bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epithelial-Mesenchymal Transition Induced by Growth Suppressor p12CDK2-AP1 Promotes Tumor Cell Local Invasion but Suppresses Distant Colony Growth
Authors: Tsuji Takanori , Ibaragi Soichiro , Shima Kaori , Hu Miaofen G. , Katsurano Miki , Sasaki Akira , Hu Guo-fu 
Published: December 2008

Abstract
Epithelial-mesenchymal transition (EMT) has been considered essential for metastasis, a multistep process including local invasion, intravasation, extravasation, and proliferation at distant sites. However, controversy remains as to whether EMT truly happens and how important it is to metastasis. We studied the involvement of EMT in individual steps of metastasis and found that p12CDK2-AP1, a down-stream effector of transforming growth factor β, induced EMT of hamster cheek pouch carcinoma-1 cells by promoting the expression of Twist2. EMT cells have an increased invasive but decreased metastatic phenotype. When s.c. inoculated, both EMT and non-EMT cells established primary tumors, but only EMT cells invaded into the adjacent tissues and blood vessels; however, neither cells formed lung metastases. When i.v. inoculated, only non-EMT cells established lung metastases. Moreover, s.c. inoculation of a mixture of the two cell types resulted in intravasation of both cell types and formation of lung metastasis from non-EMT cells. Our results allowed us to propose a novel model for the role of EMT in cancer metastasis. We showed that EMT and non-EMT cells cooperate to complete the spontaneous metastasis process. We thus hypothesize that EMT cells are responsible for degrading the surrounding matrix to lead the way of invasion and intravasation. Non-EMT cells then enter the blood stream and reestablish colonies in the secondary sites. [Cancer Res 2008;68(24):10377–86]
Systemic Blockade of Transforming Growth Factor-β Signaling Augments the Efficacy of Immunogene Therapy
Authors: Kim Samuel , Buchlis George , Fridlender Zvi G. , Sun Jing , Kapoor Veena , Cheng Guanjun , Haas Andrew , Cheung Hung Kam , Zhang Xiamei , Corbley Michael , Kaiser Larry R. , Ling Leona , Albelda Steven M. 
Published: December 2008

AbstractLocally produced transforming growth factor-β (TGF-β) promotes tumor-induced immunosuppression and contributes to resistance to immunotherapy. This article explores the potential for increased efficacy when combining immunotherapies with TGF-β suppression using the TGF-β type I receptor kinase inhibitor SM16. Adenovirus expressing IFN-β (Ad.IFN-β) was injected intratumorally once in established s.c. AB12 (mesothelioma) and LKR (lung cancer) tumors or intratracheally in a Kras orthotopic lung tumor model. Mice bearing TC1 (lung cancer) tumors were vaccinated with two injections of adenovirus expressing human papillomavirus-E7 (HPV-E7; Ad.E7). SM16 was administered orally in formulated chow. Tumor growth was assessed and cytokine expression and cell populations were measured in tumors and spleens by real-time PCR and flow cytometry. SM16 potentiated the efficacy of both immunotherapies in each of the models and caused changes in the tumor microenvironment. The combination of SM16 and Ad.IFN-β increased the number of intratumoral leukocytes (including macrophages, natural killer cells, and CD8+ cells) and increased the percentage of T cells expressing the activation marker CD25. SM16 also augmented the antitumor effects of Ad.E7 in the TC1 flank tumor model. The combination did not increase HPV-E7 tetramer-positive CD8+ T cells in the spleens but did induce a marked increase in the tumors. Tumors from SM16-treated mice showed increased mRNA and protein for immunostimulatory cytokines and chemokines, as well as endothelial adhesion molecules, suggesting a mechanism for the increased intratumoral leukocyte trafficking. Blockade of the TGF-β signaling pathway augments the antitumor effects of Ad.IFN-β immune-activating or Ad.E7 vaccination therapy. The addition of TGF-β blocking agents in clinical trials of immunotherapies may increase efficacy. [Cancer Res 2008;68(24):10247–56
The SWI/SNF ATPase Brm Is a Gatekeeper of Proliferative Control in Prostate Cancer
Authors: Shen Hui , Powers Nathan , Saini Nitin , Comstock Clay E.S. , Sharma Ankur , Weaver Katherine , Revelo Monica P. , Gerald William , Williams Erin , Jessen Walter J. , Aronow Bruce J. , Rosson Gary , Weissman Bernard , Muchardt Christian , Yaniv Moshe , Knudsen Karen E. 
Published: December 2008

