bluuebunny/crossref_metadata_2025_split huggingface dataset:
The PAX3-FKHR Fusion Gene of Rhabdomyosarcoma Cooperates with Loss of p16INK4A to Promote Bypass of Cellular Senescence
Authors: Linardic Corinne M. , Naini Sarasija , Herndon James E. , Kesserwan Chimen , Qualman Stephen J. , Counter Christopher M. 
Published: July 2007

Abstract
Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood and adolescence. Despite advances in therapy, patients with a histologic variant of rhabdomyosarcoma known as alveolar rhabdomyosarcoma (ARMS) have a 5-year survival of &lt;30%. ARMS is characterized by a chromosomal translocation generating the PAX3-FKHR fusion gene. However, ectopic expression of PAX3-FKHR often induces inhibition of cell proliferation, or cell death, when expressed in nonmuscle cells. This prompted us to explore the effect of expressing PAX3-FKHR in more relevant cells, specifically primary human skeletal muscle cells because these cells can be converted to a tumorigenic state that mimics rhabdomyosarcoma. PAX3-FKHR expression promoted both fetal and postnatal primary human skeletal muscle cell precursors to bypass the senescence growth arrest checkpoint. This bypass was accompanied by epigenetic DNA methylation of the p16INK4A promoter and correspondingly a loss of expression of this tumor suppressor. Knockdown of p16INK4A cooperated with PAX3-FKHR to drive proliferation past senescence, whereas reintroduction of wild-type p16INK4A in post-senescent cells caused growth arrest. Thus, PAX3-FKHR acts in concert with loss of p16INK4A to promote inappropriate proliferation of skeletal muscle cells. This association between PAX3-FKHR expression and p16INK4A loss was seen in human ARMS tumor tissue, as both human rhabdomyosarcoma cell lines and tissue microarrays showed a trend toward down-regulation of p16INK4A protein in alveolar subsets. We surmise that the generation of the PAX3-FKHR fusion protein may require loss of p16INK4A to promote malignant proliferation of skeletal muscle cells as an early step in ARMS tumorigenesis. [Cancer Res 2007;67(14):6691–9]
IRE1 Signaling Is Essential for Ischemia-Induced Vascular Endothelial Growth Factor-A Expression and Contributes to Angiogenesis and Tumor Growth In vivo
Authors: Drogat Benjamin , Auguste Patrick , Nguyen Duc Thang , Bouchecareilh Marion , Pineau Raphael , Nalbantoglu Josephine , Kaufman Randal J. , Chevet Eric , Bikfalvi Andréas , Moenner Michel 
Published: July 2007

Abstract
In solid tumors, cancer cells subjected to ischemic conditions trigger distinct signaling pathways contributing to angiogenic stimulation and tumor development. Characteristic features of tumor ischemia include hypoxia and glucose deprivation, leading to the activation of hypoxia-inducible factor-1–dependent signaling pathways and to complex signaling events known as the unfolded protein response. Here, we show that the activation of the endoplasmic reticulum stress sensor IRE1 is a common determinant linking hypoxia- and hypoglycemia-dependent responses to the up-regulation of vascular endothelial growth factor-A (VEGF-A). Tumor cells expressing a dominant-negative IRE1 transgene as well as Ire1α-null mouse embryonic fibroblasts were unable to trigger VEGF-A up-regulation upon either oxygen or glucose deprivation. These data correlated with a reduction of tumor angiogenesis and growth in vivo. Our results therefore suggest an essential role for IRE1-dependent signaling pathways in response to ischemia and identify this protein as a potential therapeutic target to control both the angiogenic switch and tumor development. [Cancer Res 2007;67(14):6700–7]
Targeted Cancer Gene Therapy Using a Hypoxia Inducible Factor–Dependent Oncolytic Adenovirus Armed with Interleukin-4
Authors: Post Dawn E. , Sandberg Eric M. , Kyle Michele M. , Devi Narra Sarojini , Brat Daniel J. , Xu Zhiheng , Tighiouart Mourad , Van Meir Erwin G. 
Published: July 2007

