bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exposure to the Tobacco Smoke Constituent 4-Aminobiphenyl Induces Chromosomal Instability in Human Cancer Cells
Authors: Saletta Federica , Matullo Giuseppe , Manuguerra Maurizio , Arena Sabrina , Bardelli Alberto , Vineis Paolo 
Published: August 2007

Abstract
The relationships between environmental factors and the genetic abnormalities that drive carcinogenesis are supported by experimental and epidemiologic evidence but their molecular basis has not been fully elucidated. At the genomic level, most human cancers display either chromosomal (CIN) or microsatellite (MIN) instability. The molecular mechanisms through which normal cells acquire these forms of instability are largely unknown. The arylamine 4-aminobiphenyl (4-ABP) is a tobacco smoke constituent, an environmental contaminant, and a well-established carcinogen in humans. Among others, bladder, lung, colon, and breast cancers have been associated with 4-ABP. We have investigated the effects of 4-ABP and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) on genetically stable colorectal (HCT116) and bladder (RT112) cancer cells. Cells were treated with carcinogens to generate resistant clones that were then subjected to genetic analysis to assess whether they displayed either CIN or MIN. We found that 50% to 60% of cells treated with 4-ABP developed CIN but none developed MIN as confirmed by their ability to gain and lose chromosomes. In contrast, all MNNG-treated clones (12/12) developed MIN but none developed CIN as shown by the microsatellite assay. The mismatch repair protein expression analysis suggests that the acquired mechanism of MIN resistance in the HCT116 MNNG-treated cells is associated with the reduction or the complete loss of MLH1 expression. By providing a mechanistic link between exposure to a tobacco constituent and the development of CIN, our results contribute to a better understanding of the origins of genetic instability, one of the remaining unsolved problems in cancer research. [Cancer Res 2007;67(15):7088–94]
Promoter Hypermethylation Contributes to Frequent Inactivation of a Putative Conditional Tumor Suppressor Gene Connective Tissue Growth Factor in Ovarian Cancer
Authors: Kikuchi Ryoko , Tsuda Hitoshi , Kanai Yae , Kasamatsu Takahiro , Sengoku Kazuo , Hirohashi Setsuo , Inazawa Johji , Imoto Issei 
Published: August 2007

Abstract
Connective tissue growth factor (CTGF) is a secreted protein belonging to the CCN family, members of which are implicated in various biological processes. We identified a homozygous loss of CTGF (6q23.2) in the course of screening a panel of ovarian cancer cell lines for genomic copy number aberrations using in-house array-based comparative genomic hybridization. CTGF mRNA expression was observed in normal ovarian tissue and immortalized ovarian epithelial cells but was reduced in many ovarian cancer cell lines without its homozygous deletion (12 of 23 lines) and restored after treatment with 5-aza 2′-deoxycytidine. The methylation status around the CTGF CpG island correlated inversely with the expression, and a putative target region for methylation showed promoter activity. CTGF methylation was frequently observed in primary ovarian cancer tissues (39 of 66, 59%) and inversely correlated with CTGF mRNA expression. In an immunohistochemical analysis of primary ovarian cancers, CTGF protein expression was frequently reduced (84 of 103 cases, 82%). Ovarian cancer tended to lack CTGF expression more frequently in the earlier stages (stages I and II) than the advanced stages (stages III and IV). CTGF protein was also differentially expressed among histologic subtypes. Exogenous restoration of CTGF expression or treatment with recombinant CTGF inhibited the growth of ovarian cancer cells lacking its expression, whereas knockdown of endogenous CTGF accelerated growth of ovarian cancer cells with expression of this gene. These results suggest that epigenetic silencing by hypermethylation of the CTGF promoter leads to a loss of CTGF function, which may be a factor in the carcinogenesis of ovarian cancer in a stage-dependent and/or histologic subtype-dependent manner. [Cancer Res 2007;67(15):7095–105]
Oncogenic Activity of Epidermal Growth Factor Receptor Kinase Mutant Alleles Is Enhanced by the T790M Drug Resistance Mutation
Authors: Godin-Heymann Nadia , Bryant Ianthe , Rivera Miguel N. , Ulkus Lindsey , Bell Daphne W. , Riese David J. , Settleman Jeffrey , Haber Daniel A. 
Published: August 2007

