bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma Cytokine and Angiogenic Factor Profiling Identifies Markers Associated with Tumor Shrinkage in Early-Stage Non–Small Cell Lung Cancer Patients Treated with Pazopanib
Authors: Nikolinakos Petros G. , Altorki Nasser , Yankelevitz David , Tran Hai T. , Yan Shaoyu , Rajagopalan Dilip , Bordogna Walter , Ottesen Lone H. , Heymach John V. 
Published: March 2010

Abstract
There is an unmet need for pharmacodynamic and predictive biomarkers for antiangiogenic agents. Recent studies have shown that soluble vascular endothelial growth factor receptor 2 (sVEGFR2), VEGF, and several other soluble factors may be modulated by VEGF pathway inhibitors. We conducted a broad profiling of cytokine and angiogenic factors (CAF) to investigate the relationship between baseline CAF levels, CAF changes during treatment, and tumor shrinkage in early-stage non–small cell lung cancer (NSCLC) patients treated with pazopanib, an oral angiogenesis inhibitor targeting VEGFR, platelet-derived growth factor receptor, and c-kit. Plasma samples were collected before treatment and on the last day of therapy from 33 patients with early-stage NSCLC participating in a single-arm phase II trial. Levels of 31 CAFs were measured by suspension bead multiplex assays or ELISA and correlated with change in tumor volume. Pazopanib therapy was associated with significant changes of eight CAFs; sVEGFR2 showed the largest decrease, whereas placental growth factor underwent the largest increase. Increases were also observed in stromal cell–derived factor-1α, IP-10, cutaneous T-cell–attracting chemokine, monokine induced by IFN-γ, tumor necrosis factor–related apoptosis-inducing ligand, and IFN-α. Posttreatment changes in plasma sVEGFR2 and interleukin (IL)-4 significantly correlated with tumor shrinkage. Baseline levels of 11 CAFs significantly correlated with tumor shrinkage, with IL-12 showing the strongest association. Using multivariate classification, a baseline CAF signature consisting of hepatocyte growth factor and IL-12 was associated with tumor response to pazopanib and identified responding patients with 81% accuracy. These data suggest that CAF profiling may be useful for identifying patients likely to benefit from pazopanib, and merit further investigation in clinical trials. Cancer Res; 70(6); 2171–9
MicroRNA-375 Is Downregulated in Gastric Carcinomas and Regulates Cell Survival by Targeting PDK1 and 14-3-3ζ
Authors: Tsukamoto Yoshiyuki , Nakada Chisato , Noguchi Tsuyoshi , Tanigawa Masato , Nguyen Lam Tung , Uchida Tomohisa , Hijiya Naoki , Matsuura Keiko , Fujioka Toshio , Seto Masao , Moriyama Masatsugu 
Published: March 2010

Abstract
We investigated expression profiles of microRNA (miRNA) in gastric carcinomas by use of a miRNA microarray platform covering a total of 470 human miRNAs. We identified 39 differentially expressed miRNAs in gastric carcinoma, of which six were significantly downregulated and the other 33 were upregulated. We found that miRNA-375 (miR-375) was the most downregulated and that its ectopic expression in gastric carcinoma cells markedly reduced cell viability via the caspase-mediated apoptosis pathway. Interestingly, we found that expression of miR-375 inhibited expression of PDK1, which is a direct target of miR-375, followed by suppression of Akt phosphorylation. Further analysis by gene expression microarray revealed that 14-3-3ζ, a potent antiapoptotic gene, was significantly downregulated at both the mRNA and protein levels in cells transfected with miR-375. The activity of a luciferase reporter containing the miR-375 binding sequence at the 3′ untranslated region (UTR) of 14-3-3ζ mRNA was repressed by the ectopic expression of miR-375, suggesting that miR-375 targets the 3′ UTR of 14-3-3ζ. In addition, knockdown of either PDK1 or 14-3-3ζ in gastric carcinoma cells induced caspase activation, which was also observed in miR-375–transfected cells, suggesting that miR-375 may exert its proapoptotic function, at least in part, through the downregulation of PDK1 and 14-3-3ζ. Taken together, we propose that miR-375 is a candidate tumor suppressor miRNA in gastric carcinoma. Cancer Res; 70(6); 2339–49
Combined Delivery and Magnetic Resonance Imaging of Neural Cell Adhesion Molecule–Targeted Doxorubicin-Containing Liposomes in Experimentally Induced Kaposi's Sarcoma
Authors: Grange Cristina , Geninatti-Crich Simonetta , Esposito Giovanna , Alberti Diego , Tei Lorenzo , Bussolati Benedetta , Aime Silvio , Camussi Giovanni 
Published: March 2010

