bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyperplasia and Carcinomas in Pten-Deficient Mice and Reduced PTEN Protein in Human Bladder Cancer Patients
Authors: Tsuruta Hiroshi , Kishimoto Hiroyuki , Sasaki Takehiko , Horie Yasuo , Natsui Miyuki , Shibata Yoshiko , Hamada Koichi , Yajima Nobuyuki , Kawahara Koichi , Sasaki Masato , Tsuchiya Norihiko , Enomoto Katsuhiko , Mak Tak Wah , Nakano Toru , Habuchi Tomonori , Suzuki Akira 
Published: September 2006

Abstract
PTEN is a tumor suppressor gene mutated in many human cancers. We used the Cre-loxP system to generate an urothelium-specific null mutation of Pten in mice [FabpCrePtenflox/flox (FPtenflox/flox) mice]. Histologic examination revealed that all FPtenflox/flox mice exhibited urothelial hyperplasia in which component cells showed enlarged nuclei and increased cell size. With time, 10% of FPtenflox/flox mice spontaneously developed pedicellate papillary transitional cell carcinomas (TCC). This type of tumor also arose in FPtenflox/flox mice treated with the chemical carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine. FPtenflox/flox urothelial cells were hyperproliferative and showed increased activation of the survival signaling molecules Akt and extracellular signal-regulated kinase. In humans, 53% of primary bladder cancer patients exhibited decreased or absent expression of PTEN protein in either the cytoplasm or nucleus of tumor cells. In early bladder cancers, PTEN expression was repressed in 42% of superficial papillary TCC but in only 8% of cases of carcinoma in situ (CIS). In advanced bladder cancers, PTEN protein was significantly reduced (particularly in the nucleus) in 94% of cases, and this decrease in PTEN correlated with disease stage and grade. Thus, PTEN deficiency may contribute to bladder cancer both by initiating superficial papillary TCC and by promoting the progression of CIS to advanced invasive and metastatic forms. (Cancer Res 2006; 66(17): 8389-95)
AMG 706, an Oral, Multikinase Inhibitor that Selectively Targets Vascular Endothelial Growth Factor, Platelet-Derived Growth Factor, and Kit Receptors, Potently Inhibits Angiogenesis and Induces Regression in Tumor Xenografts
Authors: Polverino Anthony , Coxon Angela , Starnes Charlie , Diaz Zobedia , DeMelfi Thomas , Wang Ling , Bready James , Estrada Juan , Cattley Russell , Kaufman Stephen , Chen Danlin , Gan Yongmei , Kumar Gondi , Meyer James , Neervannan Sesha , Alva Gonzalo , Talvenheimo Jane , Montestruque Silvia , Tasker Andrew , Patel Vinod , Radinsky Robert , Kendall Richard 
Published: September 2006

Abstract
The growth of solid tumors is dependent on the continued stimulation of endothelial cell proliferation and migration resulting in angiogenesis. The angiogenic process is controlled by a variety of factors of which the vascular endothelial growth factor (VEGF) pathway and its receptors play a pivotal role. Small-molecule inhibitors of VEGF receptors (VEGFR) have been shown to inhibit angiogenesis and tumor growth in preclinical models and in clinical trials. A novel nicotinamide, AMG 706, was identified as a potent, orally bioavailable inhibitor of the VEGFR1/Flt1, VEGFR2/kinase domain receptor/Flk-1, VEGFR3/Flt4, platelet-derived growth factor receptor, and Kit receptors in preclinical models. AMG 706 inhibited human endothelial cell proliferation induced by VEGF, but not by basic fibroblast growth factor in vitro, as well as vascular permeability induced by VEGF in mice. Oral administration of AMG 706 potently inhibited VEGF-induced angiogenesis in the rat corneal model and induced regression of established A431 xenografts. AMG 706 was well tolerated and had no significant effects on body weight or on the general health of the animals. Histologic analysis of tumor xenografts from AMG 706–treated animals revealed an increase in endothelial apoptosis and a reduction in blood vessel area that preceded an increase in tumor cell apoptosis. In summary, AMG 706 is an orally bioavailable, well-tolerated multikinase inhibitor that is presently under clinical investigation for the treatment of human malignancies. (Cancer Res 2006; 66(17): 8715-21)
Multiple Endocrine Neoplasia Type 1 Interacts with Forkhead Transcription Factor CHES1 in DNA Damage Response
Authors: Busygina Valeria , Kottemann Molly C. , Scott Kenneth L. , Plon Sharon E. , Bale Allen E. 
Published: September 2006

