bluuebunny/crossref_metadata_2025_split huggingface dataset:
SLITs Suppress Tumor Growth In vivo by Silencing Sdf1/Cxcr4 within Breast Epithelium
Authors: Marlow Rebecca , Strickland Phyllis , Lee Ji Shin , Wu Xinyan , PeBenito Milana , Binnewies Mikhail , Le Elizabeth K. , Moran Angel , Macias Hector , Cardiff Robert D. , Sukumar Saraswati , Hinck Lindsay 
Published: October 2008

Abstract
The genes encoding Slits and their Robo receptors are silenced in many types of cancer, including breast, suggesting a role for this signaling pathway in suppressing tumorigenesis. The molecular mechanism underlying these tumor-suppressive effects has not been delineated. Here, we show that loss of Slits, or their Robo1 receptor, in murine mammary gland or human breast carcinoma cells results in coordinate up-regulation of the Sdf1 and Cxcr4 signaling axis, specifically within mammary epithelium. This is accompanied by hyperplastic changes in cells and desmoplastic alterations in the surrounding stroma. A similar inverse correlation between Slit and Cxcr4 expression is identified in human breast tumor tissues. Furthermore, we show in a xenograft model that Slit overexpression down-regulates CXCR4 and dominantly suppresses tumor growth. These studies classify Slits as negative regulators of Sdf1 and Cxcr4 and identify a molecular signature in hyperplastic breast lesions that signifies inappropriate up-regulation of key prometastatic genes. [Cancer Res 2008;68(19):7819–27]
Suppression of Prostate Cancer Nodal and Systemic Metastasis by Blockade of the Lymphangiogenic Axis
Authors: Burton Jeremy B. , Priceman Saul J. , Sung James L. , Brakenhielm Ebba , An Dong Sung , Pytowski Bronislaw , Alitalo Kari , Wu Lily 
Published: October 2008

Abstract
Lymph node involvement denotes a poor outcome for patients with prostate cancer. Our group, along with others, has shown that initial tumor cell dissemination to regional lymph nodes via lymphatics also promotes systemic metastasis in mouse models. The aim of this study was to investigate the efficacy of suppressive therapies targeting either the angiogenic or lymphangiogenic axis in inhibiting regional lymph node and systemic metastasis in subcutaneous and orthotopic prostate tumor xenografts. Both androgen-dependent and more aggressive androgen-independent prostate tumors were used in our investigations. Interestingly, we observed that the threshold for dissemination is lower in the vascular-rich prostatic microenvironment compared with subcutaneously grafted tumors. Both vascular endothelial growth factor-C (VEGF-C) ligand trap (sVEGFR-3) and antibody directed against VEGFR-3 (mF4-31C1) significantly reduced tumor lymphangiogenesis and metastasis to regional lymph nodes and distal vital organs without influencing tumor growth. Conversely, angiogenic blockade by short hairpin RNA against VEGF or anti–VEGFR-2 antibody (DC101) reduced tumor blood vessel density, significantly delayed tumor growth, and reduced systemic metastasis, although it was ineffective in reducing lymphangiogenesis or nodal metastasis. Collectively, these data clarify the utility of vascular therapeutics in prostate tumor growth and metastasis, particularly in the context of the prostate microenvironment. Our findings highlight the importance of lymphangiogenic therapies in the control of regional lymph node and systemic metastasis. [Cancer Res 2008;68(19):7828–37] [Cancer Res 2008;68(19):7828–37]
Vitamin C Antagonizes the Cytotoxic Effects of Antineoplastic Drugs
Authors: Heaney Mark L. , Gardner Jeffrey R. , Karasavvas Nicos , Golde David W. , Scheinberg David A. , Smith Emily A. , O'Connor Owen A. 
Published: October 2008