AbstractThere is a need for novel therapies targeting hypoxic cells in tumors. These cells are associated with tumor resistance to therapy and express hypoxia inducible factor-1 (HIF-1), a transcription factor that mediates metabolic adaptation to hypoxia and activates tumor angiogenesis. We previously developed an oncolytic adenovirus (HYPR-Ad) for the specific killing of hypoxic/HIF-active tumor cells, which we now armed with an interleukin-4 gene (HYPR-Ad-IL4). We designed HYPR-Ad-IL4 by cloning the Ad E1A viral replication and IL-4 genes under the regulation of a bidirectional hypoxia/HIF-responsive promoter. The IL-4 cytokine was chosen for its ability to induce a strong host antitumor immune response and its potential antiangiogenic activity. HYPR-Ad-IL4 induced hypoxia-dependent IL-4 expression, viral replication, and conditional cytolysis of hypoxic, but not normoxic cells. The treatment of established human tumor xenografts with HYPR-Ad-IL4 resulted in rapid and maintained tumor regression with the same potency as that of wild-type dl309-Ad. HYPR-Ad-IL4–treated tumors displayed extensive necrosis, fibrosis, and widespread viral replication. Additionally, these tumors contained a distinctive leukocyte infiltrate and prominent hypoxia. The use of an oncolytic Ad that locally delivers IL-4 to tumors is novel, and we expect that HYPR-Ad-IL4 will have broad therapeutic use for all solid tumors that have hypoxia or active HIF, regardless of tissue origin or genetic alterations. [Cancer Res 2007;67(14):6872–81]
Systemic Treatment with the Antidiabetic Drug Metformin Selectively Impairs p53-Deficient Tumor Cell Growth
Authors: Buzzai Monica , Jones Russell G. , Amaravadi Ravi K. , Lum Julian J. , DeBerardinis Ralph J. , Zhao Fangping , Viollet Benoit , Thompson Craig B. 
Published: July 2007

Abstract
The effect of the antidiabetic drug metformin on tumor growth was investigated using the paired isogenic colon cancer cell lines HCT116 p53+/+ and HCT116 p53−/−. Treatment with metformin selectively suppressed the tumor growth of HCT116 p53−/− xenografts. Following treatment with metformin, we detected increased apoptosis in p53−/− tumor sections and an enhanced susceptibility of p53−/− cells to undergo apoptosis in vitro when subject to nutrient deprivation. Metformin is proposed to function in diabetes treatment as an indirect activator of AMP-activated protein kinase (AMPK). Treatment with AICAR, another AMPK activator, also showed a selective ability to inhibit p53−/− tumor growth in vivo. In the presence of either of the two drugs, HCT116 p53+/+ cells, but not HCT116 p53−/− cells, activated autophagy. A similar p53-dependent induction of autophagy was observed when nontransformed mouse embryo fibroblasts were treated. Treatment with either metformin or AICAR also led to enhanced fatty acid β-oxidation in p53+/+ MEFs, but not in p53−/− MEFs. However, the magnitude of induction was significantly lower in metformin-treated cells, as metformin treatment also suppressed mitochondrial electron transport. Metformin-treated cells compensated for this suppression of oxidative phosphorylation by increasing their rate of glycolysis in a p53-dependent manner. Together, these data suggest that metformin treatment forces a metabolic conversion that p53−/− cells are unable to execute. Thus, metformin is selectively toxic to p53-deficient cells and provides a potential mechanism for the reduced incidence of tumors observed in patients being treated with metformin. [Cancer Res 2007;67(14):6745–52]
ERM/ETV5 Up-regulation Plays a Role during Myometrial Infiltration through Matrix Metalloproteinase-2 Activation in Endometrial Cancer
Authors: Monge Marta , Colas Eva , Doll Andreas , Gonzalez Marta , Gil-Moreno Antonio , Planaguma Jesus , Quiles Maite , Arbos Maria Antonia , Garcia Angel , Castellvi Josep , Llaurado Marta , Rigau Marina , Alazzouzi Hafid , Xercavins Jordi , Alameda Francesc , Reventos Jaume , Abal Miguel 
Published: July 2007

