Inhibition of proliferation and induction of differentiation of pluripotent human embryonal carcinoma cells by osteogenic protein-1 (or bone morphogenetic protein-7).
BACKGROUND
Osteogenic protein-1 (OP-1) is a member of the transforming growth factor-beta super family closely related to the bone morphogenetic proteins and also known as bone morphogenetic protein-7. Other members of this family of growth factors influence cell differentiation as well as cell growth in a number of systems. The Drosophila homolog encoded by the decapentaplegic locus is involved in dorsal-ventral pattern formation during embryogenesis, whereas the expression of several bone morphogenetic proteins including OP-1 is developmentally regulated in mammalian embryos.


METHODS
The effect of recombinant human OP-1 on the proliferation and differentiation of an established pluripotent human embryonal carcinoma (EC) cell line, NTERA2, and three nullipotent human EC cell lines, 2102Ep, 833KE and TERA-1, was investigated. These cells were grown under reduced serum conditions, and differentiation was monitored by morphology and expression of marker antigens.


RESULTS
OP-1 inhibited proliferation of NTERA2 and induced their differentiation, marked by changes in cellular morphology, the loss of EC cell antigens (SSEA3, SSEA4, the liver isozyme of alkaline phosphatase), and the appearance of new antigens, notably SSEA1 and class 1 major histocompatibility complex antigens. These changes were irreversible and did not involve significant cell degeneration or cell death. The OP-1-induced differentiation of NTERA2 appeared distinct from that induced by either retinoic acid or hexamethylene bisacetamide. Nevertheless, OP-1 did induce the homeobox gene, HOXA1. By contrast, OP-1 elicited only a limited and partial response from the nullipotent EC cell lines.


CONCLUSIONS
Our results suggest that pluripotent human EC cells differentiate in response to OP-1 and that this factor can modulate the differentiation induced by retinoic acid. Like other members of the transforming growth factor-beta super family, OP-1 might play an inductive role in the early embryo. The results also suggest a possible therapeutic value for OP-1 in the treatment of some germ cell tumors.
Andrews
P W
PW
Wistar Institute of Anatomy and Biology, Philadelphia, Pennsylvania.
Damjanov
I
I
Berends
J
J
Kumpf
S
S
Zappavigna
V
V
Mavilio
F
F
Sampath
K
K
D000081:Acetamides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D018236:Carcinoma, Embryonal / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005801:Genes, Homeobox; D006801:Humans; D011506:Proteins / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000081:Acetamides; D000970:Antineoplastic Agents; C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D011506:Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D012313:RNA; C014026:hexamethylene bisacetamide