bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 130: Regulatory role of miR-29b in prostate cancer metastasis
Authors: Ray Ratna B. , Ru Peng , Steele Robert , Newhall Philip , Toth Karoly 
Published: August 2012

Abstract
Prostate cancer remains the second leading cause of cancer deaths among American men. Earlier diagnosis increases survival rate in patients. However, treatments for advanced disease are limited to hormone ablation techniques and palliative care. Thus, new methods of treatment are necessary for inhibiting progression of the disease. We have shown previously that microRNA-29b (miR-29b) expression was lower in prostate cancer cells as compared to prostate epithelial cells. Among the prostate cancer cell lines, metastatic prostate cancer cells displayed lowest expression of miR-29b. In this study, we have observed that PC-3M cells that constitutively overexpressed miR-29b failed to colonize the lungs and other organs of SCID mice after intravenous injection, while PC-3M cells expressing a control miRNA formed multiple nodules in the lung. PC-3M cells expressing miR-29b inhibited wound healing and invasiveness of cancer cells. Epithelial cell marker E-cadherin expression was enhanced in prostate cancer cells expressing miR-29b as compared to control cells. On the other hand, N-Cadherin and Snail1 expression were downregulated in PC-3M cells expressing miR-29b. Together these results suggested that miR-29b is an anti-metastatic miRNA in prostate cancer that acts at multiple steps of the metastatic cascade. Therefore, miR-29b could be a potentially new attractive target for therapeutic intervention in prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 130. doi:1538-7445.AM2012-130
Abstract 1431: A novel tumor-suppressor role of MyoD, a muscle differentiation factor, in mouse models of medulloblastoma
Authors: Dey Joyoti , Tapscott Stephen J. , Olson James M. 
Published: August 2012

Abstract
Medulloblastoma, an embryonal tumor of the cerebellum, is the most common pediatric brain cancer. For decades, it has been known that a small subset of medulloblastomas present with myogenic differentiation. However, the mechanistic basis and significance of this biological anomaly remain to be determined. We have identified hitherto unknown expression of muscle differentiation factor, MyoD in cerebellar tumors from mouse models of medulloblastoma as well as in a subset of human medulloblastomas. At a cellular level, MyoD is expressed in mitotically active cells and intriguingly, in mouse tumors does not activate its canonical targets involved in the muscle differentiation program. To understand the functional consequence of this finding in medulloblastoma genesis, we have conducted genetic studies to assess tumor formation in the SmoA1 and SmoA2 medulloblastoma models, on a MyoD-deficient background. We demonstrate that MyoD acts as a haploinsufficient tumor suppressor as the MyoD wt/-; SmoA1 and MyoD wt/-; SmoA2 mice have an accelerated onset of tumors compared to MyoD wt/wt; SmoA1 or MyoD wt/wt; SmoA2 mice respectively. Our findings suggest that the expression of MyoD might be an oncogene-induced compensatory response in the cerebellum to suppress tumor growth by restoring balance between proliferation and differentiation, similar to the role of some other bHLH transcription factors. Harnessing this latent tumor suppressor network to induce differentiation or cell cycle arrest holds promise for future therapeutic interventions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1431. doi:1538-7445.AM2012-1431
Abstract 1433: TC21/R-Ras2 is a critical mediator of the Nf1 oncogenic switch
Authors: Patmore Deanna M. , Welch Sara , Fulkerson Patricia , Wu Jianqiang , Choi Kwangmin , Eaves David , Kordich Jennifer , Collins Margaret H. , Cripe Timothy P. , Ratner Nancy 
Published: August 2012