Abstract
Specific targeting of tumors by combined delivery of drugs and of imaging agents represents an attractive strategy for treatment of cancer. The aim of the present study was to investigate whether neural cell adhesion molecule (NCAM)–targeted liposomes may enhance drug delivery and allow magnetic resonance imaging (MRI) in a severe combined immunodeficient mouse model of NCAM-positive Kaposi's sarcoma. NCAM-binding peptide–coated liposomes loaded with both doxorubicin and a lipophilic gadolinium (Gd) derivative were generated. NCAM-targeted liposomes induced an enhanced in vitro doxorubicin internalization within Kaposi's cells as detected by MRI with respect to untargeted polyethylene glycol liposomes. Internalization resulted in enhanced apoptosis. In vivo weekly administration of NCAM-targeted liposomes containing 5 mg/kg doxorubicin for 4 consecutive weeks induced a significant reduction of tumor mass and vascularization and enhanced cell necrosis and apoptosis with respect to untargeted liposomes. These effects were associated with an enhanced concentration of doxorubicin within the tumor and a reduced systemic toxicity of doxorubicin. By electron microscopy, NCAM-targeted liposomes were detected mainly within tumor cells whereas the untargeted liposomes were mainly accumulated in the extracellular space. Gd-labeled liposomes allowed the MRI visualization of drug delivery in the tumor region. The intensity of MRI signal was partially hampered by the “quenching” of the attainable relaxation enhancement on endosomal entrapment of the Gd-labeled liposomes. In conclusion, targeting NCAM may be a suitable strategy for specific drug delivery and imaging by liposomes in NCAM-expressing tumors. Moreover, treatment with NCAM-targeted liposomes showed enhanced therapeutic effect and reduced toxicity with respect to untargeted liposomes. Cancer Res; 70(6); 2180–90
A Susceptibility Locus on Chromosome 6q Greatly Increases Lung Cancer Risk among Light and Never Smokers
Authors: Amos Christopher I. , Pinney Susan M. , Li Yafang , Kupert Elena , Lee Juwon , de Andrade Mariza A. , Yang Ping , Schwartz Ann G. , Fain Pam R. , Gazdar Adi , Minna John , Wiest Jonathan S. , Zeng Dong , Rothschild Henry , Mandal Diptasri , You Ming , Coons Teresa , Gaba Colette , Bailey-Wilson Joan E. , Anderson Marshall W. 
Published: March 2010