Abstract
Activating mutations in the epidermal growth factor receptor (EGFR) characterize a subset of non–small cell lung cancers (NSCLC) with extraordinary sensitivity to targeted tyrosine kinase inhibitors (TKI). A single secondary EGFR mutation, T790M, arising in cis with the primary activating mutation, confers acquired resistance to these drugs. However, the T790M mutation is also detected in the absence of drug selection, suggesting that it may provide a growth advantage. We show here that although T790M alone has only a modest effect on EGFR function, when combined with the characteristic activating mutations L858R or del746–750, it results in a dramatic enhancement of EGFR activity. The double mutants show potent ligand-independent receptor autophosphorylation associated with altered cellular phenotypes, soft agar colony formation, and tumorigenesis in nude mice. The significant gain-of-function properties of these double mutants may explain their initial presence before drug selection and their rapid selection as the single drug resistance mutation during therapy with gefitinib/erlotinib, and suggests that they may contribute to the adverse clinical course of TKI-resistant NSCLC. [Cancer Res 2007;67(15):7319–26]
A Combination of Chemoimmunotherapies Can Efficiently Break Self-Tolerance and Induce Antitumor Immunity in a Tolerogenic Murine Tumor Model
Authors: Ko Hyun-Jeong , Kim Yeon-Jeong , Kim Yun-Sun , Chang Woo-Sung , Ko Sung-Youl , Chang Sun-Young , Sakaguchi Shimon , Kang Chang-Yuil 
Published: August 2007

AbstractHer-2/neu is a well-characterized tumor-associated antigen overexpressed in human carcinomas such as breast cancer. Because Her-2/neu is a self-antigen with poor immunogenicity due to immunologic tolerance, active immunotherapy targeting Her-2/neu should incorporate methods to overcome immunologic tolerance to self-proteins. In this study, we developed a tolerogenic tumor model in mice using mouse Her-2/neu as self-antigen and investigated whether genetic vaccination with DNA plasmid and/or adenoviral vector expressing the extracellular and transmembrane domain of syngeneic mouse Her-2/neu or xenogenic human Her-2/neu could induce mouse Her-2/neu–specific CTL responses. Interestingly, adenoviral vectors expressing xenogenic human Her-2/neu (AdhHM) proved capable of breaking immune tolerance and of thereby inducing self-reactive CTL and antibodies, but not to the degree required to induce therapeutic antitumor immunity. In attempting to generate therapeutic antitumor immunity against established tumors, we adopted several approaches. Treatment with agonistic anti-glucocorticoid-induced TNFR family-related receptor (GITR) antibody plus AdhHM immunization significantly increased self-reactive CTL responses, and α-galactosylceramide (αGalCer)–loaded dendritic cells (DC) transduced with AdhHM were shown to break self-tolerance in a tolerogenic murine tumor model. Furthermore, gemcitabine treatment together with either AdhHM plus agonistic anti-GITR antibody administration or αGalCer-loaded DC transduced with AdhHM showed potent therapeutic antitumor immunity and perfect protection against preexisting tumors. Gemcitabine treatment attenuated the tumor-suppressive environment by eliminating CD11b+/Gr-1+ myeloid-derived suppressor cells. When combined with immunotherapies, gemcitabine offers a promising strategy for the Ag-specific treatment of human cancer. [Cancer Res 2007;67(15):7477–86]
Targeting Human γδ T Cells with Zoledronate and Interleukin-2 for Immunotherapy of Hormone-Refractory Prostate Cancer
Authors: Dieli Francesco , Vermijlen David , Fulfaro Fabio , Caccamo Nadia , Meraviglia Serena , Cicero Giuseppe , Roberts Andrew , Buccheri Simona , D'Asaro Matilde , Gebbia Nicola , Salerno Alfredo , Eberl Matthias , Hayday Adrian C. 
Published: August 2007

