bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C1: GLI1 induces CD133 expression in xenografts derived from transformed astrocytes but not in cultured cells: Extrinsic control of CD133 expression in gliomas
Authors: Sasai Ken , Nodagashira Miho , Tanaka Shinya 
Published: May 2012

Abstract
Overexpression of transcription factors is often observed in malignant gliomas and the roles of such factors in tumor malignancy have been widely investigated. However, the contribution of glioma-related transcription factors to tumor initiation are largely unclear, as the majority of brain tumor studies have employed glioma-derived cell lines, which recapitulate only a subset of late-stage human tumors. In contrast to tumor-derived cell lines, which harbor numerous undefined genetic elements, normal human cells allow us to generate experimental models of human cancers by direct manipulation with defined genetic elements. Here we demonstrate that the introduction of GLI1 is sufficient for immortalized human astrocytes to be transformed whereas FOXM1 fails to induce oncogenic transformation, suggesting that GLI1, but not FOXM1, directly contributes to gliomagenesis despite both transcription factors being overexpressed in malignant gliomas. While GLI1-transformed astrocytes have the ability to form tumors in nude mice, the oncogenic potential of GLI1 is subtle compared to the active form of H-RAS. To obtain insights into the mechanisms underlying less malignant features of GLI1-transformed astrocytes, expression of inhibitors of cyclin-dependent kinases in xenografts were analyzed by immunohistochemistry. We found that p27KIP1-positive cells were frequently observed in xenografts derived from GLI1-transformed astrocytes (GLI1-xenografts) compared to those from RAS-transformed cells (RAS-xenografts): more than 60% of cells were positive for p27KIP1-staining in GLI1-xenografts whereas only ∼20% in RAS-xenografts. We also made an interesting observation that CD133-positive cells were frequently detected in GLI1-xenografts whereas they were rarely seen in RAS-xenografts. The biological relevance and regulatory mechanisms of CD133 expression in human glioma are not completely understood although the use of CD133 as a marker to sort and enrich for brain tumor stem cells is common. Since GLI1 failed to induce CD133 expression in cultured astrocytes, it is possible that additional factors present in vivo and absent in culture might collaborate with GLI1 to modulate CD133 expression and that tumor microenvironment might contribute to maintenance of brain tumor stem cells. We propose that GLI1-tranformed astrocytes may prove to be useful tools as we strive to understand the molecular mechanisms underlying CD133 expression in gliomas as well as maintenance of brain tumor stem cells.
Citation Information: Cancer Res 2009;69(23 Suppl):C1.
Abstract C10: Neural stem cells and lineage-restricted progenitors can initiate malignant astrocytoma formation in somatic tumor suppressor mouse models
Authors: Alcantara Llaguno Sheila R. , Chen Jian , Kwon Chang-Hyuk , Jackson Erica , Li Yanjiao , Yan Jingsheng , Xie Yang , Burns Dennis K. , Johnson Jane E. , Alvarez-Buylla Arturo , Parada Luis F. 
Published: May 2012

Abstract
Malignant astrocytomas are infiltrative and incurable brain tumors. Despite profound therapeutic implications, the identity of the cell (or cells) of origin has not been rigorously determined. We previously reported mouse models based on conditional inactivation of the human astrocytoma-relevant tumor suppressors Nf1, p53, and Pten, wherein through somatic loss of heterozygosity, mutant mice develop tumors with 100% penetrance. In the present study, we show that tumor suppressor inactivation in neural stem cells induces malignant astrocytoma formation. Genetic targeting of lineage-restricted progenitors alone is also sufficient to initiate astrocytomas. We demonstrate in vivo that transformed cells and their progeny undergo infiltration and multi-lineage differentiation in situ during tumor development. Analysis of mutant mice several months prior to advanced disease shows defects in proliferation, differentiation, and migration, suggesting that these are requisite processes prior to tumor formation. Gene expression profiling in pre-symptomatic mutant mice provides insight into the molecular events involved during brain tumor development.
Citation Information: Cancer Res 2009;69(23 Suppl):C10.
Abstract C13: Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth
Authors: Wang Hui , Lathia Justin , Wu Qiulian , Wang Jialiang , Li Zhizhong , Heddleston John , Eyler Christine , Elderbroom Jennifer , McLendon Roger , Wang Xiao-Fan , Hjelmland Anita , Rich Jeremy 
Published: May 2012