Abstract
We have described recently the Ets family transcription factor, ERM/ETV5, specifically up-regulated in endometrioid endometrial carcinoma (EEC) and associated with myometrial infiltration. Ets family members have been correlated to tumor progression by up-regulating the expression of matrix-degrading proteases. In the present study, we investigated the possibility that in EEC, ERM/ETV5 may act by inducing the expression of genes involved in extracellular matrix remodeling. Unraveling the molecular events associated with the initiation of tumor invasion would represent an obvious improvement for EEC patients. The overexpression of ERM/ETV5 induced scattering in the endometrial cancer cell line Hec-1A, correlating to increased matrix metalloproteinase-2 (MMP-2) gelatinase activity. Both chromatin immunoprecipitation and reversion experiments with RNA interference and specific MMP-2 inhibitor showed a functional link between ERM/ETV5 overexpression and MMP-2 activation. The increased MMP-2 activity associated with overexpressed ERM/ETV5 in a mouse model conferred invasive capacity to endometrial tumors. Orthotopically implanted overexpressing ERM/ETV5 tumors presented a more aggressive and infiltrative pattern of myometrial invasion. Finally, the specific localization of ERM/ETV5 and MMP-2 at the invasive front of myometrial infiltrating human endometrial carcinomas further reinforced the hypothesis of a role for ERM/ETV5 in the early steps of endometrial dissemination. Taken together, these results lead us to propose that in EEC, ERM/ETV5 acts through MMP-2 gelatinolytic activity to confer invasive capabilities, associated with an initial switch to myometrial infiltration. They also postulate ERM/ETV5 as a valuable marker for patient stratification and a transcription pathway that should be evaluated for therapies specifically targeting the initial steps of EEC dissemination. [Cancer Res 2007;67(14):6753–9]
Discovery and Validation of Biomarkers that Respond to Treatment with Brivanib Alaninate, a Small-Molecule VEGFR-2/FGFR-1 Antagonist
Authors: Ayers Mark , Fargnoli Joseph , Lewin Anne , Wu Qiuyan , Platero J. Suso 
Published: July 2007

Abstract
The process of neovascularization from preexisting blood vessels, referred to as angiogenesis, plays a critical role in both tumor growth and dissemination in multiple cancer types. Currently, there exists a need to identify biomarkers that can both indicate biological activity and predict efficacy at the molecular level for antiangiogenesis drugs which are anticipated to result in tumor stasis rather than regression. To identify such biomarkers, athymic mice bearing L2987 human tumor xenografts were treated with the antiangiogenic agent brivanib alaninate, which is currently under clinical evaluation. This is an orally available and selective tyrosine kinase inhibitor that targets the key angiogenesis receptors vascular endothelial growth factor receptor 2 (VEGFR-2) and fibroblast growth factor receptor 1. In the described studies, tumor samples were collected from these xenografts and RNA was extracted for gene expression profiling on Affymetrix 430A mouse GeneChips. Statistical analysis was done using a defined set of genes identified to be coexpressed with VEGFR-2 from a clinical tumor gene expression profiling database and between tumor samples isolated from brivanib alaninate–treated and untreated mice. Tyrosine kinase receptor 1 (Tie-1), collagen type IV α1 (Col4a1), complement component 1, q subcomponent receptor 1 (C1qr1), angiotensin receptor–like 1 (Agtrl1), and vascular endothelial-cadherin (Cdh5) were all identified to be significantly modulated by treatment with brivanib alaninate. These genes, which may be potentially useful as markers of brivanib alaninate activity, were further studied at the protein level in two separate in vivo human colon tumor xenograft models, HCT116 and GEO, using immunohistochemistry-based approaches. [Cancer Res 2007;67(14):6899–906]
MUTYH-Null Mice Are Susceptible to Spontaneous and Oxidative Stress–Induced Intestinal Tumorigenesis
Authors: Sakamoto Katsumi , Tominaga Yohei , Yamauchi Kazumi , Nakatsu Yoshimichi , Sakumi Kunihiko , Yoshiyama Kaoru , Egashira Akinori , Kura Shinobu , Yao Takashi , Tsuneyoshi Masazumi , Maki Hisaji , Nakabeppu Yusaku , Tsuzuki Teruhisa 
Published: July 2007