AbstractCigarette smoking is the major cause for lung cancer, but genetic factors also affect susceptibility. We studied families that included multiple relatives affected by lung cancer. Results from linkage analysis showed strong evidence that a region of chromosome 6q affects lung cancer risk. To characterize the effects that this region of chromosome 6q region has on lung cancer risk, we identified a haplotype that segregated with lung cancer. We then performed Cox regression analysis to estimate the differential effects that smoking behaviors have on lung cancer risk according to whether each individual carried a risk-associated haplotype or could not be classified and was assigned unknown haplotypic status. We divided smoking exposures into never smokers, light smokers (&lt;20 pack-years), moderate smokers (20 to &lt;40 pack-years), and heavy smokers (≥40 pack-years). Comparing results according to smoking behavior stratified by carrier status, compared with never smokers, there was weakly increasing risk for increasing smoking behaviors, with the hazards ratios being 3.44, 4.91, and 5.18, respectively, for light, moderate, or heavy smokers, whereas among the individuals from families without the risk haplotype, the risks associated with smoking increased strongly with exposure, the hazards ratios being, respectively, 4.25, 9.17, and 11.89 for light, moderate, and heavy smokers. The never smoking carriers had a 4.71-fold higher risk than the never smoking individuals without known risk haplotypes. These results identify a region of chromosome 6q that increases risk for lung cancer and that confers particularly higher risks to never and light smokers. Cancer Res; 70(6); 2359–67
LYN Is a Mediator of Epithelial-Mesenchymal Transition and a Target of Dasatinib in Breast Cancer
Authors: Choi Yoon-La , Bocanegra Melanie , Kwon Mi Jeong , Shin Young Kee , Nam Seok Jin , Yang Jung-Hyun , Kao Jessica , Godwin Andrew K. , Pollack Jonathan R. 
Published: March 2010

Abstract
Epithelial-mesenchymal transition (EMT), a switch of polarized epithelial cells to a migratory, fibroblastoid phenotype, is considered a key process driving tumor cell invasiveness and metastasis. Using breast cancer cell lines as a model system, we sought to discover gene expression signatures of EMT with clinical and mechanistic relevance. A supervised comparison of epithelial and mesenchymal breast cancer lines defined a 200-gene EMT signature that was prognostic across multiple breast cancer cohorts. The immunostaining of LYN, a top-ranked EMT signature gene and Src-family tyrosine kinase, was associated with significantly shorter overall survival (P = 0.02) and correlated with the basal-like (“triple-negative”) phenotype. In mesenchymal breast cancer lines, RNAi-mediated knockdown of LYN inhibited cell migration and invasion, but not proliferation. Dasatinib, a dual-specificity tyrosine kinase inhibitor, also blocked invasion (but not proliferation) at nanomolar concentrations that inhibit LYN kinase activity, suggesting that LYN is a likely target and that invasion is a relevant end point for dasatinib therapy. Our findings define a prognostically relevant EMT signature in breast cancer and identify LYN as a mediator of invasion and a possible new therapeutic target (and theranostic marker for dasatinib response), with particular relevance to clinically aggressive basal-like breast cancer. Cancer Res; 70(6); 2296–306
An ErbB3 Antibody, MM-121, Is Active in Cancers with Ligand-Dependent Activation
Authors: Schoeberl Birgit , Faber Anthony C. , Li Danan , Liang Mei-Chih , Crosby Katherine , Onsum Matthew , Burenkova Olga , Pace Emily , Walton Zandra , Nie Lin , Fulgham Aaron , Song Youngchul , Nielsen Ulrik B. , Engelman Jeffrey A. , Wong Kwok-Kin 
Published: March 2010

Abstract
ErbB3 is a critical activator of phosphoinositide 3-kinase (PI3K) signaling in epidermal growth factor receptor (EGFR; ErbB1), ErbB2 [human epidermal growth factor receptor 2 (HER2)], and [hepatocyte growth factor receptor (MET)] addicted cancers, and reactivation of ErbB3 is a prominent method for cancers to become resistant to ErbB inhibitors. In this study, we evaluated the in vivo efficacy of a therapeutic anti-ErbB3 antibody, MM-121. We found that MM-121 effectively blocked ligand-dependent activation of ErbB3 induced by either EGFR, HER2, or MET. Assessment of several cancer cell lines revealed that MM-121 reduced basal ErbB3 phosphorylation most effectively in cancers possessing ligand-dependent activation of ErbB3. In those cancers, MM-121 treatment led to decreased ErbB3 phosphorylation and, in some instances, decreased ErbB3 expression. The efficacy of single-agent MM-121 was also examined in xenograft models. A machine learning algorithm found that MM-121 was most effective against xenografts with evidence of ligand-dependent activation of ErbB3. We subsequently investigated whether MM-121 treatment could abrogate resistance to anti-EGFR therapies by preventing reactivation of ErbB3. We observed that an EGFR mutant lung cancer cell line (HCC827), made resistant to gefitinib by exogenous heregulin, was resensitized by MM-121. In addition, we found that a de novo lung cancer mouse model induced by EGFR T790M-L858R rapidly became resistant to cetuximab. Resistance was associated with an increase in heregulin expression and ErbB3 activation. However, concomitant cetuximab treatment with MM-121 blocked reactivation of ErbB3 and resulted in a sustained and durable response. Thus, these results suggest that targeting ErbB3 with MM-121 can be an effective therapeutic strategy for cancers with ligand-dependent activation of ErbB3. Cancer Res; 70(6); 2485–94
Chemoprevention of Intestinal Tumorigenesis in APCmin/+ Mice by Silibinin
Authors: Rajamanickam Subapriya , Velmurugan Balaiya , Kaur Manjinder , Singh Rana P. , Agarwal Rajesh 
Published: March 2010