Abstract
Glioblastomas are the most common and most lethal primary brain tumor. Recent studies implicate an important role for a restricted population of neoplastic cells (glioma stem cells (GSCs)) in glioma maintenance and recurrence. We now demonstrate that GSCs preferentially express two interleukin 6 (IL6) receptors: IL6 receptor alpha (IL6Ra) and glycoprotein 130 (gp130). Targeting IL6Ra or IL6 ligand expression in GSCs with the use of short hairpin RNAs (shRNAs) significantly reduces growth and neuro-sphere formation capacity while increasing apoptosis. Per-turbation of IL6 signaling in GSCs attenuates signal transducers and activators of transcription three (STAT3) activation, and small molecule inhibitors of STAT3 potently induce GSC apoptosis. These data indicate that STAT3 is a downstream mediator of prosurvival IL6 signals in GSCs. Targeting of IL6Ra or IL6 expression in GSCs increases the survival of mice bearing intracranial human glioma xenografts. IL6 is clinically significant because elevated IL6 ligand and receptor expression are associated with poor glioma patient survival. The potential utility of anti-IL6 therapies is demonstrated by decreased growth of subcutaneous human GSC-derived xenografts treated with IL6 antibody. Together, our data indicate that IL6 signaling contributes to glioma malignancy through the promotion of GSC growth and survival, and that targeting IL6 may offer benefit for glioma patients.
Citation Information: Cancer Res 2009;69(23 Suppl):C13.
Abstract C14: The thyroid hormone-sonic hedgehog cross-talk in the tumorigenesis of basal cell carcinoma cells
Authors: Dentice Monica , Luongo Cristina , Ambrosio Raffaele , Salvatore Domenico 
Published: May 2012

Abstract
The pro-hormone, thyroxine (T4), must be converted into T3 in order to be active. This metabolic process has been increasingly recognized as an essential mechanism that regulates thyroid hormone (TH) action at cellular level. TH action is regulated by the activity of the deiodinases, which can either activate (D1, D2) or inactivate (D3) the prohormone.
The Sonic hedgehog (Shh) pathway plays a critical role in tumor development, In skin, constitutive Shh signaling causes basal cell carcinoma (BCCs) the most common cancer in humans. We have recently demonstrated that Shh-Gli2 pathway induces D3 in human and mouse BCCs, however the role of D3 and T3-depletion in BCC tumor formation and maintenance is unknown. In the present study we tested the hypothesis that local control of TH action- through regulation of deiodinases- is a necessary step for the action of Shh pathway.
To this aim, BCC cells, G2N2c were grown in thyroid hormone deprived media (charcoal serum -CS), or CS plus exogenous T3 at different concentrations. We observed a reduction in the growing rate directly correlated to the concentrations of T3 in the media. Furthermore, in the same cells, T3 interferes specifically and directly with Gli2 expression, by reducing Gli2 protein level and activity. These data, together with the finding that Gli2 mRNA does not change in the same setting, indicate that T3 reduced Gli-2 protein at post-transcriptional level. Finally, to study the effect of thyroid hormone on the BCC tumor growth in vivo, we injected nude mice with BCC cells and treated the resulting tumors with a T3-based cream. Tumor weight, showed a significative reduction in tumors size when topically T3-treated.
In conclusion, we highlight a functional cross-talk between thyroid hormone and the Shh-signalling in BCC cells. This mechanism could have broad implications, not only to understand the general role of hormones, in particular T3, in the process of tumor formation and growth, but also may lead to the identification of novel therapeutic approaches aimed at interfering with these signals in a pathological context.
Citation Information: Cancer Res 2009;69(23 Suppl):C14.
Abstract C15: Combinatorial regulation of neuroblastoma tumor progression by HIF1α and N-myc transcriptional factors
Authors: Qing Guoliang , Mayes Patrick , Pawel Bruce , Martinez Daniel , Maris John M. , Simon M. Celeste 
Published: May 2012