Abstract
Vitamin C is an antioxidant vitamin that has been hypothesized to antagonize the effects of reactive oxygen species–generating antineoplastic drugs. The therapeutic efficacy of the widely used antineoplastic drugs doxorubicin, cisplatin, vincristine, methotrexate, and imatinib were compared in leukemia (K562) and lymphoma (RL) cell lines with and without pretreatment with dehydroascorbic acid, the commonly transported form of vitamin C. The effect of vitamin C on viability, clonogenicity, apoptosis, P-glycoprotein, reactive oxygen species (ROS), and mitochondrial membrane potential was determined. Pretreatment with vitamin C caused a dose-dependent attenuation of cytotoxicity, as measured by trypan blue exclusion and colony formation after treatment with all antineoplastic agents tested. Vitamin C given before doxorubicin treatment led to a substantial reduction of therapeutic efficacy in mice with RL cell–derived xenogeneic tumors. Vitamin C treatment led to a dose-dependent decrease in apoptosis in cells treated with the antineoplastic agents that was not due to up-regulation of P-glycoprotein or vitamin C retention modulated by antineoplastics. Vitamin C had only modest effects on intracellular ROS and a more general cytoprotective profile than N-acetylcysteine, suggesting a mechanism of action that is not mediated by ROS. All antineoplastic agents tested caused mitochondrial membrane depolarization that was inhibited by vitamin C. These findings indicate that vitamin C given before mechanistically dissimilar antineoplastic agents antagonizes therapeutic efficacy in a model of human hematopoietic cancers by preserving mitochondrial membrane potential. These results support the hypothesis that vitamin C supplementation during cancer treatment may detrimentally affect therapeutic response. [Cancer Res 2008;68(19):8031–8]
Mutations in the Focal Adhesion Targeting Region of Deleted in Liver Cancer-1 Attenuate Their Expression and Function
Authors: Liao Yi-Chun , Shih Yi-Ping , Lo Su Hao 
Published: October 2008

Abstract
Deleted in liver cancer-1 (DLC-1) is a RhoGTPase-activating protein (RhoGAP) domain containing tumor suppressor that is often down-regulated in various cancer types. Previously, we have shown that DLC-1 is recruited to focal adhesions by binding to the Src homology 2 domains of tensins and the focal adhesion localization is critical for the tumor suppression activity of DLC-1. To investigate whether mutations in the focal adhesion targeting (FAT) region might occur and attenuate the expression, localization, and function of DLC-1, we have first mapped the FAT region to the amino acid residues from 201 to 500, and then sequenced cDNAs and genomic DNAs encoding the FAT region from cancer patients. Several missense and nonsense mutations were detected. All missense mutations were further examined for the potential effect on the function of DLC-1. Although these mutations did not seem to affect the focal adhesion localization of DLC-1, the activities of suppressing tumor cell growth were impaired in two mutants: T301K and S308I. Consistent with the fact that the RhoGAP activity of DLC-1 is essential for inhibiting tumor cell growth, the RhoGAP activities were significantly reduced in these mutants, suggesting that the FAT region also contains a regulatory element for its COOH-terminal RhoGAP domain. Our studies have shown that mutations in DLC-1 may lead to loss of function and contribute to the tumorigenesis, and have revealed an allosteric regulation site for its RhoGAP activity. [Cancer Res 2008;68(19):7718–22]
Androgenic Control of Transforming Growth Factor-β Signaling in Prostate Epithelial Cells through Transcriptional Suppression of Transforming Growth Factor-β Receptor II
Authors: Song Kyung , Wang Hui , Krebs Tracy L. , Kim Seong-Jin , Danielpour David 
Published: October 2008

Abstract
The androgen receptor cross-talks with transforming growth factor-β (TGF-β) through mechanisms that remain poorly understood. Here we provide strong evidence that 5α-dihydrotestosterone (DHT) intercepts the ability of prostate epithelial cells to undergo TGF-β–induced apoptosis, and present a new model for this androgenic effect. We report that DHT decreases the level of TGF-β receptor II (TβRII) through a transcriptional mechanism, leading to suppression of the ability of TGF-β to down-regulate expression of Bcl-xL and cyclin Ds, activate caspase-3, and induce apoptosis. Promoter analysis, DNA pulldown, and electrophoretic mobility shift assays support that transcriptional down-regulation of TβRII by DHT occurs through Sp1/Sp3 response elements, with the binding of Sp1 to the TβRII promoter being suppressed by DHT, largely driven by loss of Sp1 protein and/or activity. These results provide fresh insight on the mechanism of growth control by androgens and the progression of prostate cancer to androgen independence. [Cancer Res 2008;68(19):8173–82]
Identification of Transformation-Related Pathways in a Breast Epithelial Cell Model Using a Ribonomics Approach
Authors: Mazan-Mamczarz Krystyna , Hagner Patrick R. , Dai Bojie , Wood William H. , Zhang Yongqing , Becker Kevin G. , Liu Zhenqui , Gartenhaus Ronald B. 
Published: October 2008

