
  80. Niwa H., Burdon T., Chambers I., Smith A. Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev. 1998 Jul 1;12(13):2048–2060. doi: 10.1101/gad.12.13.2048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Niwa H., Miyazaki J., Smith A. G. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet. 2000 Apr;24(4):372–376. doi: 10.1038/74199. [DOI] [PubMed] [Google Scholar]
  82. Odorico J. S., Kaufman D. S., Thomson J. A. Multilineage differentiation from human embryonic stem cell lines. Stem Cells. 2001;19(3):193–204. doi: 10.1634/stemcells.19-3-193. [DOI] [PubMed] [Google Scholar]
  83. Onishi A., Iwamoto M., Akita T., Mikawa S., Takeda K., Awata T., Hanada H., Perry A. C. Pig cloning by microinjection of fetal fibroblast nuclei. Science. 2000 Aug 18;289(5482):1188–1190. doi: 10.1126/science.289.5482.1188. [DOI] [PubMed] [Google Scholar]
  84. PIERCE B., VERNEY E. L., DIXON F. J. The biology of testicular cancer. I. Behavior after transplantation. Cancer Res. 1957 Feb;17(2):134–138. [PubMed] [Google Scholar]
  85. Papaioannou V. E., McBurney M. W., Gardner R. L., Evans M. J. Fate of teratocarcinoma cells injected into early mouse embryos. Nature. 1975 Nov 6;258(5530):70–73. doi: 10.1038/258070a0. [DOI] [PubMed] [Google Scholar]
  86. Pera M. F., Cooper S., Mills J., Parrington J. M. Isolation and characterization of a multipotent clone of human embryonal carcinoma cells. Differentiation. 1989 Oct;42(1):10–23. doi: 10.1111/j.1432-0436.1989.tb00602.x. [DOI] [PubMed] [Google Scholar]
  87. Pera M. F., Herszfeld D. Differentiation of human pluripotent teratocarcinoma stem cells induced by bone morphogenetic protein-2. Reprod Fertil Dev. 1998;10(7-8):551–555. doi: 10.1071/rd98097. [DOI] [PubMed] [Google Scholar]
  88. Pera M. F. Human pluripotent stem cells: a progress report. Curr Opin Genet Dev. 2001 Oct;11(5):595–599. doi: 10.1016/s0959-437x(00)00238-0. [DOI] [PubMed] [Google Scholar]
  89. Petersen B. E., Bowen W. C., Patrene K. D., Mars W. M., Sullivan A. K., Murase N., Boggs S. S., Greenberger J. S., Goff J. P. Bone marrow as a potential source of hepatic oval cells. Science. 1999 May 14;284(5417):1168–1170. doi: 10.1126/science.284.5417.1168. [DOI] [PubMed] [Google Scholar]
  90. Philips M. F., Muir J. K., Saatman K. E., Raghupathi R., Lee V. M., Trojanowski J. Q., McIntosh T. K. Survival and integration of transplanted postmitotic human neurons following experimental brain injury in immunocompetent rats. J Neurosurg. 1999 Jan;90(1):116–124. doi: 10.3171/jns.1999.90.1.0116. [DOI] [PubMed] [Google Scholar]
  91. Pierce G. B. Neoplasms, differentiations and mutations. Am J Pathol. 1974 Oct;77(1):103–118. [PMC free article] [PubMed] [Google Scholar]
  92. Pittenger M. F., Mackay A. M., Beck S. C., Jaiswal R. K., Douglas R., Mosca J. D., Moorman M. A., Simonetti D. W., Craig S., Marshak D. R. Multilineage potential of adult human mesenchymal stem cells. Science. 1999 Apr 2;284(5411):143–147. doi: 10.1126/science.284.5411.143. [DOI] [PubMed] [Google Scholar]
  93. Pleasure S. J., Lee V. M. NTera 2 cells: a human cell line which displays characteristics expected of a human committed neuronal progenitor cell. J Neurosci Res. 1993 Aug 15;35(6):585–602. doi: 10.1002/jnr.490350603. [DOI] [PubMed] [Google Scholar]
