bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of ASF/SF2 as a Critical, Allele-Specific Effector of the Cyclin D1b Oncogene
Authors: Olshavsky Nicholas A. , Comstock Clay E.S. , Schiewer Matthew J. , Augello Michael A. , Hyslop Terry , Sette Claudio , Zhang Jinsong , Parysek Linda M. , Knudsen Karen E. 
Published: May 2010

Abstract
The cyclin D1b oncogene arises from alternative splicing of the CCND1 transcript, and harbors markedly enhanced oncogenic functions not shared by full-length cyclin D1 (cyclin D1a). Recent studies showed that cyclin D1b is selectively induced in a subset of tissues as a function of tumorigenesis; however, the underlying mechanism(s) that control tumor-specific cyclin D1b induction remain unsolved. Here, we identify the RNA-binding protein ASF/SF2 as a critical, allele-specific, disease-relevant effector of cyclin D1b production. Initially, it was observed that SF2 associates with cyclin D1b mRNA (transcript-b) in minigene analyses and with endogenous transcript in prostate cancer (PCa) cells. SF2 association was altered by the CCND1 G/A870 polymorphism, which resides in the splice donor site controlling transcript-b production. This finding was significant, as the A870 allele promotes cyclin D1b in benign prostate tissue, but in primary PCa, cyclin D1b production is independent of A870 status. Data herein provide a basis for this disparity, as tumor-associated induction of SF2 predominantly results in binding to and accumulation of G870-derived transcript-b. Finally, the relevance of SF2 function was established, as SF2 strongly correlated with cyclin D1b (but not cyclin D1a) in human PCa. Together, these studies identify a novel mechanism by which cyclin D1b is induced in cancer, and reveal significant evidence of a factor that cooperates with a risk-associated polymorphism to alter cyclin D1 isoform production. Identification of SF2 as a disease-relevant effector of cyclin D1b provides a basis for future studies designed to suppress the oncogenic alternative splicing event. Cancer Res; 70(10); 3975–84. ©2010 AACR.
Strategic Workshops on Cancer Nanotechnology
Authors: Nagahara Larry A. , Lee Jerry S.H. , Molnar Linda K. , Panaro Nicholas J. , Farrell Dorothy , Ptak Krzysztof , Alper Joseph , Grodzinski Piotr 
Published: May 2010

Abstract
Nanotechnology offers the potential for new approaches to detecting, treating, and preventing cancer. To determine the current status of the cancer nanotechnology field and the optimal path forward, the National Cancer Institute's Alliance for Nanotechnology in Cancer held three strategic workshops, covering the areas of in vitro diagnostics and prevention, therapy and post-treatment, and in vivo diagnosis and imaging. At each of these meetings, a wide range of experts from academia, industry, the nonprofit sector, and the U.S. government discussed opportunities in the field of cancer nanotechnology and barriers to its implementation. Cancer Res; 70(11); 4265–8. ©2010 AACR.
Extranuclear Functions of ER Impact Invasive Migration and Metastasis by Breast Cancer Cells
Authors: Chakravarty Dimple , Nair Sujit S. , Santhamma Bindu , Nair Binoj C. , Wang Long , Bandyopadhyay Abhik , Agyin Joseph K. , Brann Darrell , Sun Lu-Zhe , Yeh I-Tien , Lee Francis Y. , Tekmal Rajeshwar Rao , Kumar Rakesh , Vadlamudi Ratna K. 
Published: May 2010

Abstract
The molecular basis of breast cancer progression to metastasis and the role of estrogen receptor (ER) signaling in this process remain poorly understood. Emerging evidence suggests that ER participates in extranuclear signaling in addition to genomic functions. Recent studies identified proline-, glutamic acid–, and leucine-rich protein-1 (PELP1) as one of the components of ER signalosome in the cytoplasm. PELP1 expression is deregulated in metastatic breast tumors. We examined the mechanism and significance of ER-PELP1–mediated extranuclear signals in the cytoskeletal remodeling and metastasis. Using estrogen dendrimer conjugate (EDC) that uniquely activate ER extranuclear signaling and by using model cells that stably express PELP1 short hairpin RNA (shRNA), we show that PELP1 is required for optimal activation of ER extranuclear actions. Using a yeast two-hybrid screen, we identified integrin-linked kinase 1 (ILK1) as a novel PELP1-binding protein. Activation of extranuclear signaling by EDC uniquely enhanced E2-mediated ruffles and filopodia-like structures. Using dominant-negative and dominant-active reagents, we found that estrogen-mediated extranuclear signaling promotes cytoskeleton reorganization through the ER-Src-PELP1-phosphoinositide 3-kinase-ILK1 pathway. Using in vitro Boyden chamber assays and in vivo xenograft assays, we found that ER extranuclear actions contribute to cell migration. Collectively, our results suggest that ER extranuclear actions play a role in cell motility/metastasis, establishing for the first time that endogenous PELP1 serves as a critical component of ER extranuclear actions leading to cell motility/invasion and that the ER-Src-PELP1-ILK1 pathway represents a novel therapeutic target for preventing the emergence of ER-positive metastasis. Cancer Res; 70(10); 4092–101. ©2010 AACR.
Glioma Cell Populations Grouped by Different Cell Type Markers Drive Brain Tumor Growth
Authors: Prestegarden Lars , Svendsen Agnete , Wang Jian , Sleire Linda , Skaftnesmo Kai Ove , Bjerkvig Rolf , Yan Tao , Askland Lasse , Persson Andreas , Sakariassen Per Øystein , Enger Per Øyvind 
Published: May 2010