Abstract
The TC21/R-Ras2 protein is an oncogenic member of the Ras family. Ras proteins act as binary switches which are ‘active’ when bound to GTP and ‘inactive’ when bound to GDP. GTPase activating proteins (GAPs) accelerate the hydrolysis from Ras-GTP to Ras-GDP. This Ras-related GTPase TC21 has transforming capabilities similar to H, N and K-Ras. Activated alleles of TC21 transform epithelial and fibroblast cell lines and induce tumors in vivo. To explore the role of TC21 in cancer we used a model of Ras activation driven by loss of the NF1 tumor suppressor protein, a GAP for all Ras proteins including TC21. Thus loss of NF1 predicts increased levels of activated TC21/R-Ras2. NF1 loss in Schwann cells of the peripheral nervous system causes benign tumors known as neurofibromas. Neurofibromas can transform to sarcomas known as malignant peripheral nerve sheath tumors (MPNSTs). We found that TC21 loss delayed benign neurofibroma formation in Nf1fl/fl;DhhCre mice. Nf1 loss increased mRNA encoding the cytokine transforming growth factor-beta (TGF-β) and rendered Schwann cell progenitors insensitive to TGF-β; these phenotypes could be rescued by the Ras-related protein TC21/R-Ras2 and were mediated through TGF-β receptors. Conversely, growth of Nf1;Trp53 brain tumors and NF1−/− MPNST sarcomas were accelerated by TC21 loss. MPNST from Nf1;Trp53 mice and NF1−/− MPNST xenografts had increased levels of mRNA encoding TGF- ≤ ligands, and blocking TGF- ≤ decreased sarcoma size induced by shTC21. In benign and malignant tumors an AKT-dependent pathway regulated TGF- ≤ expression. Indicating relevance to human tumorigenesis, global gene expression analyses demonstrated increases in expression of TGF- ≤ ligands and decreases in TGF- ≤ receptors in human neurofibromas and MPNSTs. Thus, we identify critical roles for TC21 in regulation of TGF- ≤ expression. The results are important because TGF- ≤ acts as a tumor suppressor in numerous types of benign tumors and is also known for its oncogenic role in cellular transformation and tumor progression. While it has been known that Ras proteins are involved in TGF- ≤ mediated tumor suppression and oncogenesis, integration between the pathways is incompletely understood, especially in vivo. The study demonstrates that TC21 can be a major regulator of the duality of TGF- ≤ effects on tumorigenesis in vivo. This work was supported by a grant to NR (NIH P50NS057531-03).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1433. doi:1538-7445.AM2012-1433
Abstract 1438: Strong expression of CD57 is associated with aggressive neuroblastoma cells in vitro and in vivo, and with undifferentiated neuroblastoma cells in situ
Authors: Schlitter Anne-Marie , Dorneburg Carmen , Barth Thomas F.E. , Wahl Joachim , Schulte Johannes H. , Brüderlein Silke , Debatin Klaus-Michael , Beltinger Christian 
Published: August 2012

Abstract
Neuroblastoma is thought to originate from neural crest-derived cells. CD57 defines migratory neural crest cells in normal development and is expressed in neuroblastomas. We therefore investigated the role of CD57 expression in neuroblastoma cells in vitro, in vivo and in situ. Compared to CD57low neuroblastoma cells, CD57high cells developed tumors with decreased latency after orthotopic transplantation into adrenal glands of immunodeficient mice. In addition, CD57high neuroblastoma cells were also more clonogenic, induced more spheres, were less lineage-restricted and showed enhanced invasiveness. After tail vein injection more CD57high cells homed to liver and lung and formed metastases than CD57low cells. In stroma-poor neuroblastoma of patients CD57high cells were associated with undifferentiated tumor cells across all stages and tended to be more frequent after chemotherapy. We thus conclude that strong expression of CD57 is associated with some aggressive attributes of neuroblastoma cells and is linked with undifferentiated neuroblastoma cells in patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1438. doi:1538-7445.AM2012-1438
Abstract 144: MicroRNA-190, regulated by estrogen receptor signaling, suppresses expression of the metastasis-promoting gene PAR-1 and is associated with breast cancer progression
Authors: Chu Hou-Wei , Cheng Chun-Wen , Chou Wen-Cheng , Hu Ling-Yueh , Wang Hsiao-Wei , Hsiung Chia-Ni , Wu Pei-Ei , Hsu Huan-Ming , Yu Jyh-Cherng , Shen Chen-Yang 
Published: August 2012