  94. Pleasure S. J., Page C., Lee V. M. Pure, postmitotic, polarized human neurons derived from NTera 2 cells provide a system for expressing exogenous proteins in terminally differentiated neurons. J Neurosci. 1992 May;12(5):1802–1815. doi: 10.1523/JNEUROSCI.12-05-01802.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Przyborski S. A., Morton I. E., Wood A., Andrews P. W. Developmental regulation of neurogenesis in the pluripotent human embryonal carcinoma cell line NTERA-2. Eur J Neurosci. 2000 Oct;12(10):3521–3528. doi: 10.1046/j.1460-9568.2000.00230.x. [DOI] [PubMed] [Google Scholar]
  96. Rendt J., Erulkar S., Andrews P. W. Presumptive neurons derived by differentiation of a human embryonal carcinoma cell line exhibit tetrodotoxin-sensitive sodium currents and the capacity for regenerative responses. Exp Cell Res. 1989 Feb;180(2):580–584. doi: 10.1016/0014-4827(89)90087-6. [DOI] [PubMed] [Google Scholar]
  97. Resnick J. L., Bixler L. S., Cheng L., Donovan P. J. Long-term proliferation of mouse primordial germ cells in culture. Nature. 1992 Oct 8;359(6395):550–551. doi: 10.1038/359550a0. [DOI] [PubMed] [Google Scholar]
  98. Reubinoff B. E., Pera M. F., Fong C. Y., Trounson A., Bongso A. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol. 2000 Apr;18(4):399–404. doi: 10.1038/74447. [DOI] [PubMed] [Google Scholar]
  99. Roach S., Cooper S., Bennett W., Pera M. F. Cultured cell lines from human teratomas: windows into tumour growth and differentiation and early human development. Eur Urol. 1993;23(1):82–88. doi: 10.1159/000474574. [DOI] [PubMed] [Google Scholar]
  100. Roach S., Schmid W., Pera M. F. Hepatocytic transcription factor expression in human embryonal carcinoma and yolk sac carcinoma cell lines: expression of HNF-3 alpha in models of early endodermal cell differentiation. Exp Cell Res. 1994 Nov;215(1):189–198. doi: 10.1006/excr.1994.1331. [DOI] [PubMed] [Google Scholar]
  101. Rousset J. P., Bucchini D., Jami J. Hybrids between F9 nullipotent teratocarcinoma and thymus cells produce multidifferentiated tumors in mice. Dev Biol. 1983 Apr;96(2):331–336. doi: 10.1016/0012-1606(83)90170-7. [DOI] [PubMed] [Google Scholar]
  102. Rousset J. P., Jami J., Dubois P., Avilès D., Ritz E. Developmental potentialities and surface antigens of mouse teratocarcinoma x lymphoid cell hybrids. Somatic Cell Genet. 1980 May;6(3):419–433. doi: 10.1007/BF01542793. [DOI] [PubMed] [Google Scholar]
  103. STEVENS L. C. EXPERIMENTAL PRODUCTION OF TESTICULAR TERATOMAS IN MICE. Proc Natl Acad Sci U S A. 1964 Sep;52:654–661. doi: 10.1073/pnas.52.3.654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  104. STEVENS L. C., HUMMEL K. P. A description of spontaneous congenital testicular teratomas in strain 129 mice. J Natl Cancer Inst. 1957 May;18(5):719–747. [PubMed] [Google Scholar]
  105. Seale P., Asakura A., Rudnicki M. A. The potential of muscle stem cells. Dev Cell. 2001 Sep;1(3):333–342. doi: 10.1016/s1534-5807(01)00049-1. [DOI] [PubMed] [Google Scholar]
  106. Shevinsky L. H., Knowles B. B., Damjanov I., Solter D. Monoclonal antibody to murine embryos defines a stage-specific embryonic antigen expressed on mouse embryos and human teratocarcinoma cells. Cell. 1982 Oct;30(3):697–705. doi: 10.1016/0092-8674(82)90274-4. [DOI] [PubMed] [Google Scholar]