Abstract
MUTYH is a mammalian DNA glycosylase that initiates base excision repair by excising adenine opposite 8-oxoguanine and 2-hydroxyadenine opposite guanine, thereby preventing G:C to T:A transversion caused by oxidative stress. Recently, biallelic germ-line mutations of MUTYH have been found in patients predisposed to a recessive form of hereditary multiple colorectal adenoma and carcinoma with an increased incidence of G:C to T:A somatic mutations in the APC gene. In the present study, a systematic histologic examination revealed that more spontaneous tumors had developed in MUTYH-null mice (72 of 121; 59.5%) than in the wild type (38 of 109; 34.9%). The increased incidence of intestinal tumors in MUTYH-null mice (11 tumors in 10 of 121 mice) was statistically significant compared with the wild type (no intestinal tumors in 109 mice). Two adenomas and seven adenocarcinomas were observed in the small intestines, and two adenomas but no carcinomas were found in the colons. In MUTYH-null mice treated with KBrO3, the occurrence of small intestinal tumors dramatically increased. The mean number of polyps induced in the small intestines of these mice was 61.88 (males, 72.75; females, 51.00), whereas it was 0.85 (males, 0.50; females, 1.00) in wild-type mice. The tumors developed predominantly in the duodenum and in the upper region of the (jejunum) small intestines. We conclude that MUTYH suppresses spontaneous tumorigenesis in mammals, thus providing experimental evidence for the association between biallelic germ-line MUTYH mutations and a recessive form of human hereditary colorectal adenoma and carcinoma. [Cancer Res 2007;67(14):6599–604]
Matrix Metalloproteinase 7 Mediates Mammary Epithelial Cell Tumorigenesis through the ErbB4 Receptor
Authors: Lynch Conor C. , Vargo-Gogola Tracy , Martin Michelle D. , Fingleton Barbara , Crawford Howard C. , Matrisian Lynn M. 
Published: July 2007

Abstract
To delineate the role of matrix metalloproteinase 7 (MMP7) in mammary tumorigenesis, MMP7 was expressed in the normal murine mammary gland cell line, c57MG. MMP7 markedly enhanced the growth rate of the c57MG cells in three-dimensional culture and promoted tumor formation in vivo. Subsequent investigation showed that MMP7 (a) up-regulated ErbB4 receptor levels, (b) solubilized the ErbB4 receptor cognate ligand heparin-bound epidermal growth factor, and (c) mediated the proteolytic processing of ErbB4 to yield a soluble intracellular domain (ICD) that localized to the cytoplasm and the nucleus. Furthermore, overexpression of the ErbB4 ICD in the c57MG cell line recapitulated the proliferative effects of MMP7 in vitro and in vivo. These data indicate a novel mechanism for mammary epithelial cell transformation by MMP7. [Cancer Res 2007;67(14):6760–7
Structural Analysis Identifies Imidazo[1,2-b]Pyridazines as PIM Kinase Inhibitors with In vitro Antileukemic Activity
Authors: Pogacic Vanda , Bullock Alex N. , Fedorov Oleg , Filippakopoulos Panagis , Gasser Christelle , Biondi Andrea , Meyer-Monard Sandrine , Knapp Stefan , Schwaller Juerg 
Published: July 2007

