bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radioresistant Cancer Cells Can Be Conditioned to Enter Senescence by mTOR Inhibition
Authors: Nam Hae Yun , Han Myung Woul , Chang Hyo Won , Lee Yoon Sun , Lee Myungjin , Lee Hyang Ju , Lee Byoung Wook , Lee Hee Jin , Lee Kyung Eun , Jung Min Kyo , Jeon Hyesung , Choi Seung-Ho , Park Neung Hwa , Kim Sang Yoon , Kim Seong Who 
Published: May 2013

Abstract
Autophagy is frequently activated in radioresistant cancer cells where it provides a cell survival strategy. The mTOR inhibitor rapamycin activates autophagy but paradoxically it also enhances radiosensitivity. In this study, we investigated the mechanisms of these opposing actions in radiation-resistant glioma or parotid carcinoma cells. Radiation treatment transiently enhanced autophagic flux for a period of 72 hours in these cells and treatment with rapamycin or the mTOR inhibitor PP242 potentiated this effect. However, these treatments also increased heterochromatin formation, irreversible growth arrest, and premature senescence, as defined by expression of senescence-associated β-galactosidase activity. This augmentation in radiosensitivity seemed to result from a restoration in the activity of the tumor suppressor RB and a suppression of RB-mediated E2F target genes. In tumor xenografts, we showed that administering rapamycin delayed tumor regrowth after irradiation and increased senescence-associated β-galactosidase staining in the tumor. Our findings suggest that a potent and persistent activation of autophagy by mTOR inhibitors, even in cancer cells where autophagy is occurring, can trigger premature senescence as a method to restore radiosensitivity. Cancer Res; 73(14); 4267–77. ©2013 AACR.
Integration of High-Resolution Methylome and Transcriptome Analyses to Dissect Epigenomic Changes in Childhood Acute Lymphoblastic Leukemia
Authors: Busche Stephan , Ge Bing , Vidal Ramon , Spinella Jean-François , Saillour Virginie , Richer Chantal , Healy Jasmine , Chen Shu-Huang , Droit Arnaud , Sinnett Daniel , Pastinen Tomi 
Published: May 2013

Abstract
B-cell precursor acute lymphoblastic leukemia (pre-B ALL) is the most common pediatric cancer. Although the genetic determinants underlying disease onset remain unclear, epigenetic modifications including DNA methylation are suggested to contribute significantly to leukemogenesis. Using the Illumina 450K array, we assessed DNA methylation in matched tumor-normal samples of 46 childhood patients with pre-B ALL, extending single CpG-site resolution analysis of the pre-B ALL methylome beyond CpG-islands (CGI). Unsupervised hierarchical clustering of CpG-site neighborhood, gene, or microRNA (miRNA) gene-associated methylation levels separated the tumor cohort according to major pre-B ALL subtypes, and methylation in CGIs, CGI shores, and in regions around the transcription start site was found to significantly correlate with transcript expression. Focusing on samples carrying the t(12;21) ETV6–RUNX1 fusion, we identified 119 subtype-specific high-confidence marker CpG-loci. Pathway analyses linked the CpG-loci–associated genes with hematopoiesis and cancer. Further integration with whole-transcriptome data showed the effects of methylation on expression of 17 potential drivers of leukemogenesis. Independent validation of array methylation and sequencing-derived transcript expression with Sequenom Epityper technology and real-time quantitative reverse transcriptase PCR, respectively, indicates more than 80% empirical accuracy of our genome-wide findings. In summary, genome-wide DNA methylation profiling enabled us to separate pre-B ALL according to major subtypes, to map epigenetic biomarkers specific for the t(12;21) subtype, and through a combined methylome and transcriptome approach to identify downstream effects on candidate drivers of leukemogenesis. Cancer Res; 73(14); 4323–36. ©2013 AACR.
Bone Marrow–Derived CD11b+Jagged2+ Cells Promote Epithelial-to-Mesenchymal Transition and Metastasization in Colorectal Cancer
Authors: Caiado Francisco , Carvalho Tânia , Rosa Isadora , Remédio Leonor , Costa Ana , Matos João , Heissig Beate , Yagita Hideo , Hattori Koichi , da Silva João Pereira , Fidalgo Paulo , Pereira António Dias , Dias Sérgio 
Published: May 2013

