Control of Cell Behavior During Vertebrate Development by
            <i>Slug</i>
            , a Zinc Finger Gene

Nieto, M. Ángela; Sargent, Michael G.; Wilkinson, David G.; Cooke, Jonathan

doi:10.1126/science.7513443

Cited by 723 publications

(628 citation statements)

References 20 publications

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“…Furthermore, the 5AdC-induced SKNAS sphere culture grown in the sphere-forming condition without 5AdC for 1.5 y (day 592) expressed higher levels of SOX2, CD133, and neural crest stem cell markers (p75 NTR , SOX9, SOX10, SLUG, Musashi-1) compared with the non-drug-treated sphere culture and the monolayer counterpart (Fig. 1C), suggesting that these SKNAS spheres express a phenotype more similar to neural crest stem cells (14)(15)(16)(17)(18). Immunocytochemical assay further showed that the 5AdC-induced SKNAS spheres at Fig.…”

Section: Short-term Treatments With Epigenetic Modifiers Enhance the mentioning

confidence: 99%

Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas

Ikegaki

Shimada

Fox

et al. 2013

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

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Cancer stem cells (CSCs) are plastic in nature, a characteristic that hampers cancer therapeutics. Neuroblastoma (NB) is a pediatric tumor of neural crest origin, and half of the cases are highly aggressive. By treating NB cell lines [SKNAS, SKNBE(2)C, CHP134, and SY5Y] with epigenetic modifiers for a short time, followed by sphere-forming culture conditions, we have established stem cell-like NB cells that are phenotypically stable for more than a year. These cells are characterized by their high expression of stemness factors, stem cell markers, and open chromatin structure. We referred to these cells as induced CSCs (iCSCs). SKNAS iCSC and SKNBE(2)C iCSC clones (as few as 100 cells) injected s.c. into SCID/Beige mice formed tumors, and in one case, SKNBE(2)C iCSCs metastasized to the adrenal gland, suggesting their increased metastatic potential. SKNAS iCSC xenografts showed the histologic appearance of totally undifferentiated large-cell NBs (LCNs), the most aggressive and deadly form of NB in humans. Immunohistochemical analyses showed that SKNAS iCSC xenografts expressed high levels of the stem cell marker CXCR4, whereas the SKNAS monolayer cell xenografts did not. The patterns of CXCR4 and MYC expression in SKNAS iCSC xenografts resembled those in the LCNs. The xenografts established from the NB iCSCs shared two common features: the LCN phenotype and high-level MYC/MYCN expression. These observations suggest both that NB cells with large and vesicular nuclei, representing their open chromatin structure, are indicative of stem cell-like tumor cells and that epigenetic changes may have contributed to the development of these most malignant NB cells.tumor initiating cells | prominent nucleoli N euroblastoma (NB) is the most common extracranial pediatric malignancy. Although some NBs are easily treatable, nearly 50% of the tumors exhibit aggressive behavior. The International Neuroblastoma Risk Group Classification is used to classify NB at diagnosis (1). High-risk NBs are associated with older age, advanced stages, unfavorable histologic features, widespread tumor dissemination, and poor long-term survival (1). Current treatment for these NBs includes high-dose chemotherapy or myeloablative cytotoxic therapy with autologous hematopoietic stem cell transplantation (2). However, late relapse is often seen despite achieving complete clinical remission. A subset of high-risk NBs, which is refractory to current frontline therapy designed for high-risk NB, is termed ultra-high-risk NB (3, 4).NB is histopathologically defined as neuroblastic tumors with less than 50% Schwannian stromal components. On the basis of the degree of neuronal differentiation, NB is further divided into undifferentiated (UD), poorly differentiated, and differentiating subtypes (5, 6). A unique histological subset of NBs within the UD and poorly differentiated subtypes has also been identified (7,8). These tumors are uniformly composed of large cells with sharply outlined nuclear membranes and one to four prominent nucleoli and are referred...