Abstract
Although CD133 has been proposed as a marker for brain tumor–initiating cells, studies show that a tumorigenic potential exists among CD133− glioma cells as well. However, it is not established whether the ability of CD133− cells to form tumors is a property confined to a small subpopulation, rather than a common trait associated with most glioma cell types. Thus, we used lentiviral vectors expressing green fluorescent protein under lineage-specific promoters to identify CD133− glioma cells expressing Nestin, glial fibrillary acidic protein (GFAP), and neuron-specific enolase (NSE). Flow cytometry analysis showed the presence of CD133− subpopulations expressing these markers in glioma cell lines and in primary cultures from human glioblastoma (GBM) biopsies. Moreover, analysis of cell cycle distribution showed that subgroups expressing Nestin, GFAP, and NSE uniformly contained actively cycling cells, when cultured in serum-containing medium and stem cell medium. These subpopulations were fluorescence-activated cell sorted from CD133− U373 glioma cells and implanted intracerebrally in severe combined immunodeficient mice. Moreover, we implanted Nestin-, GFAP-, and NSE-positive glioma cells sorted from a human GBM biopsy, following removal of CD133-positive cells. All the CD133− subpopulations produced tumors, with no significant differences in survival or tumor take rates. However, there was a trend toward lower take rates for CD133− glioma subpopulations expressing GFAP and NSE. These findings suggest that the ability to form tumors may be a general trait associated with different glioma cell phenotypes, rather than a property limited to an exclusive subpopulation of glioma stem cells. Cancer Res; 70(11); 4274–9. ©2010 AACR.
β-Lapachone Micellar Nanotherapeutics for Non–Small Cell Lung Cancer Therapy
Authors: Blanco Elvin , Bey Erik A. , Khemtong Chalermchai , Yang Su-Geun , Setti-Guthi Jagadeesh , Chen Huabing , Kessinger Chase W. , Carnevale Kevin A. , Bornmann William G. , Boothman David A. , Gao Jinming 
Published: May 2010

Abstract
Lung cancer is the leading cause of cancer-related deaths with current chemotherapies lacking adequate specificity and efficacy. β-Lapachone (β-lap) is a novel anticancer drug that is bioactivated by NAD(P)H:quinone oxidoreductase 1, an enzyme found specifically overexpressed in non–small cell lung cancer (NSCLC). Herein, we report a nanotherapeutic strategy that targets NSCLC tumors in two ways: (a) pharmacodynamically through the use of a bioactivatable agent, β-lap, and (b) pharmacokinetically by using a biocompatible nanocarrier, polymeric micelles, to achieve drug stability, bioavailability, and targeted delivery. β-Lap micelles produced by a film sonication technique were small (∼30 nm), displayed core-shell architecture, and possessed favorable release kinetics. Pharmacokinetic analyses in mice bearing subcutaneous A549 lung tumors showed prolonged blood circulation (t1/2, ∼28 h) and increased accumulation in tumors. Antitumor efficacy analyses in mice bearing subcutaneous A549 lung tumors and orthotopic Lewis lung carcinoma models showed significant tumor growth delay and increased survival. In summary, we have established a clinically viable β-lap nanomedicine platform with enhanced safety, pharmacokinetics, and antitumor efficacy for the specific treatment of NSCLC tumors. Cancer Res; 70(10); 3896–904. ©2010 AACR.
Wip1 Directly Dephosphorylates γ-H2AX and Attenuates the DNA Damage Response
Authors: Cha Hyukjin , Lowe Julie M. , Li Henghong , Lee Ji-Seon , Belova Galina I. , Bulavin Dmitry V. , Fornace Albert J. 
Published: May 2010