Abstract
Much attention has recently been focused on PIM kinases as potential targets for the treatment of hematopoietic malignancies and some solid cancers. Using protein stability shift assays, we identified a family of imidazo[1,2-b]pyridazines to specifically interact with and inhibit PIM kinases with low nanomolar potency. The high-resolution crystal structure of a PIM1 inhibitor complex revealed that imidazo[1,2-b]pyridazines surprisingly interact with the NH2-terminal lobe helix αC rather than with the kinase hinge region. Thus, the identified inhibitors are ATP competitive but not ATP mimetic compounds, explaining their enhanced selectivity with respect to conventional type I kinase inhibitors. One of the identified imidazo[1,2-b]pyridazines (K00135) was further tested in several hematopoietic cellular systems. First, K00135 dose-dependently impaired survival of murine Ba/F3 cells that have been rendered cytokine independent by overexpression of human PIMs. Second, K00135 impaired survival and clonogenic growth of a panel of human acute leukemia cells. Third, exposure of K00135 significantly suppressed in vitro growth of leukemic blasts from five acute myelogenous leukemia patients but not of normal umbilical cord blood mononuclear cells. In vitro kinase assays and immunoblotting using lysates from human MV4;11 leukemic cells showed inhibition of phosphorylation of known PIM downstream targets, such as BAD and eukaryotic translation initiation factor 4E–binding protein 1, by K00135. Taken together, we report a family of small molecules that selectively interact and block PIM kinases and could serve as a lead to develop new targeted antileukemic therapeutics. [Cancer Res 2007;67(14):6916–24]
Induction of Sonic Hedgehog Mediators by Transforming Growth Factor-β: Smad3-Dependent Activation of Gli2 and Gli1 Expression In vitro and In vivo
Authors: Dennler Sylviane , André Jocelyne , Alexaki Ismini , Li Allen , Magnaldo Thierry , ten Dijke Peter , Wang Xiao-Jing , Verrecchia Franck , Mauviel Alain 
Published: July 2007

Abstract
Hedgehog (Hh) and transforming growth factor-β (TGF-β) family members are involved in numerous overlapping processes during embryonic development, hair cycle, and cancer. Herein, we show that TGF-β induces the expression of the Hh signaling molecules Gli1 and Gli2 in various human cell types, including normal fibroblasts and keratinocytes, as well as various cancer cell lines. Gli2 induction by TGF-β is rapid, independent from Hh receptor signaling, and requires a functional Smad pathway. Gli1 expression is subsequently activated in a Gli2-dependent manner. In transgenic mice overexpressing TGF-β1 in the skin, Gli1 and Gli2 expression is also elevated and depends on Smad3. In pancreatic adenocarcinoma cell lines resistant to Hh inhibition, pharmacologic blockade of TGF-β signaling leads to repression of cell proliferation accompanied with a reduction in Gli2 expression. We thus identify TGF-β as a potent transcriptional inducer of Gli transcription factors. Targeting the cooperation of Hh and TGF-β signaling may provide new therapeutic opportunities for cancer treatment. [Cancer Res 2007;67(14):6981–6]
Cyclin-Dependent Kinase 2–Dependent Phosphorylation of ATRIP Regulates the G2-M Checkpoint Response to DNA Damage
Authors: Myers Jeremy S. , Zhao Runxiang , Xu Xin , Ham Amy-Joan L. , Cortez David 
Published: July 2007

AbstractThe ATR-ATRIP kinase complex regulates cellular responses to DNA damage and replication stress. Mass spectrometry was used to identify phosphorylation sites on ATR and ATRIP to understand how the kinase complex is regulated by post-translational modifications. Two novel phosphorylation sites on ATRIP were identified, S224 and S239. Phosphopeptide-specific antibodies to S224 indicate that it is phosphorylated in a cell cycle–dependent manner. S224 matches a consensus site for cyclin-dependent kinase (CDK) phosphorylation and is phosphorylated by CDK2-cyclin A in vitro. S224 phosphorylation in cells is sensitive to CDK2 inhibitors. Mutation of S224 to alanine causes a defect in the ATR-ATRIP–dependent maintenance of the G2-M checkpoint to ionizing and UV radiation. Thus, ATRIP is a CDK2 substrate, and CDK2-dependent phosphorylation of S224 regulates the ability of ATR-ATRIP to promote cell cycle arrest in response to DNA damage. [Cancer Res 2007;67(14):6685–90]
Tamoxifen Forms DNA Adducts in Human Colon after Administration of a Single [14C]-Labeled Therapeutic Dose
Authors: Brown Karen , Tompkins Elaine M. , Boocock David J. , Martin Elizabeth A. , Farmer Peter B. , Turteltaub Kenneth W. , Ubick Esther , Hemingway David , Horner-Glister Emma , White Ian N.H. 
Published: July 2007

