Cell Cycle Deregulation in Ewing's Sarcoma Pathogenesis

Ewing's sarcoma is a highly aggressive pediatric tumor of bone that usually contains the characteristic chromosomal translocation t(11;22)(q24;q12). This translocation encodes the oncogenic fusion protein EWS/FLI, which acts as an aberrant transcription factor to deregulate target genes necessary for oncogenesis. One key feature of oncogenic transformation is dysregulation of cell cycle control. It is therefore likely that EWS/FLI and other cooperating mutations in Ewing's sarcoma modulate the cell cycle to facilitate tumorigenesis. This paper will summarize current published data associated with deregulation of the cell cycle in Ewing's sarcoma and highlight important questions that remain to be answered

EWS/FLI Mediates Transcriptional Repression via NKX2.2 during Oncogenic Transformation in Ewing's Sarcoma

EWS/FLI is a master regulator of Ewing's sarcoma formation. Gene expression studies in A673 Ewing's sarcoma cells have demonstrated that EWS/FLI downregulates more genes than it upregulates, suggesting that EWS/FLI, and/or its targets, function as transcriptional repressors. One critical EWS/FLI target, NKX2.2, is a transcription factor that contains both transcriptional activation and transcriptional repression domains, raising the possibility that it mediates portions of the EWS/FLI transcriptional signature. We now report that microarray analysis demonstrated that the transcriptional profile of NKX2.2 consists solely of downregulated genes, and overlaps with the EWS/FLI downregulated signature, suggesting that NKX2.2 mediates oncogenic transformation via transcriptional repression. Structure-function analysis revealed that the DNA binding and repressor domains in NKX2.2 are required for oncogenesis in Ewing's sarcoma cells, while the transcriptional activation domain is completely dispensable. Furthermore, blockade of TLE or HDAC function, two protein families thought to mediate the repressive function of NKX2.2, inhibited the transformed phenotype and reversed the NKX2.2 transcriptional profile in Ewing's sarcoma cells. Whole genome localization studies (ChIP-chip) revealed that a significant portion of the NKX2.2-repressed gene expression signature was directly mediated by NKX2.2 binding. These data demonstrate that the transcriptional repressive function of NKX2.2 is necessary, and sufficient, for the oncogenic phenotype of Ewing's sarcoma, and suggest a therapeutic approach to this disease

Cell Cycle Deregulation in Ewing's Sarcoma Pathogenesis.

Ewing's sarcoma is a highly aggressive pediatric tumor of bone that usually contains the characteristic chromosomal translocation t(11;22)(q24;q12). This translocation encodes the oncogenic fusion protein EWS/FLI, which acts as an aberrant transcription factor to deregulate target genes necessary for oncogenesis. One key feature of oncogenic transformation is dysregulation of cell cycle control. It is therefore likely that EWS/FLI and other cooperating mutations in Ewing's sarcoma modulate the cell cycle to facilitate tumorigenesis. This paper will summarize current published data associated with deregulation of the cell cycle in Ewing's sarcoma and highlight important questions that remain to be answered

Fibroblast Growth Factor Receptor 1 and Related Ligands in Small-Cell Lung Cancer

