All-trans-retinoic acid and hexamethylene bisacetamide (HMBA) regulate TGF-alpha and Hst-1/kFGF expression in differentiation sensitive but not in resistant human teratocarcinomas.
The multipotent human teratocarcinoma (TC) cell NTera-2 clone D1 (abbreviated NT2/D1) differentiates into a neuronal lineage after retinoic acid (RA) treatment and a distinct phenotype after hexamethylene bisacetamide (HMBA) treatment. We previously reported that RA treatment of NT2/D1 cells reduces cellular cloning efficiency and nude mouse tumorigenicity. This accompanied a loss of mRNA expression of transforming growth factor-alpha (TGF-alpha) and the fibroblast growth factor kFGF, also known as hst-1 (abbreviated hst-1/kFGF). This study extends prior work by reporting that the distinct phenotype induced by HMBA also decreases cloning efficiency, tumorigenicity, and TGF-alpha and hst-1/kFGF mRNA expression in NT2/D1 cells. These RNA findings were confirmed by measurements of growth factor protein in the conditioned media of inducer-treated and untreated NT2/D1 cells. In two established human TC lines refractory to the actions of RA, N2102ep and Tera-1, RA fails to decrease expression of either growth factor despite induction of its nuclear receptor, RAR-beta. However, HMBA induces morphologic maturation and down-regulation of these growth factors in N2102ep cells. This indicates that the loss of TGF-alpha and hst-1/kFGF expression serves as a new marker of differentiation in human TCs. To explore the effects of these growth factors on growth and differentiation of NT2/D1 cells, TGF-alpha or hst-1/kFGF protein was added following inducer treatment or no treatment. Neither growth factor blocked immunophenotypic differentiation, but both promoted the growth of uninduced NT2/D1 cells in cloning assays.(ABSTRACT TRUNCATED AT 250 WORDS)
Miller
W H
WH
Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, New York 10021.
Maerz
W J
WJ
Kurie
J
J
Moy
D
D
Baselga
J
J
Lucas
D A
DA
Grippo
J F
JF
Masui
H
H
Dmitrovsky
E
E
D000081:Acetamides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002999:Clone Cells; D004351:Drug Resistance; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000032:analysis / Q000096:biosynthesis*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000096:biosynthesis*; D018243:Teratocarcinoma; D016211:Transforming Growth Factor alpha / Q000032:analysis / Q000096:biosynthesis*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000081:Acetamides; D000970:Antineoplastic Agents; C496445:FGF4 protein, human; D051519:Fibroblast Growth Factor 4; D011518:Proto-Oncogene Proteins; D016211:Transforming Growth Factor alpha; D014212:Tretinoin; D005346:Fibroblast Growth Factors; C014026:hexamethylene bisacetamide