Abstract
Cancer metastasis contributes to mortality of breast cancer patients. The present study, based on the fundamental concept that dissociation of the extracellular matrix is the driving force for tumor metastasis, was performed to examine the hypothesis that microRNA-190 (miR-190) is important in regulating breast cancer metastasis by decreasing the expression of protease-activated receptor-1 (PAR-1), a gene encoding a receptor for matrix metalloproteinase1 and thrombin that is associated with tumor metastasis. This hypothesis was initially suggested by the observations that the expression of a reporter gene could be regulated by a specific sequence in the 3′-untranslated region of PAR-1 and that miR-190 was complementary to this sequence. Support for our hypothesis came from the findings that (a) PAR-1 expression was directly inhibited by miR-190, (b) increased miR-190 expression suppressed cell migration and invasiveness, and (c) the level of miR-190 expression in primary breast carcinomas correlated with overall survival. Interestingly, we defined the promoter region of miR-190 and noted that it contained half of an estrogen receptor (ER) response element, supporting the breast tumorigenic contribution of miR-190. This was further confirmed by the findings that miR-190 expression was activated by 17β-estradiol and that the ER bound directly to this promoter and regulated miR-190 expression. The findings of the present study may explain why ER-positive patients usually have a favorable progression and how ER regulates cancer metastasis, i.e. ER signaling regulates miR-190 expression, thus causing suppression of PAR-1 expression, resulting in inhibition of breast cancer metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 144. doi:1538-7445.AM2012-144
Abstract 1440: Validation of potential therapeutic targeting of IL-6/JAK/STAT3 pathway by AZD1480 in neuroblastoma and other pediatric tumors
Authors: Yan Shuang , Thiele Carol J 
Published: August 2012

Abstract
Neuroblastoma is the most deadly extra-cranial solid childhood tumor. Despite advanced therapies, over 60% of high-risk NB patients have aggressive tumors spreading to bone and bone marrow and die of metastasis-related disease. IL-6 promotes the growth and survival of metastatic NB cells via activation of STAT3 in the BM and is an independent poor-prognosis marker in tumors from high-risk NB patients. This suggests that blockade of IL6/JAK/STAT3 signaling may represent a promising therapeutic strategy. We tested the anti-tumor effect of inhibition IL6/JAK/STAT3 pathway by the JAK1/2 inhibitor AZD1480, which is in Phase II clinical trials in adult tumors, in three highly metastatic pediatric tumor types (Neuroblastoma, Ewing sarcoma and rhabdomyosarcoma). AZD1480 (0.5uM) significantly blocked IL-6-induced P-STAT3-Tyr705 in all tumor types tested. AZD1480 decreased cell viability in the 6 NB, 5 RMS and 2 EWS cell lines tested (median IC50 1.17uM, ranging from 0.42-5.1uM). AZD1480 induced cell growth inhibition, G2 arrest and apoptosis in vitro. Moreover, AZD1480 inhibited the expression of identified direct STAT3 targets such as cell cycle regulators CyclinD2, CyclinD3 and CDC25A, antiapoptotic proteins Bcl-2 and Survivin, metastasis-related protein TIMP-1 and c-myc consistent with its repression of cell growth, induction of G2 arrest and apoptosis. In in vivo Neuroblastoma xenograft models, AZD1480 suppressed growth of SY5Y and KCNR xenografts and increased survival of mice bearing KCNR xenografts (P=0.0001) and SY5Y xenografts (P=0.02). Altogether, these data suggest the clinical blockade of IL6/JAK/STAT3 signaling by AZD1480 may represent a promising new therapy in NB and other pediatric tumors. We thank Dennis Huszar and AstraZeneca for the AZD1480 and helpful discussions. Key words: neuroblastoma, JAK2, STAT3, IL-6, targeted therapy
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1440. doi:1538-7445.AM2012-1440
Abstract 1450: Targeting the ATM kinase as a novel strategy for radiosensitizing glioblastoma multiforme in mice
Authors: Biddlestone-Thorpe Laura , Muhammad Sajjad , Rosenberg Elizabeth , Golding Sarah E. , Adams Bret R. , Tokarz Mary , Khalil Ashraf , Gilfor Donna , O'Connor Mark , Valerie Kristoffer 
Published: August 2012