Abstract
Deregulation of Myc and activation of hypoxia inducible factors (HIFs) frequently occur in solid tumors. In human neuroblastoma, amplification of the N-MYC gene predicts poor prognosis and resistance to therapy. Interestingly, we demonstrated here that HIF1α, but not HIF2α, is preferentially expressed in both N-MYC amplified neuroblastoma cells and primary tumors in comparison to non-amplified ones. Expression of HIF2α in N-MYC amplified cells appears to be silenced largely through DNA methylation and histone deacetylation. Interplay between N-Myc and HIF1α plays critical roles in progression of neuroblastomas. On one hand, N-Myc overrides the inhibitory function of HIF1α on cell cycle progression under hypoxia, which frequently occurs in solid tumors and is well known to inhibit cell growth. Of note, proliferation of N-MYC amplified cells is largely unaltered under hypoxia. On the other hand, HIF1α, together with N-Myc, cooperates to regulate aerobic glycolysis (the Warburg effect) of neuroblastoma. The near-universal glycolytic switch of N-MYC amplified neuroblastoma cells may be an essential tumor trait and a consequence of the cellular adaptation to intermittent hypoxia. Targeting either HIF1α or N-Myc significantly decreases expression of genes involved in glycolysis, such as lactate dehydrogenase A (LDHA), and inhibits cell proliferation in vitro under normoxia. Strikingly, N-MYC amplified cells are addicted to LDHA expression. Reduction in LDHA activity completely inhibits their proliferation under both normoxia and hypoxia. Taken together, our results demonstrate that neuroblastoma cells differentially respond to hypoxia with distinct HIFα induction patterns, and suggest the HIF1α/N-Myc axis may represent a pharmacologically tractable pathway for the potential treatment of N-MYC amplified neuroblastomas. In particular, we propose targeting LDHA may be a promising and nontoxic approach in treatment of N-MYC amplified neuroblastomas, given that depletion of LDHA expression completely inhibits growth of N-MYC amplified cells and individuals deficient in LDHA expression show no obvious symptoms under normal conditions.
Citation Information: Cancer Res 2009;69(23 Suppl):C15.
Abstract C16: Reactive oxygen species derivate of diethylnitrosamine metabolism participates in oxidation of thiol proteins
Authors: Aparicio-Bautista Diana Ivette , Gutiérrez-Nájera Nora Andrea , Arellanes-Robledo Jaime , Vásquez-Garzón Verónica Rocío , Jiménez-García Mónica Noemí , Pérez-Carreón Julio Isael , Villa-Treviño Saúl 
Published: May 2012

Abstract
Introduction: Conversion of Protein-SH into disulphides is an early event during the radical-mediated oxidation of proteins; this has prompted a great interest in the study of changes of these thiol proteins. The aim was to detect the most sensitive thiol proteins to reactive oxygen species generated by metabolism of Diethylnitrosamine (DEN) in the rat liver. DEN has been widely used to induce experimental hepatocellular carcinoma.
Methods: Twenty Male Fischer 344 rats were randomized into 4 groups: 3 groups were treated with DEN at 200 mg/kg weight. Each group was sacrificed at 6h (DEN 6), 12h (DEN 12) and 24h (DEN 24) after DEN administration. The last group was used as negative control (NC). To evaluate the formation of disulphide proteins in the liver, we compared the three DEN treated groups against the non treated rats. Total proteins were extracted and labeled with saturation dye according to method Redox-DIGE with some modifications, this method coupled to mass spectrometry was used to identify the differential oxidation protein profile.
Results: The analysis showed a tendency to increase the number of oxidized thiol proteins, through the time of DEN exposure together to a possible increase of proteins degradation. The differentially oxidized proteins at 6h, 12h and 24h were 407, 690, and 665 respectively; of those 6, 12 and 90 increased (up-oxidized) and 45, 12 and 51 decreased (down-oxidized), taking as reference two folds in their oxidation status respect to NC group. Some proteins were already identified from the different groups and according to functional classification, the identified proteins in our study are categorized as chaperone, oxidoreductase, activity isomerase, hidrolase, protein binding, cytoskeleton, activity transferase, among others.
Conclusions: DEN has an oxidative effect on thiol proteins; also, there is a tendency to increase the number of oxidized thiol proteins which depends of the time of DEN exposure and very likely related to the mechanism of carcinogenesis initiation. In addition to oxidation process, the proteins could be being degraded by DEN effect.
Citation Information: Cancer Res 2009;69(23 Suppl):C16.
Abstract C17: Diet-mediated enhancement of tumorigenesis in Drosophila
Authors: Hirabayashi Susumu , Baranski Thomas , Cagan Ross 
Published: May 2012