Introduction: Small-cell lung cancer (SCLC) accounts for 15% of all lung cancers and has been understudied for novel therapies. Signaling through fibroblast growth factors (FGF2, FGF9) and their high-affinity receptor has recently emerged as a contributing factor in the pathogenesis and progression of non-small-cell lung cancer. In this study, we evaluated fibroblast growth factor receptor 1 (FGFR1) and ligand expression in primary SCLC samples. Methods: FGFR1 protein expression, messenger RNA (mRNA) levels, and gene copy number were determined by immunohistochemistry (IHC), mRNA in situ hybridization, and silver in situ hybridization, respectively, in primary tumors from 90 patients with SCLC. Protein and mRNA expression of the FGF2 and FGF9 ligands were determined by IHC and mRNA in situ hybridization, respectively. In addition, a second cohort of 24 SCLC biopsy samples with known FGFR1 amplification by fluorescence in situ hybridization was assessed for FGFR1 protein expression by IHC. Spearman correlation analysis was performed to evaluate associations of FGFR1, FGF2 and FGF9 protein levels, respective mRNA levels, and FGFR1 gene copy number. Results: FGFR1 protein expression by IHC demonstrated a significant correlation with FGFR1 mRNA levels (p < 0.0001) and FGFR1 gene copy number (p = 0.03). The prevalence of FGFR1 mRNA positivity was 19.7%. FGFR1 mRNA expression correlated with both FGF2 (p = 0.0001) and FGF9 (p = 0.002) mRNA levels, as well as with FGF2 (p = 0.01) and FGF9 (p = 0.001) protein levels. There was no significant association between FGFR1 and ligands with clinical characteristics or prognosis. In the second cohort of specimens with known FGFR1 amplification by fluorescence in situ hybridization, 23 of 24 had adequate tumor by IHC, and 73.9% (17 of 23) were positive for FGFR1 protein expression. Conclusions: A subset of SCLCs is characterized by potentially activated FGF/FGFR1 pathways, as evidenced by positive FGF2, FGF9, and FGFR1 protein and/or mRNA expression. FGFR1 protein expression is correlated with FGFR1 mRNA levels and FGFR1 gene copy number. Combined analysis of FGFR1 and ligand expression may allow selection of patients with SCLC to FGFR1 inhibitor therapy

Thick brachiopod shell concentrations from prodelta and siliciclastic ramp in a Tortonian Atlantic–Mediterranean strait (Miocene, Guadix Basin, southern Spain)

Carbonate production by brachiopods in shallow-water habitats is generally expected to be not sufficiently high and temporally persistent to allow them to form very thick and densely packed shell concentrations. The formation of thick brachiopod concentrations requires long-term persistence of populations with high density of individuals, and such circumstances are assumed to be rare especially during the Cenozoic. However, here we show that the large-sized brachiopod Terebratula terebratula, the most common species in benthic assemblages with epifaunal bivalves and irregular echinoids, formed several decameter- to meter-thick, densely packed concentrations in shallow siliciclastic, high-energy environments, in a seaway connecting the Atlantic Ocean with the Mediterranean Sea during the Latest Tortonian (Late Miocene, Guadix Basin, southern Spain). This brachiopod formed (1) meter-scale, thick, parautochthonous concentrations in a prodelta setting and (2) thin, mainly allochthonous, tide- and storm-reworked concentrations in megaripples and dunes. The abundance of brachiopods at the spatial scale of the Guadix Basin seems to be mainly related to intermediate levels of sedimentation rate and current velocity because abundance and thickness of shell concentrations decline both (1) in onshore direction towards delta foresets with high sedimentation rate generated by debris flows and (2) in offshore direction with increasing levels of tide- and storm-induced substrate instability. Although brachiopods in dune and megaripple deposits are more fragmented, disarticulated, and sorted, and have a higher pedicle/brachial valve ratio than in prodelta deposits, taphonomic damage is still relatively high in prodelta deposits. Terebratula terebratula thus formed thick concentrations in spite of that disintegration processes were relatively intense along the whole depositional gradient. Therefore, population dynamic of this species was probably characterized by production maxima that were comparable to some Cenozoic molluscs in terms of their productivity potential to form thick shell concentrations in shallow subtidal environments. We suggest that temporal changes in brachiopod carbonate production have a significant spatial and phylogenetic component because multiple large-sized species of the family Terebratulidae, which underwent radiation during the Cenozoic, attained high abundances and formed shell concentrations in temperate regions.This research was supported by project CGL2009-07830/BTE and financed by the Spanish Ministry of Education and Science (MEC), the European Fund of Regional Development (FEDER), and Research Group RNM-200 of the Junta de Andalucía. A. Tomašových was supported by the Slovak Research and Development Agency (APVV-0248-07 and 0644-10), the Slovakian Scientific Grant Agency (VEGA 2/0068/11), and the National Science Foundation (DEB 0919451)