Abstract
Glioblastoma multiforme (GBM) is the most lethal type of brain cancer. At best, mean survival is only 12-15 months so an improvement of current therapy is long overdue. Current treatment includes surgery and chemoradiation. The short survival of GBM patients is due, in part, to the innate radioresistance and vicious invasiveness of GBM. ATM, ataxia telangiectasia (A-T) mutated, would be an excellent target for radiosensitizing GBM because of its critical role in regulating the DNA damage response (DDR) and other cellular processes. As a first step towards this goal, we tested the ability of the novel ATM kinase inhibitor KU-60019 to radiosensitize GBM in mice. Using an orthotopic xenograft model of GBM, nude mice were implanted with human glioma cells expressing reporter genes for monitoring tumor growth and spread. KU-60019 was administered intra-cranially by convection-enhanced delivery or by osmotic pump. Imaging, survival, and signs of inhibiting the DDR using immunohistochemistry were used to characterize the effects of KU-60019 on tumor and normal brain. Our results show that compared with untreated, KU-60019 alone, or radiation alone treated mice, the combined effect of KU-60019 and radiation significantly increased survival at least 2-fold and sometimes even cured the animals. Multiple glioma cell lines with varied genetic backgrounds are currently being tested. Altogether, our results show that KU-60019 is able to overcome GBM radioresistance, a major obstacle in the treatment of GBM, and significantly prolong the survival of animals. Thus, an ATM kinase inhibitor may have great potential as adjuvant therapy in the clinic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1450. doi:1538-7445.AM2012-1450
Abstract 1452: mTOR inhibition radiosensitizes bladder cancer tumor cells in vitro and in vivo: A novel strategy for treatment
Authors: Nassim Roland , Mansure Jose , Chevalier Simone , Cury Fabio , Parker William , Davis Stephen , Cury Joice , Kassouf Wassiim 
Published: August 2012

Abstract
Background: Radiation therapy for invasive bladder cancer allows for organ preservation but systemic toxicity and local control remain problematic. As such, there is a need to increase radiosensitization of tumor cells to improve efficacy. The aim of this study was to investigate if mTOR (mammalian target of rapamycin), a downstream kinase of the PI3K/Akt survival pathway, may be a target for combined bladder cancer therapy. Methods: Clonogenic assays were performed using 6 bladder cancer cell lines in order to address the effects of ionizing radiation (IR) on growth, when tested alone and in combination with RAD001, a potent mTOR inhibitor. Cell cycle analysis was performed using flow cytometry. In the in vivo study, nude mice were subcutaneously injected with KU7 and 253J-BV cells. Treatment with RAD001 (1.5 mg/kg, daily), fractionated IR (total 9 Gy), and the combination of RAD001 and IR was followed over 4 weeks. Tumor growth kinetics was measured and tumor weight at the experimental endpoint. Results: In vitro, a significant decrease in colony formation was observed in the combined treatment when compared to RAD001 or radiation alone (p&lt;0.05) in all cell lines. A G0/G1 as well as a significant increase in G2 arrest was observed in the combined treatment compared to either treatment alone. Changes in the levels of Cyclin D1, p27 and p21 correlated with the observed changes in the cell cycle. Moreover, IR rapidly activated AKT whereas RAD001 effectively inhibited the mTOR downstream signaling as shown by the inhibition of the phosphorylation of S6. Furthermore, autophagy was induced following the treatment with RAD001 and in combination as indicated by the conversion of LC3-I to LC3-II, a protein marker for autophagy. Our in vivo data confirmed our in vitro data, wherein a significant decrease in tumor weight was observed in the combined treatment arm (90% decrease, p&lt;0.001) compared to either treatment alone (60% decrease for RAD001, p&lt;0.05; 77% decrease for IR, p&lt;0.05). These findings point to additive and possibly synergistic beneficial effects of the combined on bladder cancer. Conclusions: The inhibition of mTOR signaling appears promising as a therapeutic modality for bladder cancer, especially in the context of combination with radiation therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1452. doi:1538-7445.AM2012-1452
Abstract 1463: PARP inhibition reverses radiation resistance conferred by ETS fusions in prostate cancer
Authors: Han Sumin , Brenner Chad , Sabolch Aaron , Wilder-Romans Kari , Knudsen Karen , Lawrence Theodore , Chinnaiyan Arul , Feng Felix 
Published: August 2012