Abstract
Chemoprevention is a practical and translational approach to reduce the risk of various cancers including colorectal cancer (CRC), which is a major cause of cancer-related deaths in the United States. Accordingly, here we assessed chemopreventive efficacy and associated mechanisms of long-term silibinin feeding on spontaneous intestinal tumorigenesis in the APCmin/+ mice model. Six-week-old APCmin/+ mice were p.o. fed with vehicle control (0.5% carboxymethyl cellulose and 0.025% Tween 20 in distilled water) or 750 mg silibinin/kg body weight in vehicle for 5 d/wk for 13 weeks and then sacrificed. Silibinin feeding strongly prevented intestinal tumorigenesis in terms of polyp formation in proximal, middle, and distal portions of small intestine by 27% (P &lt; 0.001), 34% (P &lt; 0.001), and 49% (P &lt; 0.001), respectively. In colon, we observed 55% (P &lt; 0.01) reduction in number of polyps by silibinin treatment. In size distribution analysis, silibinin showed significant decrease in large-size polyps (&gt;3 mm) by 66% (P &lt; 0.01) and 88% (P &lt; 0.001) in middle and distal portions of small intestine, respectively. More importantly, silibinin caused a complete suppression in &gt;3 mm sized polyps and 92% reduction in &gt;2 to 3 mm sized polyps in colon. Molecular analyses of polyps suggested that silibinin exerts its chemopreventive efficacy by inhibiting cell proliferation, inflammation, and angiogenesis; inducing apoptosis; decreasing β-catenin levels and transcriptional activity; and modulating the expression profile of cytokines. These results show for the first time the efficacy and associated mechanisms of long-term p.o. silibinin feeding against spontaneous intestinal tumorigenesis in the APCmin/+ mice model, suggesting its chemopreventive potential against intestinal cancers including CRC. Cancer Res; 70(6); 2368–78
Identification of Hypermethylated Genes Associated with Cisplatin Resistance in Human Cancers
Authors: Chang Xiaofei , Monitto Constance L. , Demokan Semra , Kim Myoung Sook , Chang Steven S. , Zhong Xiaoli , Califano Joseph A. , Sidransky David 
Published: March 2010