Abstract
The increasing evidence that γδ T cells have potent antitumor activity suggests their value in immunotherapy, particularly in areas of unmet need such as metastatic carcinoma. To this end, we initiated a phase I clinical trial in metastatic hormone-refractory prostate cancer to examine the feasibility and consequences of using the γδ T-cell agonist zoledronate, either alone or in combination with low-dose interleukin 2 (IL-2), to activate peripheral blood γδ cells. Nine patients were enlisted to each arm. Neither treatment showed appreciable toxicity. Most patients were treated with zoledronate + IL-2, but conversely only two treated with zoledronate displayed a significant long-term shift of peripheral γδ cells toward an activated effector-memory–like state (TEM), producing IFN-γ and perforin. These patients also maintained serum levels of tumor necrosis factor–related apoptosis inducing ligand (TRAIL), consistent with a parallel microarray analysis showing that TRAIL is produced by γδ cells activated via the T-cell receptor and IL-2. Moreover, the numbers of TEM γδ cells showed a statistically significant correlation with declining prostate-specific antigen levels and objective clinical outcomes that comprised three instances of partial remission and five of stable disease. By contrast, most patients treated only with zoledronate failed to sustain either γδ cell numbers or serum TRAIL, and showed progressive clinical deterioration. Thus, zoledronate + IL-2 represents a novel, safe, and feasible approach to induce immunologic and clinical responses in patients with metastatic carcinomas, potentially providing a substantially increased window for specific approaches to be administered. Moreover, γδ cell phenotypes and possibly serum TRAIL may constitute novel biomarkers of prognosis upon therapy with zoledronate + IL-2 in metastatic carcinoma. [Cancer Res 2007;67(15):7450–7]
BRCA1- and BRCA2-Deficient Cells Are Sensitive to Etoposide-Induced DNA Double-Strand Breaks via Topoisomerase II
Authors: Treszezamsky Alejandro D. , Kachnic Lisa A. , Feng Zhihui , Zhang Junran , Tokadjian Chake , Powell Simon N. 
Published: August 2007

Abstract
The function of BRCA1 and BRCA2 in DNA repair could affect the sensitivity of cells to cytotoxic agents, and would therefore be an important component of planning therapy for breast and ovarian cancers. Previously, both BRCA1- and BRCA2-deficient tumors were shown to be sensitive to mitomycin C, and the mechanism was presumed to be a defect in the repair of interstrand crosslinks by homologous recombination. Here, we show that both BRCA1 and BRCA2 determine the sensitivity to the cytotoxic drug, etoposide, using genetic complementation of BRCA-deficient cells. Etoposide is known to bind to topoisomerase II and prevent the resolution of the “cleavable complex,” in which one DNA duplex is passed through a second duplex. The specificity of this BRCA-dependent sensitivity was confirmed by the use of aclarubicin, which is a catalytic inhibitor of topoisomerase II and prevents the formation of the cleavable complex. In the presence of aclarubicin, the differential sensitivity of BRCA-proficient and BRCA-deficient cells was lost. Thus, etoposide requires the presence of topoisomerase II to show specific sensitization in the absence of the function of BRCA1 or BRCA2. We conclude that homologous recombination is used in the repair of DNA damage caused by topoisomerase II poisons. Overall, these results suggest that etoposide is a potentially useful drug in the treatment of BRCA-deficient human cancers. [Cancer Res 2007;67(15):7078–81]
IFN-β Signaling Positively Regulates Tumorigenesis in Aggressive Fibromatosis, Potentially by Modulating Mesenchymal Progenitors
Authors: Tjandra Sean S. , Hsu Claire , Goh Ingrid , Gurung Ananta , Poon Raymond , Nadesan Puviindran , Alman Benjamin A. 
Published: August 2007