Abstract
The integrity of DNA is constantly challenged throughout the life of a cell by both endogenous and exogenous stresses. A well-organized rapid damage response and proficient DNA repair, therefore, become critically important for maintaining genomic stability and cell survival. When DNA is damaged, the DNA damage response (DDR) can be initiated by alterations in chromosomal structure and histone modifications, such as the phosphorylation of the histone H2AX (the phosphorylated form is referred to as γ-H2AX). γ-H2AX plays a crucial role in recruiting DDR factors to damage sites for accurate DNA repair. On repair completion, γ-H2AX must then be reverted to H2AX by dephosphorylation for attenuation of the DDR. Here, we report that the wild-type p53–induced phosphatase 1 (Wip1) phosphatase, which is often overexpressed in a variety of tumors, effectively dephosphorylates γ-H2AX in vitro and in vivo. Ectopic expression of Wip1 significantly reduces the level of γ-H2AX after ionizing as well as UV radiation. Forced premature dephosphorylation of γ-H2AX by Wip1 disrupts recruitment of important DNA repair factors to damaged sites and delays DNA damage repair. Additionally, deletion of Wip1 enhances γ-H2AX levels in cells undergoing constitutive oncogenic stress. Taken together, our studies show that Wip1 is an important mammalian phosphatase for γ-H2AX and shows an additional mechanism for Wip1 in the tumor surveillance network. Cancer Res; 70(10); 4112–22. ©2010 AACR.
Tyrosine Kinase Inhibitor Gefitinib Enhances Topotecan Penetration of Gliomas
Authors: Carcaboso Angel M. , Elmeliegy Mohamed A. , Shen Jun , Juel Stephen J. , Zhang Ziwei M. , Calabrese Christopher , Tracey Lorraine , Waters Christopher M. , Stewart Clinton F. 
Published: May 2010

Abstract
Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, increases brain parenchymal extracellular fluid (ECF) accumulation of topotecan, a substrate of the ATP-binding cassette (ABC) transporters P-glycoprotein (Pgp/MDR-1) and breast cancer resistance protein (BCRP/ABCG2). The effect of modulating these transporters on topotecan penetration in gliomas has not been thoroughly studied. Thus, we performed intracerebral microdialysis on mice bearing orthotopic human gliomas (U87 and MT330) and assessed topotecan tumor ECF (tECF) penetration and the effect of gefitinib on topotecan tECF penetration and intratumor topotecan distribution. We found that topotecan penetration (Ptumor) of U87 was 0.96 ± 0.25 (n = 7) compared with that of contralateral brain (Pcontralateral, 0.42 ± 0.11, n = 5; P = 0.001). In MT330 tumors, Ptumor (0.78 ± 0.26, n = 6) and Pcontralateral (0.42 ± 0.11, n = 5) also differed significantly (P = 0.013). Because both tumor models had disrupted blood-brain barriers and similar Ptumor values, we used U87 and a steady-state drug administration approach to characterize the effect of gefitinib on topotecan Ptumor. At equivalent plasma topotecan exposures, we found that Ptumor after gefitinib administration was lower. In a separate cohort of animals, we determined the volume of distribution of unbound topotecan in tumor (Vu,tumor) and found that it was significantly higher in groups receiving gefitinib, implying that gefitinib administration leads to a greater proportion of intracellular topotecan. Our results provide crucial insights into the role that transporters play in central nervous system drug penetration and provide a better understanding of the effect of coadministration of transporter modulators on anticancer drug distribution within a tumor. Cancer Res; 70(11); 4499–508. ©2010 AACR.
Intratumoral Therapy of Glioblastoma Multiforme Using Genetically Engineered Transferrin for Drug Delivery
Authors: Yoon Dennis J. , Kwan Byron H. , Chao Felix C. , Nicolaides Theodore P. , Phillips Joanna J. , Lam Gretchen Y. , Mason Anne B. , Weiss William A. , Kamei Daniel T. 
Published: May 2010