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Section: Short-term Treatments With Epigenetic Modifiers Enhance the mentioning

confidence: 99%

Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas

Ikegaki

Shimada

Fox

et al. 2013

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

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“…7c). There are data implicating slug in neural crest transformation and migration (Nieto et al, 1994). (See Garcia-Castro et al, 2002, LaBonne et al, 2000, Luo et al, 2003, for further review of genes expressed by forming neural crest.…”

Section: Wnt and Tgf〉 Signaling Pathways Interact To Mediate Embryonimentioning

confidence: 99%

“…19). Compatible with this idea is the fact that Snail is expressed by fibroblasts and Slug by migrating neural crest cells (Nieto et al, 1994). Snail binds to the E-boxes (Fig.…”

Section: Mechanisms That Produce Migrating Mesenchymal Cellsmentioning

confidence: 99%

The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it

Hay

2005

Developmental Dynamics

578

479

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This review centers on the role of the mesenchymal cell in development. The creation of this cell is a remarkable process, one where a tightly knit, impervious epithelium suddenly extends filopodia from its basal surface and gives rise to migrating cells. The ensuing process of epithelial-mesenchymal transformation (EMT) creates the mechanism that makes it possible for the mesenchymal cell to become mobile, so as to leave the epithelium and move through the extracellular matrix. EMT is now recognized as a very important mechanism for the remodeling of embryonic tissues, with the power to turn an epithelial somite into sclerotome mesenchyme, and the neural crest into mesenchyme that migrates to many targets. Thus, the time has come for serious study of the underlying mechanisms and the signaling pathways that are used to form the mesenchymal cell in the embryo. In this review, I discuss EMT centers in the embryo that are ready for such serious study and review our current understanding of the mechanisms used for EMT in vitro, as well as those that have been implicated in EMT in vivo. The purpose of this review is not to describe every study published in this rapidly expanding field but rather to stimulate the interest of the reader in the study of the role of the mesenchymal cell in the embryo, where it plays profound roles in development. In the adult, mesenchymal cells may give rise to metastatic tumor cells and other pathological conditions that we will touch on at the end of the review. Developmental Dynamics 233:706 -720, 2005.

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“…Slug is a zinc finger transcription factor that has been related to neural crest (29) and limb bud development, where it may be involved in mesenchymal differentiation (30,31). A third gene not previously related to ARMS, IGFBP5, was highly induced in all PAX3-FKHR transduced lines.…”

Section: Induction Of a Myogenic Transcription Program By Pax3-fkhrmentioning

confidence: 99%

cDNA microarrays detect activation of a myogenic transcription program by the PAX3-FKHR fusion oncogene

et al. 1999

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Alveolar rhabdomyosarcoma is an aggressive pediatric cancer of striated muscle characterized in 60% of cases by a t(2;13)(q35;q14). This results in the fusion of PAX3, a developmental transcription factor required for limb myogenesis, with FKHR, a member of the forkhead family of transcription factors. The resultant PAX3-FKHR gene possesses transforming properties; however, the effects of this chimeric oncogene on gene expression are largely unknown. To investigate the actions of these transcription factors, both Pax3 and PAX3-FKHR were introduced into NIH 3T3 cells, and the resultant gene expression changes were analyzed with a murine cDNA microarray containing 2,225 elements. We found that PAX3-FKHR but not PAX3 activated a myogenic transcription program including the induction of transcription factors MyoD, Myogenin, Six1, and Slug as well as a battery of genes involved in several aspects of muscle function. Notable among this group were the growth factor gene Igf2 and its binding protein Igfbp5. Relevance of this model was suggested by verification that three of these genes (IGFBP5, HSIX1, and Slug) were also expressed in alveolar rhabdomyosarcoma cell lines. This study utilizes cDNA microarrays to elucidate the pattern of gene expression induced by an oncogenic transcription factor and demonstrates the profound myogenic properties of PAX3-FKHR in NIH 3T3 cells.

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Control of Cell Behavior During Vertebrate Development by Slug , a Zinc Finger Gene

Cited by 723 publications

References 20 publications

Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas

Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas

The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it

cDNA microarrays detect activation of a myogenic transcription program by the PAX3-FKHR fusion oncogene

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