Abstract
Epidemiological studies have demonstrated that increased cancer risk is associated with metabolic disease including obesity and diabetes, but the underlying mechanism remains poorly understood. We have recently found that feeding Drosophila a high sugar-containing diet leads to a series of metabolic dysfunctions seen in human diabetes including hyperglycemia, increased insulin levels, and accumulation of fat. Here we demonstrate that a high sugar diet enhanced cell migration and invasion within Src-mediated tumor and massive overgrowth in multigenic Ras/Src-based tumor models. These diet-enhanced Ras/Src-based tumors produced aggressive metastasis-like behavior: transformed cells left the primary tumor to invade through the hemolymph to secondary sites that led to lethality of the animals. Genetic and inhibitor studies indicated that the insulin pathway plays a primary role in this diet-induced enhanced overgrowth through regulation of dTor. We further show that tumors with insulin pathway activation are resistant to dietary effects. Moreover, utilizing the diet-enhanced lethal phenotype, we developed a drug screening platform that relies on robotics as well as rescue-from-lethality. These studies should provide insights into mechanisms of the association between metabolic dysfunction and cancer progression and allow us to take the first steps towards identifying novel candidate therapeutic compounds.
Citation Information: Cancer Res 2009;69(23 Suppl):C17.
Abstract C18: A new IGF-I-regulated micronutrient carrier in cancer cells
Authors: O'Callaghan Katie , Ayllon Veronica , O'Keeffe Jean , Wang Yanru , Cox Orla , Loughran Gary , Forgac Michael , O'Connor Rosemary 
Published: May 2012

Abstract
Cancer cells are dependent on a continuous supply of nutrients to maintain cell proliferation and migration. Nutrients are acquired through transporters whose transcription, trafficking, and degradation are tightly regulated by growth factors, especially through activity of the Insulin/IGF-I-activated PI3K/mTOR signalling pathway. The intracellular trafficking of nutrient transporters requires an acidic endosomal pH that is maintained by the Vacuolar H+ ATPase (V-ATPase) proton pump. Recent studies have indicated a role for V-ATPase activity in cancer cells, but how this is regulated is not known. We recently isolated a series of new IGF-I-regulated genes whose expression is associated with cellular transformation (1, 2). Among these was a previously uncharacterized endosomal protein, which we determined associates with the V-ATPase, and which we called EVA. This protein was separately identified in C. elegans as a member of a family of heme transporters (HRG-1) that control heme homeostasis (3). We found that EVA is present throughout the endosome compartments; in early, recycling, and late endosomes, but not in lysosomes. Upon nutrient withdrawal EVA traffics to the plasma membrane. EVA interacts with the c subunit of the V-ATPase and enhances V-ATPase activity in isolated yeast vacuoles. Suppression of EVA expression increases endosomal pH and reduces V-ATPase holoenzyme assembly. This is accompanied by decreased migration, decreased transferrin receptor trafficking, decreased cellular heme uptake, and cell death. Over-expressed EVA enhances cellular heme uptake in a V-ATPase-dependent manner. We conclude that EVA/HRG-1 regulates V-ATPase-dependent acidification of endosomes necessary for trafficking of heme receptors as well as for heme transport within endosomes. Our data suggest that IGF-I induces expression of this micro-nutrient transporter to facilitate the enhanced metabolic requirements of cancer cells.
Citation Information: Cancer Res 2009;69(23 Suppl):C18.
Abstract C22: Telomerase activity and HR-HPV infection frequently are present before detection of high grade cervical lesions
Authors: Martín-Gámez Diana Carolina , Hernandez Gustavo Adolfo , Buitrago Oscar Leonardo , Huertas Antonio , Murillo Raúl , Bravo Maria Mercedes , Moreno Pablo , Muñoz Nubia , Molano-Luque Monica 
Published: May 2012