AbstractAggressive fibromatosis (also called desmoid tumor) is a benign, locally invasive, soft tissue tumor composed of cells with mesenchymal characteristics. These tumors are characterized by increased levels of β-catenin–mediated T-cell factor (TCF)–dependent transcriptional activation. We found that type 1 IFN signaling is activated in human and murine aggressive fibromatosis tumors and that the expression of associated response genes is regulated by β-catenin. When mice deficient for the type 1 IFN receptor (Ifnar1−/−) were crossed with mice predisposed to developing aggressive fibromatosis tumors (Apc/Apc1638N), a significant decrease in aggressive fibromatosis tumor formation was observed compared with littermate controls, showing a novel role for type 1 IFN signaling in promoting tumor formation. Type 1 IFN activation inhibits cell proliferation but does not alter cell apoptosis or the level of β-catenin–mediated TCF-dependent transcriptional activation in aggressive fibromatosis cell cultures. Thus, these changes cannot explain our in vivo results. Intriguingly, Ifnar1−/− mice have smaller numbers of mesenchymal progenitor cells compared with littermate controls, and treatment of aggressive fibromatosis cell cultures with IFN increases the proportion of cells that exclude Hoechst dye and sort to the side population, raising the possibility that type 1 IFN signaling regulates the number of precursor cells present that drive aggressive fibromatosis tumor formation and maintenance. This study identified a novel role for IFN type 1 signaling as a positive regulator of neoplasia and suggests that IFN treatment is a less than optimal therapy for this tumor type. [Cancer Res 2007;67(15):7124–31]
Silencing of FLRG, an Antagonist of Activin, Inhibits Human Breast Tumor Cell Growth
Authors: Razanajaona Diane , Joguet Stéphanie , Ay Anne-Sophie , Treilleux Isabelle , Goddard-Léon Sophie , Bartholin Laurent , Rimokh Ruth 
Published: August 2007

AbstractActivin, a member of the transforming growth factor β (TGFβ) superfamily, regulates diverse processes, such as cellular growth and differentiation. There is increasing evidence that TGFβ and its signaling effectors are key determinants of tumor cell behavior. Loss of sensitivity to TGFβ-induced growth arrest is an important step toward malignancy. We previously characterized FLRG as an extracellular antagonist of activin. Here, we show that activin-induced growth inhibition is altered in FLRG-expressing breast cancer lines. Silencing FLRG induced growth inhibition, which is reversible upon addition of exogenous FLRG. We showed that FLRG silencing effects resulted from restoration of endogenous activin functions as shown by increased levels of phosphorylated smad2 and up-regulation of activin target gene transcripts. Furthermore, the growth inhibition induced by FLRG silencing was reversible by treatment with a soluble form of type II activin receptor. Finally, a strong expression of FLRG was observed in invasive breast carcinomas in contrast with the normal luminal epithelial cells in which FLRG was not detected. Our data provide strong evidence that endogenous FLRG contributes to tumor cell proliferation through antagonizing endogenous activin effects. [Cancer Res 2007;67(15):7223–9]
Antiangiogenic Strategies on Defense: On the Possibility of Blocking Rebounds by the Tumor Vasculature after Chemotherapy
Authors: Shaked Yuval , Kerbel Robert S. 
Published: August 2007