Abstract
Timely detection of colorectal cancer metastases may permit improvements in their clinical management. Here, we investigated a putative role for bone marrow–derived cells in the induction of epithelial-to-mesenchymal transition (EMT) as a marker for onset of metastasis. In ectopic and orthotopic mouse models of colorectal cancer, bone marrow–derived CD11b(Itgam)+Jagged2 (Jag2)+ cells infiltrated primary tumors and surrounded tumor cells that exhibited diminished expression of E-cadherin and increased expression of vimentin, 2 hallmarks of EMT. In vitro coculture experiments showed that the bone marrow–derived CD11b+Jag2+ cells induced EMT through a Notch-dependent pathway. Using neutralizing antibodies, we imposed a blockade on CD11b+ cells' recruitment to tumors, which decreased the tumor-infiltrating CD11b+Jag2+ cell population of interest, decreasing tumor growth, restoring E-cadherin expression, and delaying EMT. In support of these results, we found that peripheral blood levels of CD11b+Jag2+ cells in mouse models of colorectal cancer and in a cohort of untreated patients with colorectal cancer were indicative of metastatic disease. In patients with colorectal cancer, the presence of circulating CD11b+Jag2+ cells was accompanied by loss of E-cadherin in the corresponding patient tumors. Taken together, our results show that bone marrow–derived CD11b+Jag2+ cells, which infiltrate primary colorectal tumors, are sufficient to induce EMT in tumor cells, thereby triggering onset of metastasis. Furthermore, they argue that quantifying circulating CD11b+Jag2+ cells in patients may offer an indicator of colorectal cancer progression to metastatic levels of the disease. Cancer Res; 73(14); 4233–46. ©2013 AACR.
Vitronectin–αvβ3 Integrin Engagement Directs Hypoxia-Resistant mTOR Activity and Sustained Protein Synthesis Linked to Invasion by Breast Cancer Cells
Authors: Pola Carolina , Formenti Silvia C. , Schneider Robert J. 
Published: May 2013

Abstract
The tumor microenvironment is a crucial player in the ability of cancer cells to acquire the ability to survive under the hypoxic environment and promote migration and invasion. Translational regulation is an essential part of cancer development and progression. Protein synthesis consumes considerable cellular metabolic energy and is therefore highly regulated, in turn controlling tumor cell proliferation and survival in extreme tumor–host conditions. Protein synthesis is typically downregulated by hypoxia, impairing cell proliferation and migration. Here, we show that breast cancer cells expressing integrin αvβ3, when engaging the extracellular matrix (ECM) protein vitronectin, strongly upregulate both mTOR activity and cap-dependent mRNA translation, which overrides their inhibition by hypoxia and facilitates tumor cell invasion. Interaction of vitronectin with integrin αvβ3 results in the continued activation of the kinase mTOR despite hypoxia through a mechanism that is dependent on integrin-linked kinase but is independent of focal adhesion kinase. Continuous activation of mTOR despite hypoxia involves release of translation initiation factor eIF4E from its repressor protein 4E-BP1, which is required for vitronectin-mediated tumor cell invasion. As integrin αvβ3 is associated with breast cancer cell invasion and metastasis to bone, we propose that the interaction with specific ECM proteins can influence cancer cell invasion, in part, by hyperactivation of mTOR, thereby promoting and sustaining protein synthesis under hypoxic conditions. Cancer Res; 73(14); 4571–8. ©2013 AACR.
Genetic Ablation of the Fatty Acid–Binding Protein FABP5 Suppresses HER2-Induced Mammary Tumorigenesis
Authors: Levi Liraz , Lobo Glenn , Doud Mary Kathryn , von Lintig Johannes , Seachrist Darcie , Tochtrop Gregory P. , Noy Noa 
Published: May 2013

Abstract
The fatty acid–binding protein FABP5 shuttles ligands from the cytosol to the nuclear receptor PPARβ/δ (encoded for by Pparδ), thereby enhancing the transcriptional activity of the receptor. This FABP5/PPARδ pathway is critical for induction of proliferation of breast carcinoma cells by activated epidermal growth factor receptor (EGFR). In this study, we show that FABP5 is highly upregulated in human breast cancers and we provide genetic evidence of the pathophysiologic significance of FABP5 in mammary tumorigenesis. Ectopic expression of FABP5 was found to be oncogenic in 3T3 fibroblasts where it augmented the ability of PPARδ to enhance cell proliferation, migration, and invasion. To determine whether FABP5 is essential for EGFR-induced mammary tumor growth, we interbred FABP5-null mice with MMTV-ErbB2/HER2 oncomice, which spontaneously develop mammary tumors. FABP5 ablation relieved activation of EGFR downstream effector signals, decreased expression of PPARδ target genes that drive cell proliferation, and suppressed mammary tumor development. Our findings establish that FABP5 is critical for mammary tumor development, rationalizing the development of FABP5 inhibitors as novel anticarcinogenic drugs. Cancer Res; 73(15); 4770–80. ©2013 AACR.
Efficacy of the Specific Endothelin A Receptor Antagonist Zibotentan (ZD4054) in Colorectal Cancer: A Preclinical Study
Authors: Haque Samer-ul , Dashwood Michael R. , Heetun Mohammed , Shiwen Xu , Farooqui Noreen , Ramesh Bala , Welch Hazel , Savage Felicity J. , Ogunbiyi Olagunju , Abraham David J. , Loizidou Marilena 
Published: May 2013