Abstract
Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor with median survival of only 12 to 15 months under the current standard of care. To both increase tumor specificity and decrease nonspecific side effects, recent experimental strategies in the treatment of GBM have focused on targeting cell surface receptors, including the transferrin (Tf) receptor, that are overexpressed in many cancers. A major limitation of Tf-based therapeutics is the short association of Tf within the cell to deliver its payload. We previously developed two mutant Tf molecules, K206E/R632A Tf and K206E/K534A Tf, in which iron is locked into each of the two homologous lobes. Relative to wild-type Tf, we showed enhanced delivery of diphtheria toxin (DT) from these mutants to a monolayer culture of HeLa cells. Here, we extend the application of our Tf mutants to the treatment of GBM. In vitro treatment of Tf mutants to a monolayer culture of glioma cells showed enhanced cellular association as well as enhanced delivery of conjugated DT. Treatment of GBM xenografts with mutant Tf-conjugated DT resulted in pronounced regression in vivo, indicating their potential use as drug carriers. Cancer Res; 70(11); 4520–7. ©2010 AACR.
MicroRNA-21 in Pancreatic Cancer: Correlation with Clinical Outcome and Pharmacologic Aspects Underlying Its Role in the Modulation of Gemcitabine Activity
Authors: Giovannetti Elisa , Funel Niccola , Peters Godefridus J. , Del Chiaro Marco , Erozenci Leyla A. , Vasile Enrico , Leon Leticia G. , Pollina Luca E. , Groen Annemieke , Falcone Alfredo , Danesi Romano , Campani Daniela , Verheul Henk M. , Boggi Ugo 
Published: May 2010

Abstract
MicroRNA-21 (miR-21) was reported to be overexpressed and contributes to invasion and gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to evaluate whether miR-21 expression was associated with the overall survival (OS) of PDAC patients treated with gemcitabine and to provide mechanistic insights for new therapeutic targets. miR-21 expression was evaluated in cells (including 7 PDAC cell lines, 7 primary cultures, fibroblasts, and a normal pancreatic ductal cell line) and tissues (neoplastic specimens from 81 PDAC patients and normal ductal samples) isolated by laser microdissection. The role of miR-21 on the pharmacologic effects of gemcitabine was studied with a specific miR-21 precursor (pre-miR-21). Patients with high miR-21 expression had a significantly shorter OS both in the metastatic and in the adjuvant setting. Multivariate analysis confirmed the prognostic significance of miR-21. miR-21 expression in primary cultures correlated with expression in their respective tissues and with gemcitabine resistance. Pre-miR-21 transfection significantly decreased antiproliferative effects and apoptosis induction by gemcitabine, whereas matrix metalloproteinase (MMP)-2/MMP-9 and vascular endothelial growth factor expression were upregulated. Addition of inhibitors of phosphoinositide 3-kinase and mammalian target of rapamycin resulted in decrease of phospho-Akt and prevented pre-miR-21–induced resistance to the proapoptotic effects of gemcitabine. miR-21 expression correlated with outcome in PDAC patients treated with gemcitabine. Modulation of apoptosis, Akt phosphorylation, and expression of genes involved in invasive behavior may contribute to the role of miR-21 in gemcitabine chemoresistance and to the rational development of new targeted combinations. Cancer Res; 70(11); 4528–38. ©2010 AACR.
Transforming Growth Factor-β Regulator SnoN Modulates Mammary Gland Branching Morphogenesis, Postlactational Involution, and Mammary Tumorigenesis
Authors: Jahchan Nadine S. , You Young-Hyun , Muller William J. , Luo Kunxin 
Published: May 2010

Abstract
SnoN is an important negative regulator of transforming growth factor-β (TGF-β) signaling that was originally identified as a transforming oncogene in chicken embryonic fibroblasts. Both pro-oncogenic and antioncogenic activities of SnoN have been reported, but its function in normal epithelial cells has not been defined. In the mouse mammary gland, SnoN is expressed at relatively low levels, but it is transiently upregulated at late gestation before being downregulated during lactation and early involution. To assess the effects of elevated levels of SnoN, we generated transgenic mice expressing a SnoN fragment under the control of the mouse mammary tumor virus promoter. In this model system, SnoN elevation increased side-branching and lobular-alveolar proliferation in virgin glands, while accelerating involution in postlactation glands. Increased proliferation stimulated by SnoN was insufficient to induce mammary tumorigenesis. In contrast, elevated levels of SnoN cooperated with polyoma middle T antigen to accelerate the formation of aggressive multifocal adenocarcinomas and to increase the formation of pulmonary metastases. Our studies define functions of SnoN in mammary epithelial cell proliferation and involution, and provide the first in vivo evidence of a pro-oncogenic role for SnoN in mammalian tumorigenesis. Cancer Res; 70(10); 4204–13. ©2010 AACR.
Antifungal Therapy with Itraconazole Impairs the Anti-Lymphoma Effects of Rituximab by Inhibiting Recruitment of CD20 to Cell Surface Lipid Rafts
Authors: Ringshausen Ingo , Feuerstacke Yvonne , Krainz Philipp , den Hollander Jürgen , Hermann Ken , Buck Andreas , Peschel Christian , Meyer zum Bueschenfelde Christian 
Published: May 2010