  107. Simeone A., Acampora D., Arcioni L., Andrews P. W., Boncinelli E., Mavilio F. Sequential activation of HOX2 homeobox genes by retinoic acid in human embryonal carcinoma cells. Nature. 1990 Aug 23;346(6286):763–766. doi: 10.1038/346763a0. [DOI] [PubMed] [Google Scholar]
  108. Skakkebaek N. E. Possible carcinoma-in-situ of the testis. Lancet. 1972 Sep 9;2(7776):516–517. doi: 10.1016/s0140-6736(72)91909-5. [DOI] [PubMed] [Google Scholar]
  109. Sobis H., Verstuyf A., Vandeputte M. Visceral yolk sac-derived tumors. Int J Dev Biol. 1993 Mar;37(1):155–168. [PubMed] [Google Scholar]
  110. Solter D., Dominis M., Damjanov I. Embryo-derived teratocarcinoma. III. Development of tumors from teratocarcinoma-permissive and non-permissive strain embryos transplanted to F1 hybrids. Int J Cancer. 1981 Oct 15;28(4):479–483. doi: 10.1002/ijc.2910280414. [DOI] [PubMed] [Google Scholar]
  111. Solter D., Dominis M., Damjanov I. Embryo-derived teratocarcinoma: I. The role of strain and gender in the control of teratocarcinogenesis. Int J Cancer. 1979 Dec 15;24(6):770–772. doi: 10.1002/ijc.2910240612. [DOI] [PubMed] [Google Scholar]
  112. Solter D., Knowles B. B. Monoclonal antibody defining a stage-specific mouse embryonic antigen (SSEA-1). Proc Natl Acad Sci U S A. 1978 Nov;75(11):5565–5569. doi: 10.1073/pnas.75.11.5565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Solter D., Skreb N., Damjanov I. Extrauterine growth of mouse egg-cylinders results in malignant teratoma. Nature. 1970 Aug 1;227(5257):503–504. doi: 10.1038/227503a0. [DOI] [PubMed] [Google Scholar]
  114. Squires P. E., Wakeman J. A., Chapman H., Kumpf S., Fidock M. D., Andrews P. W., Dunne M. J. Regulation of intracellular Ca2+ in response to muscarinic and glutamate receptor agonists during the differentiation of NTERA2 human embryonal carcinoma cells into neurons. Eur J Neurosci. 1996 Apr;8(4):783–793. doi: 10.1111/j.1460-9568.1996.tb01263.x. [DOI] [PubMed] [Google Scholar]
  115. Stevens L. C. Experimental production of testicular teratomas in mice of strains 129, A/He, and their F1 hybrids. J Natl Cancer Inst. 1970 Apr;44(4):923–929. [PubMed] [Google Scholar]
  116. Stevens L. C., Little C. C. Spontaneous Testicular Teratomas in an Inbred Strain of Mice. Proc Natl Acad Sci U S A. 1954 Nov;40(11):1080–1087. doi: 10.1073/pnas.40.11.1080. [DOI] [PMC free article] [PubMed] [Google Scholar]
  117. Stevens L. C. Origin of testicular teratomas from primordial germ cells in mice. J Natl Cancer Inst. 1967 Apr;38(4):549–552. [PubMed] [Google Scholar]
  118. Stevens L. C. The biology of teratomas. Adv Morphog. 1967;6:1–31. doi: 10.1016/b978-1-4831-9953-5.50005-6. [DOI] [PubMed] [Google Scholar]
  119. Stevens L. C. The development of transplantable teratocarcinomas from intratesticular grafts of pre- and postimplantation mouse embryos. Dev Biol. 1970 Mar;21(3):364–382. doi: 10.1016/0012-1606(70)90130-2. [DOI] [PubMed] [Google Scholar]
  120. Stevens L. C., Varnum D. S. The development of teratomas from parthenogenetically activated ovarian mouse eggs. Dev Biol. 1974 Apr;37(2):369–380. doi: 10.1016/0012-1606(74)90155-9. [DOI] [PubMed] [Google Scholar]