Abstract
Multiple endocrine neoplasia type 1 (MEN1) is a cancer susceptibility syndrome affecting several endocrine tissues. Investigations of the biochemical function of the MEN1 protein, menin, have suggested a role as a transcriptional comodulator. The mechanism by which MEN1 inactivation leads to tumor formation is not fully understood. MEN1 was implicated to function in both regulation of cell proliferation and maintenance of genomic integrity. Here, we investigate the mechanism by which MEN1 affects DNA damage response. We found that Drosophila larval tissue and mouse embryonic fibroblasts mutant for the MEN1 homologue were deficient for a DNA damage-activated S-phase checkpoint. The forkhead transcription factor CHES1 (FOXN3) was identified as an interacting protein by a genetic screen, and overexpression of CHES1 restored both cell cycle arrest and viability of MEN1 mutant flies after ionizing radiation exposure. We showed a biochemical interaction between human menin and CHES1 and showed that the COOH terminus of menin, which is frequently mutated in MEN1 patients, is necessary for this interaction. Our data indicate that menin is involved in the activation of S-phase arrest in response to ionizing radiation. CHES1 is a component of a transcriptional repressor complex, that includes mSin3a, histone deacetylase (HDAC) 1, and HDAC2, and it interacts with menin in an S-phase checkpoint pathway related to DNA damage response. (Cancer Res 2006; 66(17): 8397-402)
p27Kip1 Repression of ErbB2-Induced Mammary Tumor Growth in Transgenic Mice Involves Skp2 and Wnt/β-Catenin Signaling
Authors: Hulit James , Lee Richard J. , Li Zhiping , Wang Chenguang , Katiyar Sanjay , Yang Jianguo , Quong Andrew A. , Wu Kongming , Albanese Chris , Russell Robert , Di Vizio Dolores , Koff Andrew , Thummala Saiinder , Zhang Hui , Harrell Jennifer , Sun Hong , Muller William J. , Inghirami Giorgio , Lisanti Michael P. , Pestell Richard G. 
Published: September 2006

Abstract
Expression of the cyclin-dependent kinase (Cdk) inhibitor (p27Kip1) is frequently reduced in human tumors, often correlating with poor prognosis. p27Kip1 functions as a haploinsufficient tumor suppressor; however, the mechanism by which one allele of p27Kip1 regulates oncogenic signaling in vivo is not well understood. We therefore investigated the mechanisms by which p27Kip1 inhibits mammary tumor onset. Using the common background strain of FVB, p27Kip1 heterozygosity (p27+/−) accelerated ErbB2-induced mammary tumorigenesis. We conducted microarray analyses of mammary tumors developing in mice with genetic haploinsufficiency for p27Kip1 expressing a mammary-targeted ErbB2 oncogene. Global gene expression profiling and Western blot analysis of ErbB2/p27+/− tumors showed that the loss of p27Kip1 induced genes promoting lymphangiogenesis, cellular proliferation, and collaborative oncogenic signaling (Wnt/β-catenin/Tcf, Cdc25a, Smad7, and Skp2). Skp2 expression was induced by ErbB2 and repressed by p27Kip1. Degradation of p27Kip1 involves an SCF-type E3 ubiquitin ligase, including Skp2. The Skp2 component of the SCFSKP2 complex that degrades p27Kip1 was increased in ErbB2 tumors correlating with earlier tumor onset. In both murine and human ErbB2-overexpressing breast cancers, p27Kip1 levels correlated inversely with Skp2. p27Kip1 haploinsufficiency activated Wnt/β-catenin/hedgehog signaling. Reintroduction of p27Kip1 inhibited β-catenin induction of Tcf-responsive genes (Siamosis, c-Myc, and Smad7). p27Kip1 is haploinsufficient for ErbB2 mammary tumor suppression in vivo and functions to repress collaborative oncogenic signals including Skp2 and Wnt/β-catenin signaling. (Cancer Res 2006; 66(17): 8529-41)
Chromosomal Instability Correlates with Genome-wide DNA Demethylation in Human Primary Colorectal Cancers
Authors: Rodriguez Jairo , Frigola Jordi , Vendrell Elisenda , Risques Rosa-Ana , Fraga Mario F. , Morales Cristina , Moreno Victor , Esteller Manel , Capellà Gabriel , Ribas Maria , Peinado Miguel A. 
Published: September 2006