Abstract
Immunotherapy with rituximab alone or in conjunction with chemotherapy has significantly improved the treatment outcome of B-cell lymphoma patients. Nevertheless, a subpopulation of patients does not respond to rituximab. The reason for treatment failure as well as the exact mechanism of action is still uncertain. The function of rituximab has long been associated with the partitioning of CD20 molecules to membrane microdomains. Here, we show that concomitant antifungal treatment with itraconazole impairs the rituximab anti-lymphoma effect both in vitro and in vivo. At the molecular level, recruitment of CD20 to lipid rafts is inhibited in the presence of itraconazole. Furthermore, calcium influx, which is crucial for rituximab-mediated cell death, was nearly completely abolished by itraconazole treatment. In contrast, the antifungal drug caspofungin did not inhibit CD20 recruitment to lipid rafts, nor did it affect calcium influx or the cytotoxic effect of rituximab. The finding that itraconazole also abolished the cytotoxic effects of other therapeutic antibodies directed against lipid raft–associated molecules (i.e., CD20 and CD52) but not those against the non–raft-associated molecule CD33 further supported our proposed mechanism of action. Our results argue that concomitant medications must be adjusted carefully to achieve optimal antitumor effects with monoclonal antibodies. Cancer Res; 70(11); 4292–6. ©2010 AACR.
Princess Takamatsu Symposium on DNA Repair and Human Cancers
Authors: Loeb Lawrence A. , Nishimura Susumu 
Published: May 2010

Abstract
The 40th International Symposium of the Princess Takamatsu Cancer Research Fund, entitled “DNA Repair and Human Cancers,” was held on November 10–12, 2009 at Hotel Grand Palace, Tokyo, Japan. The meeting focused on the role of DNA repair in preventing mutations by endogenous and exogenous DNA damage and increasing the efficacy of chemotherapeutic agents by interfering with DNA repair. The 14 presentations by the speakers from the United States, four from the United Kingdom, one each from Italy, The Netherlands, and France, and 13 from Japan, covered most aspects of DNA repair, spanning DNA damage, molecular structures of repair enzymes, and clinical studies on inhibition of DNA repair processes. Extensive time was reserved for discussions with the active participation of the 150 invited Japanese scientists. The choice of a symposium on DNA repair in human cancers resulted in part from the excellent basic and clinical studies that have been carried out for many years in Japan, and the general lack of recognition versus the importance of DNA repair in understanding carcinogenesis. Cancer Res; 70(11); 4269–73. ©2010 AACR.
FTY720 Shows Promising In vitro and In vivo Preclinical Activity by Downmodulating Cyclin D1 and Phospho-Akt in Mantle Cell Lymphoma
Authors: Liu Qing , Alinari Lapo , Chen Ching-Shih , Yan Fengting , Dalton James T. , Lapalombella Rosa , Zhang Xiaoli , Mani Rajeswaran , Lin Teresa , Byrd John C. , Baiocchi Robert A. , Muthusamy Natarajan 
Published: May 2010

Abstract
Purpose: Despite the progress that has been made in the treatment of mantle cell lymphoma (MCL), all patients invariably relapse with the currently available therapies. Because of the absence of curative therapy for MCL, we explored FTY720 as a novel agent against MCL.
Experimental Design: The cytotoxic effect of FTY720 in primary MCL tumor cells and cell lines were evaluated in vitro. The effects of FTY720 on caspase activation, generation of reactive oxygen species, and modulation of Cyclin D1 and Akt, which are implied in the pathogenesis of MCL, were investigated. The in vivo efficacy of FTY720 was evaluated in a Jeko-severe combined immunodeficient xenograft model of human MCL.
Results: FTY720 mediated time- and dose-dependent cytotoxicity in primary MCL tumor cells and MCL cell lines in vitro. FTY720-induced cytotoxicity occured independent of caspase activation but dependent on the generation of ROS in MCL. In addition, FTY720 treatment resulted in the time-dependent downmodulation of Cyclin D1 and accumulation of cells in G0-G1 and G2-M phases of the cell cycle with concomitant decrease in S-phase entry. Furthermore, concentrations of FTY720 that induced cytotoxicity led to decreased phospho-Akt in primary MCL cells and cell lines. Most importantly, the in vivo therapeutic activity of FTY720 was shown in severe combined immunodeficient mice engrafted with the Jeko MCL cell line.
Conclusions: These results provide the first evidence for a potential use of FTY720 in targeting key pathways that are operable in the pathogenesis of MCL and warrant further investigation of FTY720 in clinical trials to treat patients with MCL. Clin Cancer Res; 16(12); 3182–92. ©2010 AACR.