Abstract
Endothelin 1 (ET-1) is overexpressed in cancer, contributing to disease progression. We previously showed that ET-1 stimulated proliferative, migratory, and contractile tumorigenic effects via the ETA receptor. Here, for the first time, we evaluate zibotentan, a specific ETA receptor antagonist, in the setting of colorectal cancer, in cellular models. Pharmacologic characteristics were further determined in patient tissues. Colorectal cancer lines (n = 4) and fibroblast strains (n = 6), isolated from uninvolved areas of colorectal cancer specimens, were exposed to ET-1 and/or ETA/B receptor antagonists. Proliferation (methylene blue), migration (scratch wounds), and contraction (gel lattices) were assessed. Receptor distribution and binding characteristics (Kd, Bmax) were determined using autoradiography on tissue sections and homogenates and cytospun cells, supported by immunohistochemistry. Proliferation was inhibited by ETA (zibotentan &gt; BQ123; P &lt; 0.05), migration by ETB &gt; ETA, and contraction by combined ETA and ETB antagonism. Intense ET-1 stromal binding correlated with fibroblasts and endothelial cells. Colorectal cancer lines and fibroblasts revealed high density and affinity ET-1 binding (Bmax = 2.435 fmol/1 × 106 cells, Kd = 367.7 pmol/L; Bmax = 3.03 fmol/1 × 106 cells, Kd = 213.6 pmol/L). In cancer tissues, ETA receptor antagonists (zibotentan; BQ123) reduced ET-1 binding more effectively (IC50: 0.1–10 μmol/L) than ETB receptor antagonist BQ788 (∼IC50, 1 mmol/L). ET-1 stimulated cancer-contributory processes. Its localization to tumor stroma, with greatest binding/affinity to fibroblasts, implicates these cells in tumor progression. ETA receptor upregulation in cancer tissues and its role in tumorigenic processes show the receptor's importance in therapeutic targeting. Zibotentan, the most specific ETA receptor antagonist available, showed the greatest inhibition of ET-1 binding. With its known safety profile, we provide evidence for zibotentan's potential role as adjuvant therapy in colorectal cancer. Mol Cancer Ther; 12(8); 1556–67. ©2013 AACR.
Genetic and Chemical Targeting of Epithelial-Restricted with Serine Box Reduces EGF Receptor and Potentiates the Efficacy of Afatinib
Authors: Zhang Manchao , Taylor Christopher E. , Piao Longzhu , Datta Jharna , Bruno Paul A. , Bhave Sanjay , Su Tizhi , Lang James C. , Xie Xiujie , Teknos Theodoros N. , Mapp Anna K. , Pan Quintin 
Published: May 2013

Abstract
EGF receptor (EGFR) is elevated in more than 90% of head and neck squamous cell carcinoma (HNSCC). However, a majority of patients with HNSCC do not respond to anti-EGFR therapeutics. Insensitivity to EGFR inhibitors may be due to kinase-independent actions of EGFR and/or activation of Her2. Strategies to reduce EGFR and Her2 protein levels in concert may be an optimal approach to enhance the efficacy of current anti-EGFR molecules. In this study, knockdown of epithelial-restricted with serine box (ESX) decreased EGFR and Her2 promoter activity, expression, and levels. ESX was elevated in primary HNSCC tumors and associated with increased EGFR and Her2. Genetic ablation of ESX decreased EGFR and Her2 levels and enhanced the antiproliferative effects of EGFR/Her2 tyrosine kinase inhibitors (TKI), lapatinib and afatinib. Biphenyl isoxazolidine, a novel small-molecule ESX inhibitor, reduced EGFR and Her2 levels and potentiated the antiproliferative efficacy of afatinib. Single-agent biphenyl isoxazolidine retarded the in vivo tumorigenicity of CAL27 cells. Importantly, the combination of biphenyl isoxazolidine and afatinib was significantly superior in vivo and resulted in a 100% response rate with a 94% reduction in tumor volume. Targeting EGFR/Her2 levels with an ESX inhibitor and EGFR/Her2 kinase activity with a TKI simultaneously is a highly active therapeutic approach to manage HNSCC. Our work provides evidence to support the further development of ESX inhibitors as an adjuvant to enhance the response rate of patients with HNSCC to current anti-EGFR/Her2 therapeutics. Mol Cancer Ther; 12(8); 1515–25. ©2013 AACR.
Impact of Tumor HER2/ERBB2 Expression Level on HER2-Targeted Liposomal Doxorubicin-Mediated Drug Delivery: Multiple Low-Affinity Interactions Lead to a Threshold Effect
Authors: Hendriks Bart S. , Klinz Stephan G. , Reynolds Joseph G. , Espelin Christopher W. , Gaddy Daniel F. , Wickham Thomas J. 
Published: May 2013