Abstract
DNA hypomethylation is a common trait of colorectal cancer. Studies in tumor cell lines and animal models indicate that genome-wide demethylation may cause genetic instability and hence facilitate or accelerate tumor progression. Recent studies have shown that DNA hypomethylation precedes genomic damage in human gastrointestinal cancer, but the nature of this damage has not been clearly established. Here, we show a thorough analysis of DNA methylation and genetic alterations in two series of colorectal carcinomas. The extent of DNA demethylation but not of hypermethylation (both analyzed by amplification of intermethylated sites in near 200 independent sequences arbitrarily selected) correlated with the cumulated genomic damage assessed by two different techniques (arbitrarily primed PCR and comparative genomic hybridization). DNA hypomethylation–related instability was mainly of chromosomal nature and could be explained by a genome-wide effect rather than by the concurrence of the most prevalent genetic and epigenetic alterations. Moreover, the association of p53 mutations with genomic instability was secondary to DNA hypomethylation and the correlation between DNA hypomethylation and genomic instability was observed in tumors with and without mutation in the p53 gene. Our data support a direct link between genome-wide demethylation and chromosomal instability in human colorectal carcinogenesis and are consistent with the studies in model systems demonstrating a role of DNA demethylation in inducing chromosomal instability. (Cancer Res 2006; 66(17): 8462-8)
Human β-Defensin-1, a Potential Chromosome 8p Tumor Suppressor: Control of Transcription and Induction of Apoptosis in Renal Cell Carcinoma
Authors: Sun Carrie Q. , Arnold Rebecca , Fernandez-Golarz Carina , Parrish Amanda B. , Almekinder Tara , He Ju , Ho Shuk-mei , Svoboda Pavel , Pohl Jan , Marshall Fray F. , Petros John A. 
Published: September 2006

Abstract
Human β-defensin-1 (hBD-1) is a candidate tumor suppressor gene located on chromosome 8p23. Previously, we showed that cancer-specific loss of hBD-1 was found in 90% of renal clear cell carcinomas and in 82% of prostate cancers. To investigate the possible mechanisms of decreased gene expression and determine the function of hBD-1 protein in urological cancers, we sequenced hBD-1 gene coding regions in prostatic and renal cancer samples. We then analyzed the frequency distribution of promoter polymorphisms and determined the effect of these base changes on transcriptional activity of the hBD-1 promoter. A polymorphism at −688 bases upstream of the ATG start codon affects hBD-1 promoter activity, leading to a rate of reporter gene transcription that is 40% to 50% lower than the wild-type sequence when tested in either DU145 or TSU-Pr1 cell lines. In addition, a polymorphism at −44 bases was shown to enhance transcription up to 2.3 times more than the wild-type sequence in the same cell lines. In addition, three novel hBD-1 promoter mutations were found in renal and prostate cancer clinical samples. An iso-5-aza-2′-deoxycytidine treatment was effective in transcription up-regulation in DU145, suggesting a possible upstream methylation-dependent effect. Synthetic hBD-1 peptide inhibited bladder cancer cell TSU-Pr1 proliferation. Overexpression of the hBD-1 gene in renal cancer cells SW156 resulted in caspase-3-mediated apoptosis. These data support the hypothesis that hBD-1 is a potential tumor suppressor gene for urological cancers. Promoter point mutations may be responsible for cancer-specific loss of hDB-1 expression. (Cancer Res 2006; 66(17): 8542-9)
A Small-Molecule Inhibitor of Bcl-XL Potentiates the Activity of Cytotoxic DrugsIn vitroandIn vivo
Authors: Shoemaker Alex R. , Oleksijew Anatol , Bauch Joy , Belli Barbara A. , Borre Tony , Bruncko Milan , Deckwirth Thomas , Frost David J. , Jarvis Ken , Joseph Mary K. , Marsh Kennan , McClellan William , Nellans Hugh , Ng ShiChung , Nimmer Paul , O'Connor Jacqueline M. , Oltersdorf Tilman , Qing Weiguo , Shen Wang , Stavropoulos Jason , Tahir Stephen K. , Wang Baole , Warner Robert , Zhang Haichao , Fesik Stephen W. , Rosenberg Saul H. , Elmore Steven W. 
Published: September 2006