Abstract
Telomerase activation have been considered as a fundamental step in the immortalization process because majority nonmalignant somatic tissue shows undetectable or no telomerase activity. A few numbers of studies in cervical cancer have showed an increase in the telomerase activity with grade of lesion, and Human Papillomavirus (HPV) infection has been associated in some studies with telomerase activation. However until now there are not follow up studies that measure the telomerase activity along the time. We describe here results about telomerase activity and HPV infection during 7 years of follow up in women that belong to the Bogotá cohort.
Samples were obtained every six months during follow up and we had in average four samples by woman. Telomerase activity was analyzed in 58 samples of 17 women that during follow up developed High Grade Squamous Intraepithelial Lesions (HGSIL) and 149 samples of 34 women that during follow up had normal cytology using a TeloTAGGG Telomerase PCR ELISA kit (Roche Applied Science). The HPV infection was previously tested using a GP5+/GP6+mediated PCR-EIA and typing using a Reverse Line Blot assay (RLB).
Of the 17 women that developed HGSIL along follow up; 12 (70.5%) had HPV infection and telomerase activity at the same time of HGSIL diagnosis or in a previous visit, these women had infections with high risk types (HR) principally with those belong to the alpha 9 specie, 2 (17.7%) showed only transitory events of HPV infection and 2 (11.8%) had normal cytology without HPV infection or telomerase activity. Average time to develop HGSIL was 13.5 months. In normal women we observed diverse results. Of the 34 women; 21 (61.8%) had HPV transitory infections with high risk and/or low risk types sometime during follow up and only 12 (35.2%) of them were positive for telomerase activity sometime in follow up independently of HPV infection. Interestingly, 8 (23.5%) women had HPV-HR infection during follow up and they were never positive for telomerase activity and 5 (14.7%) women didn't have HPV infection and telomerase activity.
Detection of HR-HPV infection and telomerase activity at the same time likes to predict the risk of HGSIL. Our results support the idea that telomerase activity and HR-HPV infection can be used as progression markers for the development of HGSIL.
Citation Information: Cancer Res 2009;69(23 Suppl):C22.
Abstract C3: Gene expression profiling supports the hypothesis that human ovarian surface epithelia are pluripotent and capable of serving as ovarian cancer initiating cells
Authors: Bowen Nathan J. , Walker L. DeEtte , Matyunina Lilya V. , Logani Sanjay , Totten Kimberly A. , Benigno Benedict B. , McDonald John F. 
Published: May 2012

Abstract
Accumulating evidence suggests that somatic stem cells undergo mutagenic transformation into cancer initiating cells. The serous subtype of ovarian adenocarcinoma in humans has been hypothesized to arise from at least two possible classes of progenitor cells: the ovarian surface epithelia (OSE) and/or an as yet undefined class of progenitor cells residing in the distal end of the fallopian tube. Comparative gene expression profiling analyses were carried out on OSE removed from the surface of normal human ovaries and ovarian cancer epithelial cells (CEPI) isolated by laser capture microdissection (LCM) from human serous papillary ovarian adenocarcinomas. Differentially expressed genes were analyzed using gene ontology, molecular pathway, and gene set enrichment analysis algorithms. Consistent with pluripotent capacity, genes in pathways previously associated with adult stem cell maintenance are highly expressed in ovarian surface epithelia and are not expressed or expressed at very low levels in serous ovarian adenomcarcinoma. The results of the gene expression analyses were selectively confirmed using immunohistochemistry. Among the over 2000 genes that are significantly differentially expressed, a number of pathways and novel pathway interactions are identified that may contribute to ovarian adenocarcinoma development. Our results are consistent with the hypothesis that human ovarian surface epithelia are pluripotent and capable of serving as the origin of ovarian adenocarcinoma. While our findings do not rule out the possibility that ovarian cancers may also arise from other sources, they are inconsistent with claims that ovarian surface epithelia cannot serve as the origin of ovarian cancer initiating cells.
Citation Information: Cancer Res 2009;69(23 Suppl):C3.