Abstract
The aberrant expression of many genes is a common feature in the malignant transformation of cells. In mammalian cells, posttranscriptional gene regulatory processes are emerging as critical determinants controlling gene expression both in physiologic and pathologic conditions. These regulatory mechanisms are directed primarily by the interaction of mRNAs with specific RNA-binding proteins (RBP). There is an emerging body of data demonstrating that two RBPs, AUF1 and HuR, can antagonistically affect the posttranscriptional fate of target mRNAs, as well as concurrently bind to common target transcripts. Employing MCT-1 oncogene-mediated transformation of immortalized breast epithelial MCF10A cells, we characterized the largely reciprocal association of these two RBPs with target mRNAs and their influence on protein expression vis-a-vis cellular transformation. Using a ribonomics approach, we identified mRNAs from cancer-related pathways whose association with AUF1 and/or HuR were altered when comparing immortalized with transformed MCF10A cells. Significantly, we were able to show that knockdown of HuR expression using RNA interference reduced anchorage-independent growth capacity in transformed MCF10A cells and decreased protein expression of a number of validated target genes. Our data show that the global alterations in binding of HuR and AUF1 with target transcripts have a critical role in posttranscriptional regulation of genes encoding proteins involved in breast epithelial cell transformation. These findings further support the feasibility of using a ribonomics approach for the identification of cancer-related pathways. [Cancer Res 2008;68(19):7730–5]
Identification of GRP75 as an Independent Favorable Prognostic Marker of Neuroblastoma by a Proteomics Analysis
Authors: Hsu Wen-Ming , Lee Hsinyu , Juan Hsueh-Fen , Shih Yu-Yin , Wang Bo-Jeng , Pan Chien-Yuan , Jeng Yung-Ming , Chang Hsiu-Hao , Lu Meng-Yao , Lin Kai-Hsin , Lai Hong-Shiee , Chen Wei-Jao , Tsay Yeou-Guang , Liao Yung-Feng , Hsieh Fon-Jou 
Published: October 2008

AbstractPurpose: Neuroblastoma (NB) is a heterogeneous neoplasm. Detailed biological discrimination is critical for the effective treatment of this disease. Because the tumor behavior of NB is closely associated with the histologic state of differentiation, we thus aimed to identify novel differentiation-associated markers of NB with prognostic implication.Experimental Design: A human NB cell line SH-SY5Y was used as a model system to explore potential biomarkers for the differentiation of NB by proteomic analyses. Seventy-two NB tumor tissues were subsequently investigated by immunohistochemistry to validate the correlations between the expression of a novel prognostic marker, various clinicopathologic and biological factors, and patient survival.Results: Using two-dimensional differential gel electrophoresis, we found a total of 24 spots of proteins in SH-SY5Y cells whose expression was enhanced following differentiation. Glucose-regulated protein 75 (GRP75) was unambiguously identified as one of the five proteins that were dramatically up-regulated following differentiation. Immunohistochemical analyses of 72 NB tumor tissues further revealed that positive GRP75 immunostaining is strongly correlated with differentiated histologies (P &lt; 0.001), mass-screened tumors (P = 0.016), and early clinical stages (P &lt; 0.001) but inversely correlated with MYCN amplification (P = 0.010). Univariate and multivariate survival analyses showed that GRP75 expression is an independent favorable prognostic factor.Conclusions: The present findings clearly showed that our proteomics-based novel experimental paradigm could be a powerful tool to uncover novel biomarkers associated with the differentiation of NB. Our data also substantiate an essential role of GRP75 in the differentiation of NB.
The Use of Genomics in Clinical Trial Design
Authors: Simon Richard 
Published: October 2008

Abstract
Many cancer treatments benefit only a minority of patients who receive them. This results in an enormous burden on patients and on the health care system. The problem will become even greater with the increasing use of molecularly targeted agents whose benefits are likely to be more selective unless the drug development process is modified to include codevelopment of companion diagnostics. Whole genome biotechnology and decreasing costs of genome sequencing make it increasingly possible to achieve an era of predictive medicine in oncology therapeutics. The challenges are numerous and substantial but are not primarily technological. They involve organizing publicly funded diagnostics of deregulated pathways, adopting new paradigms for drug development, and developing incentives for industry to incur the complexity and expense of codevelopment of drugs and companion diagnostics. This article reviews some designs for phase III clinical trials that may facilitate movement to a more predictive oncology.
Validation of Analytic Methods for Biomarkers Used in Drug Development
Authors: Chau Cindy H. , Rixe Olivier , McLeod Howard , Figg William D. 
Published: October 2008

