Retinoid Target Gene Activation during Induced Tumor Cell Differentiation: Human Embryonal Carcinoma as a Model

Abstract

Many agents that exhibit chemopreventive activity are able to mediate a differentiation response in premalignant and malignant tissues. One of the most widely studied classes of tumor differentiation agents is the retinoids. There is rapidly evolving evidence for beneficial retinoid actions in the prevention or treatment of clinical tumors. However, the use of retinoids in the clinic is limited by acquired resistance and toxicity, especially when administered chronically in preventive strategies. Although retinoids are known to regulate gene transcription by activating retinoid receptors, the identity of the target genes that mediate the beneficial effects of retinoids are largely unknown. Here we review a useful model of retinoid-induced tumor cell differentiation: human embryonal carcinoma. The pluripotent nature and ease of use make human embryonal carcinoma cells a valuable and practical complement to human embryonic stem cells as an in vitro model of early human development. In addition, retinoid treatment of human embryonal carcinoma is an important model of induced tumor cell differentiation because retinoids cause the reversal of the malignant phenotype coincident with terminal neuronal differentiation. We have used both de novo and candidate approaches with this system in an effort to uncover critical downstream targets of retinoid receptors during differentiation induction. J. Nutr. 133: 273S-276S, 2003.

Differential Expression of ETS Family Transcription Factors in NCCIT Human Embryonic Carcinoma Cells upon Retinoic Acid-Induced Differentiation

“…6,7) In this study, we measured the expression patterns of 27 ETS transcription factors in NCCIT cells upon RA-mediated differentiation. Differentiation was induced by treating cells with RA for 10 d, and qRT-PCR was performed using primers specific for genes encoding each of the 27 ETS family transcription factors and the stem cell transcription factor OCT4, as a control 18) (Table 2).…”

“…5) Moreover, RA markedly inhibits clonal growth and tumorigenesis in cancer-derived stem cells. [6][7][8] Therefore, RA-mediated differentiation of EC cells is a useful model for studies of stem cell-derived pluripotency and tumorigenesis.…”

“…In fact, the expression profiles of ETS family members in cancer cell lines derived from breast and prostate tissues are highly variable and context-dependent. [7][8][9][10][11][12][13][14][15][16][17][18][19] In this study, to identify critical ETS transcription factor(s) implicated in the regulatory mechanism of pluripotent and tumorigenic EC cells, we explored the relative mRNA expression levels of ETS factors in NCCIT cells upon RA-mediated differentiation, and then investigated the effects of selected factors on cell proliferation potential. The findings of this study contribute to our understanding of the roles of oncogenic ETS factors in tumorigenic and pluripotent processes of stem cells.…”

A p53-dominant transcriptional response to cisplatin in testicular germ cell tumor-derived human embyronal carcinoma

“…NT2/D1 cells were derived from a metastasis of a TGCT patient and retain the major cytogenetic and cellular features of these tumors (Sperger et al, 2003). NT2/D1 cells are highly malignant but can be induced to differentiate and lose tumorigenicity with all-trans retinoic acid (Andrews, 1998;Spinella et al, 2003). Thus, they are an excellent model of differentiation of tumor cells and pluripotent stem cells.…”

p53 in human embryonal carcinoma: identification of a transferable, transcriptional repression domain in the N-terminal region of p53

“…It has been proposed that EC sensitivity to cisplatin may be due to the presence of abundant, wild-type p53 (Chresta et al, 1996;Lutzker and Levine, 1996;Houldsworth et al, 1998;Zamble et al, 1998;Zeng et al, 2000;Curtin et al, 2001;Lutzker et al, 2001), although conflicting reports on the relative importance of p53 in cisplatin response do exist (Burger et al, 1998(Burger et al, , 1999Kersemaekers et al, 2002). Curability of human EC has been proposed to be linked to their retained maturation potential (Jones and Vasey, 2003;Spinella et al, 2003). Cultured human EC differentiate in response to RA treatment, undergoing arrest in the G1 phase of the cell cycle, differentiation along a neuronal pathway, and loss of tumorigenicity (Spinella et al, 1999.…”