AbstractNumerous targeted nanotherapeutics have been described for potential treatment of solid tumors. Although attention has focused on antigen selection and molecular design of these systems, there has been comparatively little study of how cellular heterogeneity influences interaction of targeted nanoparticles with tumor cells. Antigens, such as HER2/ERBB2, are heterogeneously expressed across different indications, across patients, and within individual tumors. Furthermore, antigen expression in nontarget tissues necessitates optimization of the therapeutic window. Understanding the performance of a given nanoparticle under different regimens of antigen expression has the ability to inform patient selection and clinical development decisions. In this work, HER2-targeted liposomal doxorubicin was used as a model-targeted nanoparticle to quantitatively investigate the effect of HER2 expression levels on delivery of doxorubicin to the nucleus. We find quantitatively greater nuclear doxorubicin delivery with increasing HER2 expression, exhibiting a threshold effect at approximately 2 × 105 HER2 receptors/cell. Kinetic modeling indicated that the threshold effect arises from multiple low-affinity interactions between the targeted liposome and HER2. These results support previous data showing little or no uptake into human cardiomyocytes, which express levels of HER2 below the threshold. Finally, these results suggest that HER2-targeted liposomal doxorubicin may effectively target tumors that fall below traditional definitions of HER2-positive tumors, thereby expanding the potential population of patients that might benefit from this agent. Mol Cancer Ther; 12(9); 1816–28. ©2013 AACR.
B56γ Tumor-Associated Mutations Provide New Mechanisms for B56γ-PP2A Tumor Suppressor Activity
Authors: Nobumori Yumiko , Shouse Geoffrey P. , Wu Yong , Lee Kyu Joon , Shen Binghui , Liu Xuan 
Published: May 2013

Abstract
The hetero-trimeric PP2A serine/threonine phosphatases containing the regulatory subunit B56, and in particular B56γ, can function as tumor suppressors. In response to DNA damage, the B56γ subunit complexes with the PP2A AC core (B56γ-PP2A) and binds p53. This event promotes PP2A-mediated dephosphorylation of p53 at Thr55, which induces expression of p21, and the subsequent inhibition of cell proliferation and transformation. In addition to dephosphorylation of p53, B56γ-PP2A also inhibits cell proliferation and transformation by a second, as yet unknown, p53-independent mechanism. Here, we interrogated a panel of B56γ mutations found in human cancer samples and cell lines and showed that these mutations lost B56γ tumor-suppressive activity by two distinct mechanisms: one is by disrupting interactions with the PP2A AC core and the other with B56γ-PP2A substrates (p53 and unknown proteins). For the first mechanism, due to the absence of the C catalytic subunit in the complex, the mutants are unable to mediate dephosphorylation of any substrate and thus failed to promote both the p53-dependent and -independent tumor-suppressive functions of B56γ-PP2A. For the second mechanism, the mutants lacked specific substrate interactions and thus partially lost tumor-suppressive function, i.e., either the p53-dependent or p53-independent contingent upon which substrate binding was affected. Overall, these data provide new insight into the mechanisms of tumor suppression by B56γ.
Implications: This study further indicates the importance of B56γ-PP2A in tumorigenesis. Mol Cancer Res; 11(9); 995–1003. ©2013 AACR.
Unraveling the Role of FOXQ1 in Colorectal Cancer Metastasis
Authors: Abba Mohammed , Patil Nitin , Rasheed Kabeer , Nelson Laura D. , Mudduluru Giridhar , Leupold Jörg Hendrik , Allgayer Heike 
Published: May 2013

