Differentiation of TERA-2 human embryonal carcinoma cells into neurons and HCMV permissive cells

Pw, Andrews; Gönczöl, Éva; Sa, Plotkin; M, Dignazio; Jw, Oosterhuis

doi:10.1111/j.1432-0436.1986.tb00392.x

Cited by 72 publications

(39 citation statements)

References 39 publications

(28 reference statements)

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“…Although not a specific stem cell marker, SSEA expression is characteristic ofembryonic cells and embryonal carcinoma cells (11). It has been reported that db-cAMP treatment induces neuronal differentiation and down-regulation of SSEA expression in the teratocarcinoma cell line F9 (12). These preliminary data suggest that prostate carcinoma cells may express some stem cell markers and that these markers can be down-regulated by cytodifferentiation.…”

mentioning

confidence: 73%

Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP.

Bang

Pirnia²,

Fang³

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

230

172

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Recent clinicopathologic studies have shown that many prostatic adenonomas express focal neuroendocrine differentiation and that neuroendocrine differentiation is most apparent in advanced anaplastic tumors. While studying growth-regulatory signal nsduction events in human prostate carcinoma cell lines, we found that in two of four cell lines, the androgen-sensitive line LNCaP and the highly metastatic androgen-independent line PC-3-M, elevation of cAMP through addition of cAMP analogues or phosphodiesterase inhibitors induced a markediy neuronal morphology. Also in LNCaP cells ultrtructural analysis showed that cAMP induced the appearance of neurosecretory cell-like dense-core granules. Phenotypic analysis of untreated LNCaP and PC-3-M cells showed that both cell lines express markers of the neural crest incuding S-100, chromogranin A, pp60 , and neuron-specific enolase as well as the epithelial marker KS1/4 and stage-specific embryonic antigen 4. In PC-3-M cells, cAMP markedly elevated neuron-specific enolase protein and caused an increase in the specific activity of the neuroendocrine marker ppWw, and in both cell lines expression ofKS1/4 and stage-specific embryonic antigen 4 was down-regulated. In addiion to effects on lineage markers, cAMP treatment induced GI synchronization, growth arrest, and loss of clonogenicity, indicating terminal differentiation. Our data provide direct evidence of plastic in the lineag commitment of adenocarcinoma of the prostate. We have shown that cellpermeant cAMP analogue can induce terminal differentiation, suggesting that hydrolysis-resistant cyclic nucleotides may present an additional approach to the treatment of advanced prostate cancer.In an effort to develop new anticancer drugs directed at unique aspects of prostate cancer biology, we have been studying the signal transduction pathways regulating the growth of human prostate adenocarcinoma cells in vitro. As reported previously, we found that addition of dibutyryl (db) cAMP to the androgen-independent prostate carcinoma cell line PC-3 causes induction of type (32 transforming growth factor (TGF-g32) mRNA, production of bioactive TGF-P2, and growth arrest (1).We have subsequently studied the effect of cAMP derivatives and phosphodiesterase inhibitors on the other two commonly available prostate carcinoma cell lines, DU 145 and LNCaP, as well as the highly metastatic variant of PC-3, PC-3-M, and found that all lines were growth inhibited by elevation of intracellular cAMP (data not shown). Data presented here demonstrate that in two ofthese lines, LNCaP and PC-3-M, elevation of intracellular cAMP induces permanent conversion from an epithelial to a neuronal morphology and that these cells express markers of the neuroendocrine phenotype. These data suggest that these cell lines, which are derived from metastatic adenocarcinoma of the prostate, contain or consist of multipotent cells capable of both neuroendocrine and epithelial differentiation.

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mentioning

confidence: 73%

Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP.