AbstractRapid or accelerated tumor cell repopulation after significant tumor cell killing induced by various cytotoxic agents often compromises the expected therapeutic benefit of such tumor responses. Here, we discuss the concept that tumor cell repopulation after certain cytotoxic therapies, using vascular disrupting agents as an example, may be aided by a reactive, systemic host response involving the mobilization of bone marrow–derived circulating cells, including endothelial progenitor cells, which subsequently home to the vasculature of treated tumors and promote tumor neovascularization. These vasculogenic “rebounds” can be blocked, at least in some cases, by treatment with an antiangiogenic drug. There is limited preliminary evidence that maximum tolerated dose chemotherapy causes a similar effect. This could constitute one way by which antiangiogenic therapy could increase the efficacy of conventional cytotoxic chemotherapy regimens; it also raises the specter of new molecular targets for systemic cancer therapies which are involved in therapy-induced bone marrow–derived cell mobilization, homing to tumors, and tumor retention. [Cancer Res 2007;67(15):7055–8]
Nm23-H1 Suppresses Tumor Cell Motility by Down-regulating the Lysophosphatidic Acid Receptor EDG2
Authors: Horak Christine E. , Lee Jong Heun , Elkahloun Abdel G. , Boissan Mathieu , Dumont Sylvie , Maga Tara K. , Arnaud-Dabernat Sandrine , Palmieri Diane , Stetler-Stevenson William G. , Lacombe Marie-Lise , Meltzer Paul S. , Steeg Patricia S. 
Published: August 2007

Abstract
Exogenous overexpression of the metastasis suppressor gene Nm23-H1 reduces the metastatic potential of multiple types of cancer cells and suppresses in vitro tumor cell motility and invasion. Mutational analysis of Nm23-H1 revealed that substitution mutants P96S and S120G did not inhibit motility and invasion. To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. Reduced expression of these genes coincident with elevated Nm23-H1 expression was observed in human breast tumor cohorts, a panel of breast carcinoma cell lines, and hepatocellular carcinomas from control versus Nm23-M1 knockout mice. The functional significance of the down-regulated genes was assessed by transfection and in vitro motility assays. Only EDG2 overexpression significantly restored motility to Nm23-H1–suppressed cancer cells, enhancing motility by 60-fold in these cells. In addition, silencing EDG2 expression with small interfering RNA reduced the motile phenotype of metastatic breast cancer cells. These data suggest that Nm23-H1 suppresses metastasis, at least in part, through down-regulation of EDG2 expression. [Cancer Res 2007;67(15):7238–46]
Statin-Induced Breast Cancer Cell Death: Role of Inducible Nitric Oxide and Arginase-Dependent Pathways
Authors: Kotamraju Srigiridhar , Willams Carol L. , Kalyanaraman Balaraman 
Published: August 2007

AbstractStatins are widely used cholesterol-lowering drugs that selectively inhibit the enzyme 3-hydroxy-3-methylglutaryl CoA reductase, leading to decreased cholesterol biosynthesis. Emerging data indicate that statins stimulate apoptotic cell death in several types of proliferating tumor cells, including breast cancer cells, which is independent of its cholesterol-lowering property. The objective here was to elucidate the molecular mechanism(s) by which statins induce breast cancer cell death. Fluvastatin and simvastatin (5–10 μmol/L) treatment enhanced the caspase-3–like activity and DNA fragmentation in MCF-7 cells, and significantly inhibited the proliferation of MCF-7 cells but not MCF-10 cells (noncancerous epithelial cells). Statin-induced cytotoxic effects were reversed by mevalonate, an immediate metabolic product of the acetyl CoA/3-hydroxy-3-methylglutaryl CoA reductase reaction. Both simvastatin and fluvastatin enhanced nitric oxide (·NO) levels which were inhibited by mevalonate. Statin-induced ·NO and tumor cell cytotoxicity were inhibited by 1400W, a more specific inhibitor of inducible nitric oxide synthase (iNOS or NOS II). Both fluvastatin and simvastatin increased iNOS mRNA and protein expression. Stimulation of iNOS by statins via inhibition of geranylgeranylation by GGTI-298, but not via inhibition of farnesylation by FTI-277, enhanced the proapoptotic effects of statins in MCF-7 cells. Statin-mediated antiproliferative and proapoptotic effects were exacerbated by sepiapterin, a precursor of tetrahydrobiopterin, an essential cofactor of ·NO biosynthesis by NOS. We conclude that iNOS-mediated ·NO is responsible in part for the proapoptotic, tumoricidal, and antiproliferative effects of statins in MCF-7 cells. [Cancer Res 2007;67(15):7386–94]
Novel Tryptophan Catabolic Enzyme IDO2 Is the Preferred Biochemical Target of the Antitumor Indoleamine 2,3-Dioxygenase Inhibitory Compound d-1-Methyl-Tryptophan
Authors: Metz Richard , DuHadaway James B. , Kamasani Uma , Laury-Kleintop Lisa , Muller Alexander J. , Prendergast George C. 
Published: August 2007