Abstract
Background: ETS gene fusions, which are found in approximately half of all prostate cancers, result in overexpression of ETS transcription factors, of which ERG is the prototype. We previously discovered that ERG interacts with the DNA damage response protein poly (ADP-ribose) polymerase 1 (PARP1). Therefore, we hypothesized that the ERG-PARP1 interaction may confer radiation resistance by increasing DNA repair efficiency, and this radioresistance can be reversed with PARP1 inhibition. Methods: We used lentiviral approaches to establish isogenic models of ERG overexpression in PC3 and DU145 prostate cancer cell lines. We then assessed the role of ERG overexpression on 1) PARP1 activity (via immunoblots for poly ADP-ribose (PAR) formation), 2) DNA repair (via COMET assays and immunofluorescent microscopy for gamma-H2aX foci), and 3) clonogenic survival, before and following radiation +/− the PARP1 inhibitor olaparib. We also created ERG mutants with a point mutation (Y373) which disrupted the ERG-PARP interaction, and assessed the role of this interaction on radiation response. Finally, we established xenografts from ERG-overexpressing and control PC3 cells, and treated these xenografts with radiation +/− PARP1 inhibition. Results: In both PC3 and DU145 cells, ERG overexpression resulted in increased PARP1 activity and quicker repair of DNA damage, both of which were reversed with olaparib. ERG overexpression resulted in a 1.3 fold increase in clonogenic survival following radiation, consistent with radioresistance. PARP1 inhibition with olaparib preferentially radiosensitized ERG-positive cells, by a factor of 1.5 relative to ERG-negative cells (p&lt;0.05). Additionally, disruption of ERG-PARP interaction via point mutation reversed the ERG-mediated increase in clonogenic survival following radiation. Within PC3 xenografts, ERG overexpression also conferred radioresistance which was reversed with PARP1 inhibition. Conclusions: In these prostate cancer cell models, ERG overexpression confers radiation resistance via increased efficiency of DNA repair following radiation. This radioresistance is dependent on the ERG-PARP1 interaction, and can be reversed via inhibition of PARP1 both in vitro and in vivo. These novel findings motivate the use of PARP1 inhibitors as radiosensitizers in patients with localized ETS fusion-positive prostate cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1463. doi:1538-7445.AM2012-1463
Abstract 1471: Role of ferritin heavy chain in therapeutic sensitivity of human glioblastoma cells
Authors: Pang Min , Liu Xiaoli , Madhankumar A. B. , Connor James 
Published: August 2012

Abstract
Elevated iron requirements and heightened iron metabolism is key to the survival and proliferation of cancer cells. As one of the major iron regulatory proteins, ferritin is elevated in cancer cells and we have previously shown that decreasing ferritin expression in human glioblastoma cells will increase the sensitivity to BCNU and radiation both in vitro and in vivo. In this study, we investigate the underlying mechanism of this finding. Through a nanotechnology-based transfection platform, the human glioma cell line U251 was transfected with H-ferritin siRNA and an effective knockdown efficiency of protein was achieved within 48 hours. H-ferritin down-regulation in glioma cells was associated with a transient decrease in transferrin receptor, suggesting a release of intracellular iron with loss of ferritin. This iron release in turn generated intracellular oxidative stress, which was demonstrated by protein oxidation. The stability of hypoxia-inducible factors (HIFs), which is an indicator of radioresistance, was decreased in glioma cells with H-ferritin down-regulation. This observation is consistent with the increased sensitivity to treatment. Exposure to radiation resulted in increased protein oxidation which could be exacerbated by H-ferritin down-regulation. Thus there is a synergistic effect of radiation and H-ferritin down-regulation; possibly also including the destabilization of HIFs. Additionally, we have previously demonstrated a DNA protection role for H-ferritin. Down-regulation of H-ferritin is associated with increased DNA vulnerability when cells were exposed to ionizing radiation. Moreover, the activation of DNA repair mechanisms was impaired when H-ferritin was absent. Finally, we expanded the vulnerability studies to include the first-line chemotherapeutic agent temozolomide and found that H-ferritin down-regulation increased the sensitivity of glioma cells to this DNA alkylating agent. This study suggests that the iron management protein, H-ferritin, has a cytoprotective role in human glioma cells, which renders them more resistant to conventional therapies. Therefore down-regulation of H-ferritin via nanoliposomes delivering siRNA is a potential adjuvant therapy in glioma treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1471. doi:1538-7445.AM2012-1471