AbstractThe role of biomarkers in drug discovery and development has gained precedence over the years. As biomarkers become integrated into drug development and clinical trials, quality assurance and, in particular, assay validation become essential with the need to establish standardized guidelines for analytic methods used in biomarker measurements. New biomarkers can revolutionize both the development and use of therapeutics but are contingent on the establishment of a concrete validation process that addresses technology integration and method validation as well as regulatory pathways for efficient biomarker development. This perspective focuses on the general principles of the biomarker validation process with an emphasis on assay validation and the collaborative efforts undertaken by various sectors to promote the standardization of this procedure for efficient biomarker development.
Salivary Proteomics for Oral Cancer Biomarker Discovery
Authors: Hu Shen , Arellano Martha , Boontheung Pinmanee , Wang Jianghua , Zhou Hui , Jiang Jiang , Elashoff David , Wei Roger , Loo Joseph A. , Wong David T. 
Published: October 2008

Abstract
Purpose: This study aims to explore the presence of informative protein biomarkers in the human saliva proteome and to evaluate their potential for detection of oral squamous cell carcinoma (OSCC).
Experimental Design: Whole saliva samples were collected from patients (n = 64) with OSCC and matched healthy subjects (n = 64). The proteins in pooled whole saliva samples of patients with OSCC (n = 16) and matched healthy subjects (n = 16) were profiled using shotgun proteomics based on C4 reversed-phase liquid chromatography for prefractionation, capillary reversed-phase liquid chromatography with quadruple time-of-flight mass spectrometry, and Mascot sequence database searching. Immunoassays were used for validation of the candidate biomarkers on a new group of OSCC (n = 48) and matched healthy subjects (n = 48). Receiver operating characteristic analysis was exploited to evaluate the diagnostic value of discovered candidate biomarkers for OSCC.
Results: Subtractive proteomics revealed several salivary proteins at differential levels between the OSCC patients and matched control subjects. Five candidate biomarkers were successfully validated using immunoassays on an independent set of OSCC patients and matched healthy subjects. The combination of these candidate biomarkers yielded a receiver operating characteristic value of 93%, sensitivity of 90%, and specificity of 83% in detecting OSCC.
Conclusion: Patient-based saliva proteomics is a promising approach to searching for OSCC biomarkers. The discovery of these new targets may lead to a simple clinical tool for the noninvasive diagnosis of oral cancer. Long-term longitudinal studies with large populations of individuals with oral cancer and those who are at high risk of developing oral cancer are needed to validate these potential biomarkers.
Liposome-Encapsulated Curcumin Suppresses Growth of Head and Neck Squamous Cell CarcinomaIn vitroand in Xenografts through the Inhibition of Nuclear Factor κB by an AKT-Independent Pathway
Authors: Wang Dorothy , Veena Mysore S. , Stevenson Kerry , Tang Christopher , Ho Baran , Suh Jeffrey D. , Duarte Victor M. , Faull Kym F. , Mehta Kapil , Srivatsan Eri S. , Wang Marilene B. 
Published: October 2008