Abstract
Factors that drive prostate cancer progression remain poorly defined, thus hindering the development of new therapeutic strategies. Disseminated tumors are treated through regimens that ablate androgen signaling, as prostate cancer cells require androgen for growth and survival. However, recurrent, incurable tumors that have bypassed the androgen requirement ultimately arise. This study reveals that the Brm ATPase, a component of selected SWI/SNF complexes, has significant antiproliferative functions in the prostate that protect against these transitions. First, we show that targeted ablation of Brm is causative for the development of prostatic hyperplasia in mice. Second, in vivo challenge revealed that Brm−/− epithelia acquire the capacity for lobe-specific, castration-resistant cellular proliferation. Third, investigation of human specimens revealed that Brm mRNA and protein levels are attenuated in prostate cancer. Fourth, Brm down-regulation was associated with an increased proliferative index, consistent with the mouse model. Lastly, gene expression profiling showed that Brm loss alters factors upstream of E2F1; this was confirmed in murine models, wherein Brm loss induced E2F1 deregulation in a tissue-specific manner. Combined, these data identify Brm as a major effector of serum androgen–induced proliferation in the prostate that is disrupted in human disease, and indicate that loss of Brm confers a proliferative advantage in prostate cancer. [Cancer Res 2008;68(24):10154–62]
Hypoxia-Inducible Factor 1α Mediates Anoikis Resistance via Suppression of α5 Integrin
Authors: Rohwer Nadine , Welzel Martina , Daskalow Katjana , Pfander David , Wiedenmann Bertram , Detjen Katharina , Cramer Thorsten 
Published: December 2008

Abstract
The transcription factor hypoxia-inducible factor 1 (HIF-1) α is abundantly expressed in the majority of human carcinomas and their metastases. HIF-1α controls central metastasis-associated pathways such as glycolysis, angiogenesis, and invasion. Functional inhibition of HIF-1α leads to impaired metastasis formation in murine tumor models. However, the precise molecular mechanisms underlying the metastasis-promoting role of HIF-1α have not been fully characterized. The ability of transformed epithelial cells to initiate the metastatic cascade relies on their ability to escape anoikis, a default program of apoptosis induction following loss of integrin anchoring to the extracellular matrix. Therefore, we addressed the function of HIF-1α in anoikis resistance and anchorage-independent growth. Inhibition of HIF-1α via RNA interference resulted in up-regulation of α5 integrin on the cell surface of human gastric cancer cells, whereas other integrins remained unaffected. Integrin α5 induction occurred at the level of transcription and was dependent on elevated intracellular superoxide in HIF-1α-knockdown cells. HIF-1α–deficient cells displayed significantly increased anoikis susceptibility due to up-regulated α5 integrin. Finally, colony formation in soft agar was shown to be dependent on HIF-1α as HIF-1α–deficient cells displayed a 70% reduction in anchorage-independent proliferation. Results obtained by RNA interference could be entirely confirmed by application of the pharmacologic HIF-1α-inhibitor 2-methoxyestradiol. Hence, our data argue for a pivotal role for HIF-1α in anoikis control via suppression of α5 integrin. HIF-1α–inhibiting drugs might therefore offer an innovative strategy for antimetastatic cancer therapy. [Cancer Res 2008;68(24):10113–20]
MicroRNAs Impair MET-Mediated Invasive Growth
Authors: Migliore Cristina , Petrelli Annalisa , Ghiso Elena , Corso Simona , Capparuccia Lorena , Eramo Adriana , Comoglio Paolo M. , Giordano Silvia 
Published: December 2008

Abstract
MicroRNAs (miRNA) are a recently identified class of noncoding, endogenous, small RNAs that regulate gene expression, mainly at the translational level. These molecules play critical roles in several biological processes, such as cell proliferation and differentiation, development, and aging. It is also known that miRNAs play a role in human cancers where they can act either as oncogenes, down-regulating tumor suppressor genes, or as onco-suppressors, targeting molecules critically involved in promotion of tumor growth. One of such molecules is the tyrosine kinase receptor for hepatocyte growth factor, encoded by the MET oncogene. The MET receptor promotes a complex biological program named “invasive growth” that results from stimulation of cell motility, invasion, and protection from apoptosis. This oncogene is deregulated in many human tumors, where its most frequent alteration is overexpression. In this work, we have identified three miRNAs (miR-34b, miR-34c, and miR-199a*) that negatively regulate MET expression. Inhibition of these endogenous miRNAs, by use of antagomiRs, resulted in increased expression of MET protein, whereas their exogenous expression in cancer cells blocked MET-induced signal transduction and the execution of the invasive growth program, both in cells expressing normal levels of MET and in cancer cells overexpressing a constitutively active MET. Moreover, we show that these same miRNAs play a role in regulating the MET-induced migratory ability of melanoma-derived primary cells. In conclusion, we have identified miRNAs that behave as oncosuppressors by negatively targeting MET and might thus provide an additional option to inhibit this oncogene in tumors displaying its deregulation. [Cancer Res 2008;68(24):10128–36]
Genetic Variants in Apoptosis and Immunoregulation-Related Genes Are Associated with Risk of Chronic Lymphocytic Leukemia
Authors: Enjuanes Anna , Benavente Yolanda , Bosch Francesc , Martín-Guerrero Idoia , Colomer Dolors , Pérez-Álvarez Susana , Reina Oscar , Ardanaz Maria T. , Jares Pedro , García-Orad Africa , Pujana Miguel A. , Montserrat Emili , de Sanjosé Silvia , Campo Elias 
Published: December 2008