Bang

Pirnia²,

Fang³

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

230

172

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“…A low level conversion of retinol to RA has been detected in murine F9 embryonal carcinoma cells (Williams and Napoli, 1985). Retinol has also been reported to mediate neuronal dierentiation of F9 and NT2/D1 cells but requires much higher doses than RA (Williams and Napoli, 1985;Andrews et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

Specific retinoid receptors cooperate to signal growth suppression and maturation of human embryonal carcinoma cells

et al. 1998

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This study addresses the contributions of speci®c retinoid receptors during all-trans-retinoic acid (RA)-mediated dierentiation and growth suppression of human embryonal carcinoma cells. The pleiotropic eects of RA are mediated by retinoic acid receptors (RARs) and retinoid X receptors (RXRs), members of the nuclear receptor family of transcription factors. After RA-treatment the multipotent human embryonal carcinoma cell line NTERA-2 clone D1 (NT2/D1) displays limited proliferative potential, reduced tumorigenicity, and morphologic and immunophenotypic neuronal maturation. RARg over-expression in NT2/D1 cells signals mesenchymal NT2/D1 terminal dierentiation while RARa and RARb do not and RARg overcomes retinoid resistance in an NT2/D1 clone (NT2/D1-R1) having deregulated RARg expression. Since RARg transfectants do not display neuronal maturation, this study sought to identify cooperating retinoid receptors engaged in NT2/D1 dierentiation. Through gain of function experiments, this report highlights RXRb as playing an important role along with RARg in signaling dierentiation of NT2/D1 cells. Stable over-expression of RXRb, but not RXRa or RXRg, was found to signal NT2/D1 growth suppression and to induce a non-neuronal morphology and immunophenotype. Notably, co-transfection of RARg and RXRb resulted in marked growth suppression and for the ®rst time, expression of typical neuronal markers of NT2/D1 dierentiation. To clarify the role of RXRb and RARg in this dierentiation program, a modi®ed transient ®broblast growth factor-4 (FGF4) promoter-enhancer reporter assay that re¯ects eective RA-mediated dierentiation of NT2/D1 cells was employed. Transfection of RARg or RXRb in NT2/D1 cells augments transcriptional repression of the FGF4 reporter and RARg and RXRb co-transfection markedly repressed reporter activity, indicating the combined role of these receptors in RA-induced NT2/D1 dierentiation. Taken together, these ®ndings reveal speci®c retinoid receptors must cooperate to signal terminal growth suppression and maturation of NT2/D1 cells. Since the transcriptional repression of FGF4 is coupled to the eective maturation of human embryonal carcinoma cells, the described co-transfection strategy should prove useful to identify genes with positive or negative eects on the dierentiation program of these tumor cells.

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“…In the presence of RA, the human embryonal carcinoma cell line NT-2/D1 differentiates in vitro, predominantly into cell types of neuronal lineage (23)(24)(25). hCMV can replicate in RA-induced differentiated cells but not in uninduced NT-2/D1 cells, suggesting a link between RA action and CMV replication in this in vitro model for developmental expression (24,26).…”

mentioning

confidence: 99%

“…hCMV can replicate in RA-induced differentiated cells but not in uninduced NT-2/D1 cells, suggesting a link between RA action and CMV replication in this in vitro model for developmental expression (24,26). The failure of hCMV to replicate in the uninduced cells, which resemble cells in very early embryonic stages, is due to extremely low levels of transcription initiation by the major immediate-early (IE) gene promoter (MIEP) (27)(28)(29).…”

mentioning

confidence: 99%

Retinoic acid receptors initiate induction of the cytomegalovirus enhancer in embryonal cells.

Ghazal

DeMattei

Giulietti

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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Reactivation of latent virus is believed to result from a signal transduction event that induces Im teearly (IE) gene transcription. Evidence is presented that the major IE promoter (MIEP) of human cytomegalovirus (hCMV) is activated by physiological levels of retinoic acid (RA) in human embryonal cardnoma cells. Mutagenesis experiments localized in the MIEP enhancer, a retinoic acidresponsive element composed of a direct repeat separated by five nucleotides. Protein-DNA binding experiments revealed that this element functions as a specific target site for the direct interaction of nuclear receptor proteins for RA. These fildings implicate the biologically active derivative of vitamin A (RA) as a potential modulator of hCMV pathogenesis in infants and immunocompromised adults.

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Differentiation of TERA-2 human embryonal carcinoma cells into neurons and HCMV permissive cells

Cited by 72 publications

References 39 publications

Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP.

Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP.

Specific retinoid receptors cooperate to signal growth suppression and maturation of human embryonal carcinoma cells

Retinoic acid receptors initiate induction of the cytomegalovirus enhancer in embryonal cells.

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