Abstract
Malignant cell transformation, invasion, and metastasis are dependent on the coordinated rewiring of gene expression. A major component in the scaffold of these reprogramming events is one in which epithelial cells lose intercellular connections and polarity to adopt a more motile mesenchymal phenotype, which is largely supported by a robust transcriptional machinery consisting mostly of developmental transcription factors. This study demonstrates that the winged helix transcription factor, FOXQ1, contributes to this rewiring process, in part by directly modulating the transcription of TWIST1, itself a key mediator of metastasis that transcriptionally regulates the expression of important molecules involved in epithelial-to-mesenchymal transition. Forced expression and RNA-mediated silencing of FOXQ1 led to enhanced and suppressed mRNA and protein levels of TWIST1, respectively. Mechanistically, FOXQ1 enhanced the reporter activity of TWIST1 and directly interacted with its promoter. Furthermore, enhanced expression of FOXQ1 resulted in increased migration and invasion in colorectal cancer cell lines, whereas knockdown studies showed the opposite effect. Moreover, using the in vivo chicken chorioallantoic membrane metastasis assay model, FOXQ1 significantly enhanced distant metastasis with minimal effects on tumor growth.
Implications: These findings reveal FOXQ1 as a modulator of TWIST1-mediated metastatic phenotypes and support its potential as a biomarker of metastasis. Mol Cancer Res; 11(9); 1017–28. ©2013 AACR.
HDAC6 and SIRT2 Regulate the Acetylation State and Oncogenic Activity of Mutant K-RAS
Authors: Yang Moon Hee , Laurent Gaelle , Bause Alexandra S. , Spang Robert , German Natalie , Haigis Marcia C. , Haigis Kevin M. 
Published: May 2013

AbstractActivating point mutations in K-RAS are extremely common in cancers of the lung, colon, and pancreas and are highly predictive of poor therapeutic response. One potential strategy for overcoming the deleterious effects of mutant K-RAS is to alter its posttranslational modification. Although therapies targeting farnesylation have been explored, and have ultimately failed, the therapeutic potential of targeting other modifications remains to be seen. Recently, it was shown that acetylation of lysine 104 attenuates K-RAS transforming activity by interfering with GEF-induced nucleotide exchange. Here, the deacetylases HDAC6 and SIRT2 were shown to regulate the acetylation state of K-RAS in cancer cells. By extension, inhibition of either of these enzymes has a dramatic impact on the growth properties of cancer cells expressing activation mutants of K-RAS. These results suggest that therapeutic targeting of HDAC6 and/or SIRT2 may represent a new way to treat cancers expressing mutant forms of K-RAS.Implications: This study suggests that altering K-RAS acetylation is a feasible approach to limiting tumorigenic potential. Mol Cancer Res; 11(9); 1072–7. ©2013 AACR.
Angiotensin-(1–7) Dose-Dependently Inhibits Atherosclerotic Lesion Formation and Enhances Plaque Stability by Targeting Vascular Cells
Authors: Yang Jian Min , Dong Mei , Meng Xiao , Zhao Yu Xia , Yang Xiao Yan , Liu Xiao Ling , Hao Pan Pan , Li Jing Jing , Wang Xu Ping , Zhang Kai , Gao Fei , Zhao Xue Qiang , Zhang Ming Xiang , Zhang Yun , Zhang Cheng 
Published: May 2013

Objective—
To test the hypothesis that chronic infusion of angiotensin-(1–7) [Ang-(1–7)] may dose-dependently inhibit atherosclerotic lesion formation by targeting vascular smooth muscle cells and a large dose of Ang-(1–7) may stabilize mature plaque by targeting macrophages.

Approach and Results—

In vivo, the effects of Ang-(1–7) on atherogenesis and plaque stability were observed in ApoE
−/−
mice fed a high-fat diet and chronic angiotensin II infusion. In vitro, the effects of Ang-(1–7) on vascular smooth muscle cells’ proliferation and migration, and macrophage inflammatory cytokines were examined. Ang-(1–7) dose-dependently attenuated early atherosclerotic lesions and inhibited vascular smooth muscle cells’ proliferation and migration via suppressing extracellular regulated protein kinase/P38 mitogen-activated protein kinase and janus kinase/signal transducers and activators of transcription activities and enhancing smooth muscle 22α and angiotensin II type 2 receptor expression. Ang-(1–7) treatment resulted in high contents of collagen and vascular smooth muscle cells, and low contents of macrophages and lipids in carotid mature plaques. Ang-(1–7) lowered the expression levels of proinflammatory cytokines and activities of matrix metalloproteinases in mature plaques.

Conclusions—

Ang-(1–7) treatment inhibits early atherosclerotic lesions and increases plaque stability in ApoE
−/−
mice, thus providing a novel and promising approach to the treatment of atherosclerosis.