The investigation of cell lines derived from human teratocarcinomas can provide information pertinent to the characteristics of human embryonic cells, as well as knowledge essential for improving methods for clinically managing these tumors. Of crucial importance is the definition of the embryonal carcinoma (EC) stem cells and analysis of their properties. Previously, we cloned a line of human EC cells, 2102Ep, which undergoes limited differentiation along a trophoblastic lineage in culture. These studies have shown that human EC cells, in contrast with their murine counterparts, express the cell surface antigen SSEA-3, but not SSEA-1, low levels of HLA-A,B,C and beta-2-microglobulin, and also EGF receptor. Spontaneous differentiation under some culture conditions leads to the appearance of SSEA-1-positive cells, which synthesize fibronectin, and also a small number of cells with the ultrastructural features of trophoblastic giant cells and cytoplasmic HCG. Further work has now led to the identification of a new monoclonal antibody-defined antigenic determinant, SSEA-4, also characteristically expressed by human EC cells. Both SSEA-3 and SSEA-4 epitopes are contained within a group of globoseries oligosaccharides occurring as glycosphingolipids in the plasma membrane of these cells. They are thus related to the P-blood group system and are also found on red blood cells but few other cell types. Other monoclonal antibodies raised to human EC cells include two defining epitopes associated with the liver isozyme of alkaline phosphatase, an enzyme strongly expressed on the surface of human EC cells; two antibodies, TRA-1-60 and TRA-1-81, defining two new epitopes characteristic of human EC cells; and also two defining widely distributed antigens encoded by genes on human chromosomes 1 and 11. A second series of cloned human EC cells derived from the teratocarcinoma line TERA-2 have been characterized. Most of these cells express the characteristic properties of human EC cells, but, unlike the other available lines, they are able to differentiate into a variety of somatic cell types: injected into nude mice they form tumors containing glandular structures and neural elements as well as nests of EC cells; in culture, they can be induced to differentiate into various cells, including neurons, by exposure to retinoic acid. This differentiation is irreversible and accompanied by the loss of the human EC cell characteristics. Among the differentiated cells are those permissive for HCMV replication; a virus responsible for a variety of birth defects associated with the nervous system; the EC cells are not permissive. Preliminary data suggest that at least two cell lineages arise following exposure to retinoic acid, and we are currently studying these by following the differential expression of a number of cell surface antigens. (M)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA029894-06
Application #
3168909
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1982-08-01
Project End
1988-07-31
Budget Start
1987-08-01
Budget End
1988-07-31
Support Year
6
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Andrews, P W; Casper, J; Damjanov, I et al. (1996) Comparative analysis of cell surface antigens expressed by cell lines derived from human germ cell tumours. Int J Cancer 66:806-16
Rideg, K; Hirka, G; Prakash, K et al. (1994) DNA-binding proteins that interact with the 19-base pair (CRE-like) element from the HCMV major immediate early promoter in differentiating human embryonal carcinoma cells. Differentiation 56:119-29
Andrews, P W; Damjanov, I; Berends, J et al. (1994) Inhibition of proliferation and induction of differentiation of pluripotent human embryonal carcinoma cells by osteogenic protein-1 (or bone morphogenetic protein-7). Lab Invest 71:243-51
Wenk, J; Andrews, P W; Casper, J et al. (1994) Glycolipids of germ cell tumors: extended globo-series glycolipids are a hallmark of human embryonal carcinoma cells. Int J Cancer 58:108-15
Ackerman, S L; Knowles, B B; Andrews, P W (1994) Gene regulation during neuronal and non-neuronal differentiation of NTERA2 human teratocarcinoma-derived stem cells. Brain Res Mol Brain Res 25:157-62
Fenderson, B A; Radin, N; Andrews, P W (1993) Differentiation antigens of human germ cell tumours: distribution of carbohydrate epitopes on glycolipids and glycoproteins analyzed using PDMP, an inhibitor of glycolipid synthesis. Eur Urol 23:30-6;discussion 36-7
Giwercman, A; Andrews, P W; Jorgensen, N et al. (1993) Immunohistochemical expression of embryonal marker TRA-1-60 in carcinoma in situ and germ cell tumors of the testis. Cancer 72:1308-14
Fenderson, B A; Andrews, P W (1992) Carbohydrate antigens of embryonal carcinoma cells: changes upon differentiation. APMIS Suppl 27:109-18
Marrink, J; Andrews, P W; van Brummen, P J et al. (1991) TRA-1-60: a new serum marker in patients with germ-cell tumors. Int J Cancer 49:368-72
Andrews, P W; Marrink, J; Hirka, G et al. (1991) The surface antigen phenotype of human embryonal carcinoma cells: modulation upon differentiation and viral infection. Recent Results Cancer Res 123:63-83

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