AbstractInhibition of the prosurvival members of the Bcl-2 family of proteins represents an attractive strategy for the treatment of cancer. We have previously reported the activity of ABT-737, a potent inhibitor of Bcl-2, Bcl-XL, and Bcl-w, which exhibits monotherapy efficacy in xenograft models of small-cell lung cancer and lymphoma and potentiates the activity of numerous cytotoxic agents. Here we describe the biological activity of A-385358, a small molecule with relative selectivity for binding to Bcl-XL versus Bcl-2 (Ki's of 0.80 and 67 nmol/L for Bcl-XL and Bcl-2, respectively). This compound efficiently enters cells and co-localizes with the mitochondrial membrane. Although A-385358 shows relatively modest single-agent cytotoxic activity against most tumor cell lines, it has an EC50 of &lt;500 nmol/L in cells dependent on Bcl-XL for survival. In addition, A-385358 enhances the in vitro cytotoxic activity of numerous chemotherapeutic agents (paclitaxel, etoposide, cisplatin, and doxorubicin) in several tumor cell lines. In A549 non–small-cell lung cancer cells, A-385358 potentiates the activity of paclitaxel by as much as 25-fold. Importantly, A-385358 also potentiated the activity of paclitaxel in vivo. Significant inhibition of tumor growth was observed when A-385358 was added to maximally tolerated or half maximally tolerated doses of paclitaxel in the A549 xenograft model. In tumors, the combination therapy also resulted in a significant increase in mitotic arrest followed by apoptosis relative to paclitaxel monotherapy. (Cancer Res 2006; 66(17): 8731-9)
Reassessing Epithelial to Mesenchymal Transition as a Prerequisite for Carcinoma Invasion and Metastasis
Authors: Christiansen Jason J. , Rajasekaran Ayyappan K. 
Published: September 2006

Abstract
For most carcinomas, progression toward malignancy is accompanied by loss of epithelial differentiation and a shift towards a mesenchymal phenotype. This process, referred to as epithelial to mesenchymal transition (EMT), exacerbates motility and invasiveness of many cell types and is often considered a prerequisite for tumor infiltration and metastasis. However, there are numerous examples of advanced carcinomas that adopt some mesenchymal features, yet retain characteristics of well-differentiated epithelial cells. We provide a review of these reports and describe mechanisms to explain the morphologic and molecular heterogeneity and plasticity of malignant carcinoma cells, including incomplete EMT, reversion to an epithelial phenotype, and collective migration. We suggest that these mechanisms can manifest in a series of independent and reversible steps and that EMT represents just one mechanism in the global metastatic carcinoma development process. (Cancer Res 2006; 66(17): 8319-26)
A Carbohydrate Recognition–Based Drug Delivery and Controlled Release System using Intraperitoneal Macrophages as a Cellular Vehicle
Authors: Ikehara Yuzuru , Niwa Toru , Biao Le , Ikehara Sanae Kabata , Ohashi Norifumi , Kobayashi Takeshi , Shimizu Yoshitaka , Kojima Naoya , Nakanishi Hayao 
Published: September 2006

AbstractThe lymphoid tissue in the omentum, at the so-called milky spots, is known as an initial place for disseminated cancer cells to develop into solid tumors. In the present study, i.p. macrophages significantly took up oligomannose-coated liposomes (OMLs) that were injected into the peritoneal cavity, and then gradually accumulated in the omentum and the other lymphoid tissues within 24 hours of i.p. injection of OMLs. When 5-fluorouracil (5-FU) was encapsulated in the OMLs, &gt;60% of administered 5-FU accumulated in the omentum. Treatment of macrophages at 39°C for 30 minutes led to the release of 5-FU from the macrophages, suggesting that controlled release from macrophages could be achieved by mild hyperthermia. We encased magnetic nanoparticles, which are known to convert electromagnetic energy to heat in the OMLs to achieve in vivo hyperthermia at the site. Using this system in a mouse i.p. metastasis model, we successfully controlled tumor development by coadministration of OML-encased 5-FU and OML-encased magnetic nanoparticles, followed by treatment with an alternating magnetic field. No apparent reduction was seen in tumor growth with the administration of OML-encased magnetic nanoparticles or OML-encased 5-FU alone. Thus, we have established the use of i.p. macrophages as a novel drug delivery system for the control of cancer metastatic to milky spots. (Cancer Res 2006; 66(17): 8740-8)
Tumor Cell Radiosensitivity Is a Major Determinant of Tumor Response to Radiation
Authors: Gerweck Leo E. , Vijayappa Shashirekha , Kurimasa Akihiro , Ogawa Kazuhiko , Chen David J. 
Published: September 2006