Abstract
Small-molecule inhibitors of indoleamine 2,3-dioxygenase (IDO) are currently being translated to clinic for evaluation as cancer therapeutics. One issue related to trials of the clinical lead inhibitor, d-1-methyl-tryptophan (D-1MT), concerns the extent of its biochemical specificity for IDO. Here, we report the discovery of a novel IDO-related tryptophan catabolic enzyme termed IDO2 that is preferentially inhibited by D-1MT. IDO2 is not as widely expressed as IDO but like its relative is also expressed in antigen-presenting dendritic cells where tryptophan catabolism drives immune tolerance. We identified two common genetic polymorphisms in the human gene encoding IDO2 that ablate its enzymatic activity. Like IDO, IDO2 catabolizes tryptophan, triggers phosphorylation of the translation initiation factor eIF2α, and (reported here for the first time) mobilizes translation of LIP, an inhibitory isoform of the immune regulatory transcription factor NF-IL6. Tryptophan restoration switches off this signaling pathway when activated by IDO, but not IDO2, arguing that IDO2 has a distinct signaling role. Our findings have implications for understanding the evolution of tumoral immune tolerance and for interpreting preclinical and clinical responses to D-1MT or other IDO inhibitors being developed to treat cancer, chronic infection, and other diseases. [Cancer Res 2007;67(15):7082–7]
Phase 1 Study of Lumiliximab with Detailed Pharmacokinetic and Pharmacodynamic Measurements in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia
Authors: Byrd John C. , O'Brien Susan , Flinn Ian W. , Kipps Thomas J. , Weiss Mark , Rai Kanti , Lin Thomas S. , Woodworth James , Wynne Dee , Reid Jennifer , Molina Arturo , Leigh Bryan , Harris Sarah 
Published: August 2007

Abstract
Purpose: Therapeutic antibodies have improved the outcome for patients with chronic lymphocytic leukemia (CLL). We conducted a phase 1, dose escalation and schedule optimization study of the primatized anti-CD23 antibody, lumiliximab, in patients with previously treated and refractory CLL.
Experimental Design: Forty-six patients were assigned sequentially to cohorts 1 through 6 and received lumiliximab at 125, 250, or 375 mg/m2 weekly for 4 weeks; 500 mg/m2 weekly for 4 weeks [500(A)]; 500 mg/m2 thrice during week 1 then 500 mg/m2 weekly for the next 3 weeks [500(B)]; or 500 mg/m2 thrice a week for 4 weeks [500(C)], respectively.
Results: The median age was 62 years (range, 47-80), and the median number of prior regimens was four (range, 1-13). No partial or complete responses were observed. Toxicity was limited and unrelated to dose. The pharmacokinetics of lumiliximab was similar to other IgG1 monoclonal antibodies with accumulation at doses ≥250 mg/m2 and a median terminal half-life of 7 days. Pharmacodynamic studies showed dose-dependent increases in soluble CD23, but no down-regulation of CD23 antigen. Saturation of CD23 receptors occurred at 250 mg/m2 and was maintained for ≥1 week following completion of therapy at ≥375 mg/m2.
Conclusions: Treatment with lumiliximab seemed to be well tolerated and to have clinical activity in patients with relapsed or refractory CLL.