Abstract
To identify low-penetrance susceptibility alleles for chronic lymphocytic leukemia (CLL), we performed a case-control study genotyping 768 single-nucleotide polymorphisms (SNP) in 692 cases of CLL and 738 controls. We investigated nonsynonymous SNPs, SNPs with potential functional effect, and tag SNPs in regulatory gene regions in a total of 172 genes involved in cancer biology. After adjustment for multiple testing, we found a strong association between CLL risk and six genetic variants: CCNH (rs2266690, V270A), APAF1 (rs17028658, 3′region), IL16 (rs4505265, first intron), CASP8 (rs1045485, D302H), NOS2A (rs2779251, promoter), and CCR7 (rs3136687, intron 1). We found association with CLL susceptibility and 22 haplotypes in APAF1, IL6, TNFRSF13B, IL16, CASP3, CCR7, LTA/TNF, BAX, BCL2, CXCL12, CASP10/CASP8, CASP1, CCL2, BAK1, and IL1A candidate genes. Finally, we evaluated using public data sets the potential functional effect on gene expression levels of the CLL associated genetic variants detected in regulatory regions. Minor alleles for APAF1 and IL16 were associated with lower mRNA levels; no expression differences were observed for CCR7, whereas NOS2A could not be assessed. This study suggests that common genetic variation in apoptosis- and immunoregulation-related genes is associated with the CLL risk. [Cancer Res 2008;68(24):10178–86]
250K Single Nucleotide Polymorphism Array Karyotyping Identifies Acquired Uniparental Disomy and Homozygous Mutations, Including Novel Missense Substitutions of c-Cbl, in Myeloid Malignancies
Authors: Dunbar Andrew J. , Gondek Lukasz P. , O'Keefe Christine L. , Makishima Hideki , Rataul Manjot S. , Szpurka Hadrian , Sekeres Mikkael A. , Wang Xiao Fei , McDevitt Michael A. , Maciejewski Jaroslaw P. 
Published: December 2008

Abstract
Two types of acquired loss of heterozygosity are possible in cancer: deletions and copy-neutral uniparental disomy (UPD). Conventionally, copy number losses are identified using metaphase cytogenetics, whereas detection of UPD is accomplished by microsatellite and copy number analysis and as such, is not often used clinically. Recently, introduction of single nucleotide polymorphism (SNP) microarrays has allowed for the systematic and sensitive detection of UPD in hematologic malignancies and other cancers. In this study, we have applied 250K SNP array technology to detect previously cryptic chromosomal changes, particularly UPD, in a cohort of 301 patients with myelodysplastic syndromes (MDS), overlap MDS/myeloproliferative disorders (MPD), MPD, and acute myeloid leukemia. We show that UPD is a common chromosomal defect in myeloid malignancies, particularly in chronic myelomonocytic leukemia (CMML; 48%) and MDS/MPD-unclassifiable (38%). Furthermore, we show that mapping minimally overlapping segmental UPD regions can help target the search for both known and unknown pathogenic mutations, including newly identified missense mutations in the proto-oncogene c-Cbl in 7 of 12 patients with UPD11q. Acquired mutations of c-Cbl E3 ubiquitin ligase may explain the pathogenesis of a clonal process in a subset of MDS/MPD, including CMML. [Cancer Res 2008;68(24):10349–57]
Wnt1 Expression Induces Short-Range and Long-Range Cell Recruitments That Modify Mammary Tumor Development and Are Not Induced by a Cell-Autonomous β-Catenin Effector
Authors: Kim Young Chul , Clark Rod J. , Ranheim Erik A. , Alexander Caroline M. 
Published: December 2008