Abstract
Cisplatin is among the most widely used cytotoxic anticancer agents in solid tumors; however, the development of secondary resistance remains a major obstacle to clinical efficacy. Treatment-related DNA hypermethylation may play a role in creating drug-resistant phenotypes by inactivating genes that are required for cytotoxicity. We applied a pharmacologic unmasking approach to detect hypermethylated genes whose inactivation contributes to cisplatin resistance. Using three pairs of isogeneic, cisplatin-sensitive, and cisplatin-resistant cell lines derived from two parental cell lines (KB-3-1 and SCC25), we identified several hundred genes that were downregulated in each resistant cell line and reactivated by the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine. Among them, 30 genes were common to two or more cell lines and/or reported to be downregulated in previous studies. Bisulfite sequencing confirmed that 14 genes were hypermethylated in resistant cell lines but not in the sensitive parental cell lines. Six of 14 genes (SAT, C8orf4, LAMB3, TUBB, G0S2, and MCAM) were cisplatin inducible in sensitive but not in resistant cell lines. Small interfering RNA knockdown of two genes, SAT and S100P, increased cell viability with cisplatin treatment in sensitive parental cell lines. S100P knockdown significantly decreased the S-phase fraction of parental sensitive cell lines and slowed cell proliferation, which was associated with decreased sensitivity to cisplatin. Based on these findings, we conclude that DNA methylation is a frequent event in cells that are chronically exposed to cisplatin and that methylation-induced gene silencing may play a role in the development of resistance to cytotoxic chemotherapeutic agents. Cancer Res; 70(7); 2870–9
A Genome-Wide Screen for Microdeletions Reveals Disruption of Polarity Complex Genes in Diverse Human Cancers
Authors: Rothenberg S. Michael , Mohapatra Gayatry , Rivera Miguel N. , Winokur Daniel , Greninger Patricia , Nitta Mai , Sadow Peter M. , Sooriyakumar Gaya , Brannigan Brian W. , Ulman Matthew J. , Perera Rushika M. , Wang Rui , Tam Angela , Ma Xiao-Jun , Erlander Mark , Sgroi Dennis C. , Rocco James W. , Lingen Mark W. , Cohen Ezra E.W. , Louis David N. , Settleman Jeffrey , Haber Daniel A. 
Published: March 2010

Abstract
In a genome-wide screen of 684 cancer cell lines, we identified homozygous intragenic microdeletions involving genes encoding components of the apical-basal cell polarity complexes. Among these, PARD3 is disrupted in cell lines and primary tumors from squamous carcinomas and glioblastomas. Reconstituting PARD3 expression in both cell types restores tight junctions and retards contact-dependent proliferation. Searching specifically for small intragenic microdeletions using high-resolution genomic arrays may be complementary to other genomic deletion screens and resequencing efforts in identifying new tumor suppressor genes. Cancer Res; 70(6); 2158–64
Exon Array Analyses across the NCI-60 Reveal Potential Regulation of TOP1 by Transcription Pausing at Guanosine Quartets in the First Intron
Authors: Reinhold William C. , Mergny Jean-Louis , Liu Hongfang , Ryan Michael , Pfister Thomas D. , Kinders Robert , Parchment Ralph , Doroshow James , Weinstein John N. , Pommier Yves 
Published: March 2010

Abstract
Because topoisomerase 1 (TOP1) is critical for the relaxation of DNA supercoils and because it is the target for the anticancer activity of camptothecins, we assessed TOP1 transcript levels in the 60 cell line panel (the NCI-60) of the National Cancer Institute's anticancer drug screen. TOP1 expression levels varied over a 5.7-fold range across the NCI-60. HCT116 colon and MCF-7 breast cancer cells were the highest expressers; SK-MEL-28 melanoma and HS578T breast carcinoma cells were the lowest. TOP1 mRNA expression was highly correlated with Top1 protein levels, indicating that TOP1 transcripts could be conveniently used to monitor Top1 protein levels and activity in tissues. Assessment of the TOP1 locus by array comparative genomic hybridization across the NCI-60 showed copy numbers ranging from 1.71 to 4.13 and a statistically significant correlation with TOP1 transcript levels (P &lt; 0.01). Further analyses of TOP1 expression on an exon-specific basis revealed that exon 1 expression was generally higher and less variable than expression of the other exons, suggesting some form of transcriptional pausing regulation between exons 1 and 2. Accordingly, we found the presence of multiple evolutionarily conserved potential G-quadruplex–forming sequences in the first TOP1 intron. Physicochemical tests for actual quadruplex formation by several of those sequences yielded quadruplex formation for two of them and duplex formation for one. The observations reported here suggest the hypothesis that there is a conserved negative transcription regulator within intron 1 of the TOP1 gene associated with a quadruplex-prone region. Cancer Res; 70(6); 2191–203
Luteolin Inhibits Protein Kinase Cϵ and c-Src Activities and UVB-Induced Skin Cancer
Authors: Byun Sanguine , Lee Ki Won , Jung Sung Keun , Lee Eun Jung , Hwang Mun Kyung , Lim Sung Hwan , Bode Ann M. , Lee Hyong Joo , Dong Zigang 
Published: March 2010