  121. Stoter G. Treatment strategies of testicular cancer in Europe. Int J Androl. 1987 Feb;10(1):407–415. doi: 10.1111/j.1365-2605.1987.tb00211.x. [DOI] [PubMed] [Google Scholar]
  122. Strickland S., Mahdavi V. The induction of differentiation in teratocarcinoma stem cells by retinoic acid. Cell. 1978 Oct;15(2):393–403. doi: 10.1016/0092-8674(78)90008-9. [DOI] [PubMed] [Google Scholar]
  123. Strickland S., Smith K. K., Marotti K. R. Hormonal induction of differentiation in teratocarcinoma stem cells: generation of parietal endoderm by retinoic acid and dibutyryl cAMP. Cell. 1980 Sep;21(2):347–355. doi: 10.1016/0092-8674(80)90471-7. [DOI] [PubMed] [Google Scholar]
  124. Temple S. The development of neural stem cells. Nature. 2001 Nov 1;414(6859):112–117. doi: 10.1038/35102174. [DOI] [PubMed] [Google Scholar]
  125. Teshima S., Shimosato Y., Hirohashi S., Tome Y., Hayashi I., Kanazawa H., Kakizoe T. Four new human germ cell tumor cell lines. Lab Invest. 1988 Sep;59(3):328–336. [PubMed] [Google Scholar]
  126. Thomson J. A., Itskovitz-Eldor J., Shapiro S. S., Waknitz M. A., Swiergiel J. J., Marshall V. S., Jones J. M. Embryonic stem cell lines derived from human blastocysts. Science. 1998 Nov 6;282(5391):1145–1147. doi: 10.1126/science.282.5391.1145. [DOI] [PubMed] [Google Scholar]
  127. Thomson J. A., Kalishman J., Golos T. G., Durning M., Harris C. P., Becker R. A., Hearn J. P. Isolation of a primate embryonic stem cell line. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7844–7848. doi: 10.1073/pnas.92.17.7844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  128. Tippett P., Andrews P. W., Knowles B. B., Solter D., Goodfellow P. N. Red cell antigens P (globoside) and Luke: identification by monoclonal antibodies defining the murine stage-specific embryonic antigens -3 and -4 (SSEA-3 and SSEA-4). Vox Sang. 1986;51(1):53–56. doi: 10.1111/j.1423-0410.1986.tb00209.x. [DOI] [PubMed] [Google Scholar]
  129. Umezawa A., Maruyama T., Inazawa J., Imai S., Takano T., Hata J. Induction of mcl1/EAT, Bcl-2 related gene, by retinoic acid or heat shock in the human embryonal carcinoma cells, NCR-G3. Cell Struct Funct. 1996 Apr;21(2):143–150. doi: 10.1247/csf.21.143. [DOI] [PubMed] [Google Scholar]
  130. Wakayama T., Perry A. C., Zuccotti M., Johnson K. R., Yanagimachi R. Full-term development of mice from enucleated oocytes injected with cumulus cell nuclei. Nature. 1998 Jul 23;394(6691):369–374. doi: 10.1038/28615. [DOI] [PubMed] [Google Scholar]
  131. Wilmut I., Schnieke A. E., McWhir J., Kind A. J., Campbell K. H. Viable offspring derived from fetal and adult mammalian cells. Nature. 1997 Feb 27;385(6619):810–813. doi: 10.1038/385810a0. [DOI] [PubMed] [Google Scholar]
  132. Xu C., Inokuma M. S., Denham J., Golds K., Kundu P., Gold J. D., Carpenter M. K. Feeder-free growth of undifferentiated human embryonic stem cells. Nat Biotechnol. 2001 Oct;19(10):971–974. doi: 10.1038/nbt1001-971. [DOI] [PubMed] [Google Scholar]
  133. Yeom Y. I., Fuhrmann G., Ovitt C. E., Brehm A., Ohbo K., Gross M., Hübner K., Schöler H. R. Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells. Development. 1996 Mar;122(3):881–894. doi: 10.1242/dev.122.3.881. [DOI] [PubMed] [Google Scholar]

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