AbstractXenograft model studies have shown that tumor-associated, or genetically modified, activated stromal cells can promote tumor cell growth. Here, we examined mammary tumors arising in response to two different transgene-mediated Wnt signaling effectors: Wnt1 (a ligand with cell-nonautonomous effects) and ΔNβ-catenin (a constitutively active form of the intracellular effector). Although the route of tumor development has been shown to be similar for these two models, histologic analysis shows that Wnt1-induced tumors are associated with tracts of activated stroma, whereas most ΔNβ-catenin–induced tumors are solid adenocarcinomas. Furthermore, quantification of the “reactive stroma index” indicates that abundant activated stroma correlates with accelerated tumor progression. Wnt1-expressing mammary epithelial cells induce Wnt-specific target gene expression in local stromal cells (Wnt1-induced secreted protein 1/CCN4) but also induce long-range effects. Thus, mice with rapid tumor progression have 2-fold more circulating endothelial progenitor cells in peripheral blood than control or ΔNβ-catenin transgenic mice. Using tagged bone marrow (BM) transplants, we show that BM-derived cells are massively recruited to infiltrate the stroma of Wnt1-induced tumors where they differentiate into multiple cell types. Thus, localized ectopic expression of the proto-oncogene Wnt1 in mammary glands induces systemic responses, and we propose that this response modifies the tumorigenic outcome. [Cancer Res 2008;68(24):10145–53]
Negative Regulation of AKT Activation by BRCA1
Authors: Xiang Tao , Ohashi Amiko , Huang Yuping , Pandita Tej K. , Ludwig Thomas , Powell Simon N. , Yang Qin 
Published: December 2008

Abstract
The breast cancer susceptibility gene 1 (BRCA1) plays a key role in mammary tumorigenesis. However, the reasons why silencing the Brca1 gene leads to tumorigenesis are not clearly understood. We report here that BRCA1 deficiency activates the AKT oncogenic pathway, one of the most common alterations associated with human malignancy. Mutation of Brca1 gene increases the phosphorylation and the kinase activity of AKT. The BRCA1-BRCT domains bind to phosphorylated AKT (pAKT) and lead to its ubiquitination toward protein degradation. BRCA1 mutant cells lacking the BRCT repeats accumulate nuclear pAKT and consequently inactivate the transcription functions of FOXO3a, a main nuclear target of pAKT. Our results show that BRCA1 is a negative regulator of the AKT pathway and imply the significance of the BRCA1/AKT pathway in tumorigenesis. [Cancer Res 2008;68(24):10040–4]
Racial Disparity in Breast Cancer and Functional Germ Line Mutation in Galectin-3 (rs4644): A Pilot Study
Authors: Balan Vitaly , Nangia-Makker Pratima , Schwartz Ann G. , Jung Young Suk , Tait Larry , Hogan Victor , Raz Tirza , Wang Yi , Yang Zeng Quan , Wu Gen Sheng , Guo Yongjun , Li Huixiang , Abrams Judith , Couch Fergus J. , Lingle Wilma L. , Lloyd Ricardo V. , Ethier Stephen P. , Tainsky Michael A. , Raz Avraham 
Published: December 2008

AbstractFor reasons largely unknown, Caucasian women are at a significantly higher risk of developing breast cancer than Asian women. Over a decade ago, mutations in BRCA1/2 were identified as genetic risk factors; however, the discovery of additional breast cancer genes and genes contributing to racial disparities are lacking. We report a functional germline mutation (polymorphism) in the galectin-3 gene at position 191 (rs4644) substituting proline with histidine (P64H), which results in susceptibility to matrix metalloproteinase cleavage and acquisition of resistance to drug-induced apoptosis. This substitution correlates with incidence of breast cancer and racial disparity. Genotype analysis of 338 Caucasian (194 disease free and 144 breast cancer patients) and 140 Asian (79 disease free and 61 breast cancer patients) women showed that the allele homozygous for H64 exists in disease free Caucasian and Asian women at a frequency of 12% and 5%, respectively, versus 37% and 82% in breast cancer patients. The data indicate that H/H allele is associated with increased breast cancer risk in both races. The data implicate galectin-3 H64 in breast cancer and explain, in part, the noted racial disparity, thus providing a novel target for diagnosis and treatment. [Cancer Res 2008;68(24):10045–50]
Second-Generation Anti–Carcinoembryonic Antigen Designer T Cells Resist Activation-Induced Cell Death, Proliferate on Tumor Contact, Secrete Cytokines, and Exhibit Superior Antitumor ActivityIn vivo: A Preclinical Evaluation
Authors: Emtage Peter C.R. , Lo Agnes S.Y. , Gomes Erica M. , Liu David L. , Gonzalo-Daganzo Rosa M. , Junghans Richard P. 
Published: December 2008