Abstract
Tamoxifen is widely prescribed for the treatment of breast cancer and is also licensed in the United States for the prevention of this disease. However, tamoxifen therapy is associated with an increased occurrence of endometrial cancer in women, and there is also evidence that it may elevate the risk of colorectal cancer. The underlying mechanisms responsible for tamoxifen-induced carcinogenesis in women have not yet been elucidated, but much interest has focused on the role of DNA adduct formation. We investigated the propensity of tamoxifen to bind irreversibly to colorectal DNA when given to 10 women as a single [14C]-labeled therapeutic (20 mg) dose, ∼18 h before undergoing colon resections. Using the sensitive technique of accelerator mass spectrometry, coupled with high-performance liquid chromatography separation of enzymatically digested DNA, a peak corresponding to authentic dG-N2-tamoxifen adduct was detected in samples from three patients, at levels ranging from 1 to 7 adducts/109 nucleotides. No [14C]-radiolabel associated with tamoxifen or its major metabolites was detected. The presence of detectable CYP3A4 protein in all colon samples suggests that this tissue has the potential to activate tamoxifen to α-hydroxytamoxifen, in addition to that occurring in the systemic circulation, and direct interaction of this metabolite with DNA could account for the binding observed. Although the level of tamoxifen-induced damage displayed a degree of interindividual variability, when present, it was ∼10 to 100 times higher than that reported for other suspect human colon carcinogens such as 2-amino-1-methyl-6-phenyimidazo[4,5-b]pyridine. These findings provide a mechanistic basis through which tamoxifen could increase the incidence of colon cancers in women. [Cancer Res 2007;67(14):6995–7002]
Nerve Regeneration after Radiofrequency Application
Authors: Ochiai Nobuyasu , Tasto James P. , Ohtori Seiji , Takahashi Norimasa , Moriya Hideshige , Amiel David 
Published: July 2007

Background Many patients with chronic tendinosis have experienced early pain relief after application of bipolar radiofrequency treatment. It is hypothesized that the mechanism of action may be the acute degeneration and/or ablation of sensory nerve fibers. Hypothesis After ablation or degeneration by bipolar radiofrequency, nerve fibers will have the ability to regenerate with time. Study Design Controlled laboratory study. Methods Eighteen Sprague-Dawley rats were used in this study. These rats were divided into 3 groups (30, 60, and 90 days after bipolar radiofrequency). These rats were treated with 2 points of bipolar radiofrequency applications to the left hindpaws with the Topaz microdebrider device. Right hindpaws were used as the contralateral control. Tissues were processed for neural class III β-tubulin or calcitonin gene-related peptide immunohistochemistry by using the free-floating avidin biotin complex technique. The numbers of neural class III β-tubulin—immunoreactive and calcitonin gene-related peptide-immunoreactive nerve fibers in the epidermis were counted and compared with those in the contralateral control. Results Although the numbers of nerve fibers demonstrated by both the antibodies of neural class III β-tubulin and calcitonin gene-related peptide were significantly decreased (P < .0001) until 60 days after bipolar radiofrequency treatment, regeneration of the epidermal nerve fibers occurred 90 days after treatment. Conclusion Bipolar radiofrequency treatment induced degeneration of sensory nerve fibers immediately after treatment, but by 90 days posttreatment, there was evidence of complete regeneration. Clinical Relevance Early degeneration followed by later regeneration of nerve fibers after bipolar radiofrequency treatment may explain long-term postoperative pain relief after microtenotomy for tendinosis.