Abstract
Luteolin, a flavonoid present in various vegetables including onion and broccoli, has been reported to possess anticarcinogenic effects. However, its chemopreventive effect on UV-induced skin cancer and its mechanism are not fully understood. Herein, we examined the chemopreventive effect and associated mechanisms of luteolin in the JB6 P+ cell line and the SKH-1 hairless mouse model. Luteolin suppressed UVB-induced cyclooxygenase-2 expression and activator protein-1 and nuclear factor-κB activity in JB6 P+ cells. Immunoblot and kinase assay data showed that luteolin attenuated protein kinase Cϵ (PKCϵ) and Src kinase activities and subsequently inhibited UVB-induced phosphorylation of mitogen-activated protein kinases and the Akt signaling pathway. In addition, pull-down assays revealed that luteolin binds directly to PKCϵ and Src in an ATP-competitive manner. Importantly, luteolin suppressed tumor incidence, multiplicity, and overall size in SKH-1 hairless mice. Analysis of the skin by immunohistochemistry and immunoblotting showed that luteolin-treated groups had a substantial reduction in the levels of cyclooxygenase-2, tumor necrosis factor-α, and proliferating cell nuclear antigen compared with groups treated with only UVB. Further analysis using skin lysates showed that luteolin inhibited PKCϵ and Src kinase activity. Together, these data suggest that luteolin exerts potent chemopreventive activity against UVB-induced skin cancer mainly by targeting PKCϵ and Src. Cancer Res; 70(6); 2415–23
Loss of DNA Polymerase ζ Enhances Spontaneous Tumorigenesis
Authors: Wittschieben John P. , Patil Vaishali , Glushets Veronika , Robinson Lisa J. , Kusewitt Donna F. , Wood Richard D. 
Published: March 2010

Abstract
Mammalian genomes encode at least 15 distinct DNA polymerases, functioning as specialists in DNA replication, DNA repair, recombination, or bypass of DNA damage. Although the DNA polymerase ζ (polζ) catalytic subunit REV3L is important in defense against genotoxins, little is known of its biological function. This is because REV3L is essential during embryogenesis, unlike other translesion DNA polymerases. Outstanding questions include whether any adult cells are viable in the absence of polζ and whether polζ status influences tumorigenesis. REV3L-deficient cells have properties that could influence the development of neoplasia in opposing ways: markedly reduced damage-induced point mutagenesis and extensive chromosome instability. To answer these questions, Rev3L was conditionally deleted from tissues of adult mice using MMTV-Cre. Loss of REV3L was tolerated in epithelial tissues but not in the hematopoietic lineage. Thymic lymphomas in Tp53−/− Rev3L conditional mice occurred with decreased latency and higher incidence. The lymphomas were populated predominantly by Rev3L-null T cells, showing that loss of Rev3L can promote tumorigenesis. Remarkably, the tumors were frequently oligoclonal, consistent with accelerated genetic changes in the absence of Rev3L. Mammary tumors could also arise from Rev3L-deleted cells in both Tp53+/+ and Tp53+/− backgrounds. Mammary tumors in Tp53+/− mice deleting Rev3L formed months earlier than mammary tumors in Tp53+/− control mice. Prominent preneoplastic changes in glandular tissue adjacent to these tumors occurred only in mice deleting Rev3L and were associated with increased tumor multiplicity. Polζ is the only specialized DNA polymerase yet identified that inhibits spontaneous tumor development. Cancer Res; 70(7); 2770–8