AbstractPurpose: The purpose of this study was to determine whether a liposomal formulation of curcumin would suppress the growth of head and neck squamous cell carcinoma (HNSCC) cell lines CAL27 and UM-SCC1 in vitro and in vivo.Experimental Design: HNSCC cell lines were treated with liposomal curcumin at different doses and assayed for in vitro growth suppression using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. A reporter gene assay was done on cell lines to study the effect of liposomal curcumin on nuclear factor κB (NFκB) activation. Western blot analysis was done to determine the effect of curcumin on the expression of NFκB, phospho-IκBα, phospho-AKT (pAKT), phospho-S6 kinase, cyclin D1, cyclooxygenase-2, matrix metalloproteinase-9, Bcl-2, Bcl-xL, Mcl-1L, and Mcl-1S. Xenograft mouse tumors were grown and treated with intravenous liposomal curcumin. After 5 weeks, tumors were harvested and weighed. Immunohistochemistry and Western blot analyses were used to study the effect of liposomal curcumin on the expression of NFκB and pAKT.Results: The addition of liposomal curcumin resulted in a dose-dependent growth suppression of both cell lines. Liposomal curcumin treatment suppressed the activation of NFκB without affecting the expression of pAKT or its downstream target phospho-S6 kinase. Expression of cyclin D1, cyclooxygenase-2, matrix metalloproteinase-9, Bcl-2, Bcl-xL, Mcl-1L, and Mcl-1S were reduced, indicating the effect of curcumin on the NFκB pathway. Nude mice xenograft tumors were suppressed after 3.5 weeks of treatment with i.v. liposomal curcumin, and there was no demonstrable toxicity of liposomal curcumin upon autopsy. Immunohistochemistry and Western blot analysis on xenograft tumors showed the inhibition of NFκB without affecting the expression of pAKT.Conclusions: Liposomal curcumin suppresses HNSCC growth in vitro and in vivo. The results suggest that liposomal curcumin is a viable nontoxic therapeutic agent for HNSCC that may work via an AKT-independent pathway.
Transesophageal Endoscopic Ultrasound with Fine Needle Aspiration in the Preoperative Staging of Malignant Pleural Mesothelioma
Authors: Tournoy Kurt G. , Burgers Sjaak A. , Annema Jouke T. , Vermassen Frank , Praet Marleen , Smits Marianne , Klomp Houke M. , van Meerbeeck Jan P. , Baas Paul 
Published: October 2008

Abstract
Purpose: Surgical resection as part of a multimodality approach in malignant pleural mesothelioma (MPM) has a high morbidity and mortality. Because mediastinal lymph node (MLN) metastases are a negative prognostic factor, preoperative staging is of paramount importance. Transesophageal endoscopic ultrasound with real-time guided fine needle aspiration (EUS-FNA) enables accurate MLN staging in lung cancer.
Experimental Design: The feasibility and yield of EUS-FNA in MLN staging were prospectively analyzed in patients with presumed early-stage MPM considered for multimodality therapy. MLN reference pathology was defined by either pathologic staging or the formal demonstration of malignant cells by either EUS-FNA or mediastinoscopy.
Results: Thirty-two consecutive patients (81% males; median age, 61 years) with proven MPM underwent EUS-FNA. In 11 (34%) patients, a negative EUS-FNA or mediastinoscopy was not confirmed by surgical MLN dissection because of clinical deterioration or disease progression. In 21 (66%) patients, a formal pathology of the MLN was obtained and staging with EUS-FNA was positive in 4 (19%). Mediastinoscopy did not result in a greater yield of MLN metastasis as compared with EUS-FNA. Thoracotomy with complete lymph node dissection was done in 17 (81%). The overall prevalence of MLN metastasis was 24%, and the sensitivity of EUS-FNA was 80% (95% confidence interval, 28-99%) with a specificity of 100% (95% confidence interval, 79-100%). One patient had esophageal perforation related to EUS-FNA.
Conclusions: EUS-FNA is feasible and sensitive for MLN staging in patients with MPM who are candidate for multimodality treatment. These data warrant further evaluation.
Single-Agent and Combination Therapeutic Strategies to Inhibit Hepatocyte Growth Factor/MET Signaling in Cancer
Authors: Toschi Luca , Jänne Pasi A. 
Published: October 2008

Abstract
Receptor tyrosine kinases are often aberrantly activated in human malignancies and contribute to cancer development and progression. Specific receptor tyrosine kinase inhibitors have been shown to be clinically effective therapies in subsets of cancer patients with either hematologic or solid tumors. Activation of the hepatocyte growth factor (HGF)/MET signaling pathway has been found to play a critical role in oncogenesis, cancer metastasis, and drug resistance. These observations have led to the development of agents that can effectively inhibit HGF/MET signaling through direct inhibition of the receptor (anti-MET antibodies), through inactivation of its ligand HGF (AMG102, L2G7), by interfering with HGF binding to MET (NK4), or by inhibiting MET kinase activity (PHA-665752 and SU11274). Moreover, the combination of anti-MET therapeutic agents with either signal transduction inhibitors (ERBB family or mTOR inhibitors) or with cytotoxic chemotherapy has been evaluated in preclinical models. These studies provide insight into the rational development of combination therapeutic strategies that can be evaluated in clinical trials. This review will discuss different strategies of MET inhibition with a specific focus on combination therapeutic approaches.