All-trans-retinoic acid and hexamethylene bisacetamide (HMBA) regulate TGF-α and Hst-1/kFGF expression in differentiation sensitive but not in resistant human teratocarcinomas
Wilson H. Miller Jr.
Laboratory of Molecular Medicine, Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, New York, USA
Search for more papers by this authorWolfgang J. Maerz
Laboratory of Molecular Medicine, Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, New York, USA
Search for more papers by this authorJonathan Kurie
Laboratory of Molecular Medicine, Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, New York, USA
Search for more papers by this authorDenise Moy
Laboratory of Molecular Medicine, Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, New York, USA
Search for more papers by this authorJose Baselga
Laboratory of Receptor Biology, Sloan-Kettering Institute, New York, New York, USA
Search for more papers by this authorDebra A. Lucas
Department of Toxicology and Pathology, Hoffman LaRoche, Nutley, New Jersey, USA
Search for more papers by this authorJoseph F. Grippo
Department of Toxicology and Pathology, Hoffman LaRoche, Nutley, New Jersey, USA
Search for more papers by this authorHideo Masui
Laboratory of Receptor Biology, Sloan-Kettering Institute, New York, New York, USA
Search for more papers by this authorEthan Dmitrovsky
Laboratory of Molecular Medicine, Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, New York, USA
Search for more papers by this authorWilson H. Miller Jr.
Laboratory of Molecular Medicine, Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, New York, USA
Search for more papers by this authorWolfgang J. Maerz
Laboratory of Molecular Medicine, Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, New York, USA
Search for more papers by this authorJonathan Kurie
Laboratory of Molecular Medicine, Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, New York, USA
Search for more papers by this authorDenise Moy
Laboratory of Molecular Medicine, Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, New York, USA
Search for more papers by this authorJose Baselga
Laboratory of Receptor Biology, Sloan-Kettering Institute, New York, New York, USA
Search for more papers by this authorDebra A. Lucas
Department of Toxicology and Pathology, Hoffman LaRoche, Nutley, New Jersey, USA
Search for more papers by this authorJoseph F. Grippo
Department of Toxicology and Pathology, Hoffman LaRoche, Nutley, New Jersey, USA
Search for more papers by this authorHideo Masui
Laboratory of Receptor Biology, Sloan-Kettering Institute, New York, New York, USA
Search for more papers by this authorEthan Dmitrovsky
Laboratory of Molecular Medicine, Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, New York, USA
Search for more papers by this authorAbstract
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-α (TGF-α) 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-α 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-β. However, HMBA induces morphologic maturation and down-regulation of these growth factors in N2102ep cells. This indicates that the loss of TGF-α 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-α 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. Growth factor expression studies were extended from cultured TCs to germ cell tumor biopsies, where TGF-α was expressed in all and hst-1/kFGF was expressed in a subset of examined tumors. Together, these findings reveal that TGF-α and hst-1/kFGF are differentiation markers in human teratocarcinomas that appear to promote tumor cell growth without blocking differentiation.
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