Abstract
Substantial evidence suggests that the radiosensitivity of the tumor cells is the primary determinant of tumor response to radiation. More recent studies suggest that tumor stroma radiosensitivity is the principle determinant of response. To assess the relationship between intrinsic tumor cell radiosensitivity and tumor response, we altered the intrinsic radiosensitivity of a cloned tumor cell line and analyzed the effect of this alteration on tumor response. A cloned tumor cell line derived from DNA double-strand break repair–deficient severe combined immunodeficient mice was transfected with the double-strand break repair gene DNA-PKcs. The intrinsic radiosensitivity of the transfected tumor line was decreased by a factor of ∼1.5. The isogenic lines were used to initiate tumors in NCr-nu/nu mice. When transplanted in the same strain of mice and exposed to the same dose of radiation, the isogenic tumors may be expected to exhibit a similar response to radiation if radiation damage to host stroma is the principle determinant of response. This was not observed. Over the dose range of 20 Gy in four 5-Gy fractions to a single dose of 30 Gy, the 1.5-fold increase in intrinsic tumor cell radioresistance conferred by the introduction of DNA-PKcs caused a 1.5-fold decrease in tumor growth delay. The results show that the intrinsic radiosensitivity of tumor cells is a major determinant of tumor response to radiation. (Cancer Res 2006; 66(17): 8352-5)
Fluorodeoxyuridine Modulates Cellular Expression of the DNA Base Excision Repair Enzyme Uracil-DNA Glycosylase
Authors: Fischer Jennifer A. , Muller-Weeks Susan , Caradonna Salvatore J. 
Published: September 2006

AbstractThe thymidylate synthase inhibitor 5-fluorouracil (5-FU) continues to play a pivotal role in the treatment of cancer. A downstream event of thymidylate synthase inhibition involves the induction of a self-defeating base excision repair process. With the depletion of TTP pools, there is also an increase in dUMP. Metabolism of dUMP to the triphosphate dUTP results in elevated pools of this atypical precursor for DNA synthesis. Under these conditions, there is a destructive cycle of dUMP incorporation into DNA, removal of uracil by the base excision repair enzyme uracil-DNA glycosylase (UDG), and reincorporation of dUMP during the synthesis phase of DNA repair. The end point is DNA strand breaks and loss of DNA integrity, which contributes to cell death. Evidence presented here indicates that both the nuclear and the mitochondrial isoforms of UDG are modulated by FdUrd (and 5-FU) treatment in certain cell lines but not in others. Modulation occurs at the transcriptional and post-translational levels. Under normal conditions, nUDG protein appears in G1 and is degraded during the S to G2 phase transition. The present study provides evidence that, in certain cell lines, FdUrd mediates an atypical turnover of nUDG. Additional data indicate that, for cell lines that do not down-regulate nUDG, small interfering RNA–mediated knockdown of nUDG significantly increases resistance to the cytotoxic effects of FdUrd. Results from these studies show that nUDG is an additional determinant in FdUrd-mediated cytotoxicity and bolster the notion that the self-defeating base excision repair pathway, instigated by elevated dUTP (FdUTP) pools, contributes to the cytotoxic consequences of 5-FU chemotherapy. (Cancer Res 2006; 66(17): 8829-37)
E6AP Mediates Regulated Proteasomal Degradation of the Nuclear Receptor Coactivator Amplified in Breast Cancer 1 in Immortalized Cells
Authors: Mani Aparna , Oh Annabell S. , Bowden Emma T. , Lahusen Tyler , Lorick Kevin L. , Weissman Allan M. , Schlegel Richard , Wellstein Anton , Riegel Anna T. 
Published: September 2006

Abstract
The steroid receptor coactivator oncogene, amplified in breast cancer 1 (AIB1; also known as ACTR/RAC-3/TRAM-1/SRC-3/p/CIP), is amplified and overexpressed in a variety of epithelial tumors. AIB1 has been reported to have roles in both steroid-dependent and steroid-independent transcription during tumor progression. In this report, we describe that the cellular levels of AIB1 are controlled through regulated proteasomal degradation. We found that serum withdrawal or growth in high cell density caused rapid degradation of AIB1 protein, but not mRNA, in immortalized cell lines. Proteasome inhibitors prevented this process, and high molecular weight ubiquitylated species of AIB1 were detected. Nuclear export was required for proteasomal degradation of AIB1 and involved the ubiquitin ligase, E6AP. AIB1/E6AP complexes were detected in cellular extracts, and reduction of cellular E6AP levels with E6AP short interfering RNA prevented proteasomal degradation of AIB1. Conversely, overexpression of E6AP promoted AIB1 degradation. The COOH terminus of AIB1 interacted with E6AP in vitro and deletion of this region in AIB1 rendered it resistant to degradation in cells. From our results, we propose a model whereby signals promoted by changes in the cellular milieu initiate E6AP-mediated proteasomal degradation of AIB1 and thus contribute to the control of steady-state levels of this protein. (Cancer Res 2006; 66(17): 8680-6)