AbstractPurpose: This report describes the development and preclinical qualification tests of second-generation anti-carcinoembryonic (CEA) designer T cells for use in human trials.Experimental Design: The progenitor first-generation immunoglobulin-T-cell receptor (IgTCR) that transmits Signal 1-only effectively mediated chimeric immune receptor (CIR)–directed cytotoxicity, but expressor T cells succumbed to activation-induced cell death (AICD). The second-generation CIR (termed “Tandem” for two signals) was designed to transmit TCR Signal 1 and CD28 Signal 2 to render T cells resistant to AICD and provide prolonged antitumor effect in vivo.Results: A CIR was created that combines portions of CD28, TCRζ, and a single chain antibody domain (sFv) specific for CEA into a single molecule (IgCD28TCR). As designed, the gene-modified Tandem T cells exhibit the new property of being resistant to AICD, showing instead an accelerated proliferation on tumor contact. Tandem T cells are more potent than first generation in targeting and lysing CEA+ tumor. Tandem T cells secrete high levels of interleukin-2 and IFNγ on tumor contact that first-generation T cells lacked, but secretion was exhaustible, suggesting a need for interleukin-2 supplementation in therapy even for these second-generation agents. Finally, second-generation T cells were more effective in suppressing tumor in animal models.Conclusion: An advanced generation of anti-CEA designer T cells is described with features that promise a more potent and enduring antitumor immune response in vivo. These preclinical data qualify the human use of this agent that is currently undergoing trial in patients with CEA+ cancers.
High Shed Antigen Levels within Tumors: An Additional Barrier to Immunoconjugate Therapy
Authors: Zhang Yujian , Pastan Ira 
Published: December 2008

AbstractShedding of cell surface antigens is an important biological process that is used by cells to modulate responses to signals in the extracellular environment. Because antibody-based therapies of cancer target cell surface antigens, it is important to understand more about the shedding process and how it affects tumor responses to this type of therapy. Up to now most attention has been focused on measuring the concentration of shed antigens in the blood and using these to determine the presence of a tumor and as a measure of response. The recent finding that the concentration of the tumor antigen mesothelin is extremely high within the interstitial space of tumors, where it can block antibody action, and that the concentration of shed mesothelin within the tumor is lowered by chemotherapy has important implications for the successful treatment of solid tumors by immunoconjugates and whole antibodies.
Protein Expression Profiling in Esophageal Adenocarcinoma Patients Indicates Association of Heat-Shock Protein 27 Expression and Chemotherapy Response
Authors: Langer Rupert , Ott Katja , Specht Katja , Becker Karen , Lordick Florian , Burian Maria , Herrmann Ken , Schrattenholz Andre , Cahill Michael A. , Schwaiger Markus , Hofler Heinz , Wester Hans-Jurgen 
Published: December 2008

Abstract
Purpose: To identify pretherapeutic predictive biomarkers in tumor biopsies of patients with locally advanced esophageal adenocarcinomas treated with neoadjuvant chemotherapy, we used an explorative proteomic approach to correlate pretherapeutic protein expression profiles with tumor response to neoadjuvant chemotherapy.
Experimental Design: Thirty-four patients with locally advanced esophageal adenocarcinomas who received neoadjuvant platin/5-fluorouracil–based chemotherapy before surgical resection were enrolled in this study. Response to chemotherapy was determined (a) by the amount of decline of [18F]fluorodeoxyglucose tumor uptake 2 weeks after the start of chemotherapy measured by positron emission tomography and (b) by histopathologic evaluation of tumor regression after surgical resection. Explorative quantitative and qualitative protein expression analysis was done through a quantitative differential protein expression analysis that used dual-isotope radioactive labeling of protein extracts. Selected identified biomarkers were validated by immunohistochemistry and quantitative real time reverse transcription-PCR.
Results: Proteomic analysis revealed four cellular stress response–associated proteins [heat-shock protein (HSP) 27, HSP60, glucose-regulated protein (GRP) 94, GRP78] and a number of cytoskeletal proteins whose pretherapeutic abundance was significantly different (P &lt; 0.001) between responders and nonresponders. Immunohistochemistry and gene expression analysis confirmed these data, showing a significant association between low HSP27 expression and nonresponse to neoadjuvant chemotherapy (P = 0.049 and P = 0.032, respectively).
Conclusions: Albeit preliminary, our encouraging data suggest that protein expression profiling may distinguish cancers with a different response to chemotherapy. Our results suggest that response to chemotherapy may be related to a different activation of stress response and inflammatory biology in general. Moreover, the potential of HSPs and GRPs as biomarkers of chemotherapy response warrants further validation.