bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor Necrosis Factor-α Promotes Malignant Pleural Effusion
Authors: Stathopoulos Georgios T. , Kollintza Androniki , Moschos Charalampos , Psallidas Ioannis , Sherrill Taylor P. , Pitsinos Emmanuel N. , Vassiliou Spyridoula , Karatza Marilena , Papiris Spyros A. , Graf Daniel , Orphanidou Dora , Light Richard W. , Roussos Charis , Blackwell Timothy S. , Kalomenidis Ioannis 
Published: October 2007

AbstractTumor necrosis factor (TNF)-α is present in the microenvironment of human tumors, including malignant pleural effusion (MPE). Although the cytokine is produced in the pleural cavity by both tumor and host cells, its effects on MPE formation are unknown. In these studies, we sought to determine the role of TNF-α in the pathogenesis of MPE and to assess the therapeutic effects of its neutralization in a preclinical model. For this, MPEs were generated in immunocompetent mice using intrapleural injection of mouse lung adenocarcinoma cells. The roles of tumor- and host-derived TNF-α were assessed using combined experimentation with TNF-α gene–deficient mice and in vivo TNF-α neutralization. To expand the scope of preclinical data, TNF-α and vascular endothelial growth factor (VEGF) expression were determined in human cancer cell lines and human MPE. In the MPE model, TNF-α of host and tumor origin was present. TNF-α neutralization significantly limited tumor dissemination, effusion formation, vascular hyperpermeability, TNF-α and VEGF expression, and angiogenesis, thereby improving survival. In contrast, these variables were not different between TNF-α gene–sufficient and TNF-α gene–deficient mice. In mouse cancer cells, TNF-α functioned via nuclear factor-κB– and neutral sphingomyelinase–dependent pathways to induce TNF-α and VEGF, respectively. These results were recapitulated in human cancer cells, and a correlation was detected between TNF-α and VEGF content of human MPE. We conclude that tumor-derived TNF-α is important in the development of MPE in mice, and provide preclinical evidence supporting the efficacy of TNF-α blockade against malignant pleural disease. [Cancer Res 2007;67(20):9825–34]
The Addition of AG-013736 to Fractionated Radiation Improves Tumor Response without Functionally Normalizing the Tumor Vasculature
Authors: Fenton Bruce M. , Paoni Scott F. 
Published: October 2007

Abstract
Although antiangiogenic strategies have proven highly promising in preclinical studies and some recent clinical trials, generally only combinations with cytotoxic therapies have shown clinical effectiveness. An ongoing question has been whether conventional therapies are enhanced or compromised by antiangiogenic agents. The present studies were designed to determine the pathophysiologic consequences of both single and combined treatments using fractionated radiotherapy plus AG-013736, a receptor tyrosine kinase inhibitor that preferentially inhibits vascular endothelial growth factor receptors. DU145 human prostate xenograft tumors were treated with (a) vehicle alone, (b) AG-013736, (c) 5 × 2 Gy/wk radiotherapy fractions, or (d) the combination. Automated image processing of immunohistochemical images was used to determine total and perfused blood vessel spacing, overall hypoxia, pericyte/collagen coverage, proliferation, and apoptosis. Combination therapy produced an increased tumor response compared with either monotherapy alone. Vascular density progressively declined in concert with slightly increased α-smooth muscle actin–positive pericyte coverage and increased overall tumor hypoxia (compared with controls). Although functional vessel endothelial apoptosis was selectively increased, reductions in total and perfused vessels were generally proportionate, suggesting that functional vasculature was not specifically targeted by combination therapy. These results argue against either an AG-013736- or a combination treatment–induced functional normalization of the tumor vasculature. Vascular ablation was mirrored by the increased appearance of dissociated pericytes and empty type IV collagen sleeves. Despite the progressive decrease in tumor oxygenation over 3 weeks of treatment, combination therapy remained effective and tumor progression was minimal. [Cancer Res 2007;67(20):9921–8]
Progestin-Dependent Progression of Human Breast Tumor Xenografts: A Novel Model for Evaluating Antitumor Therapeutics
Authors: Liang Yayun , Besch-Williford Cynthia , Brekken Rolf A. , Hyder Salman M. 
Published: October 2007

Abstract
Recent clinical trials indicate that synthetic progestins may stimulate progression of breast cancer in postmenopausal women, a result that is consistent with studies in chemically-induced breast cancer models in rodents. However, progestin-dependent progression of breast cancer tumor xenografts has not been shown. This study shows that xenografts obtained from BT-474 and T47-D human breast cancer cells without Matrigel in estrogen-supplemented nude mice begin to regress within days after tumor cell inoculation. However, their growth is resumed if animals are supplemented with progesterone. The antiprogestin RU-486 blocks progestin stimulation of growth, indicating involvement of progesterone receptors. Exposure of xenografts to medroxyprogesterone acetate, a synthetic progestin used in postmenopausal hormone replacement therapy and oral contraception, also stimulates growth of regressing xenograft tumors. Tumor progression is dependent on expression of vascular endothelial growth factor (VEGF); growth of progestin-dependent tumors is blocked by inhibiting synthesis of VEGF or VEGF activity using a monoclonal anti-VEGF antibody (2C3) or by treatment with PRIMA-1, a small-molecule compound that reactivates mutant p53 into a functional protein and blocks VEGF production. These results suggest a possible model system for screening potential therapeutic agents for their ability to prevent or inhibit progestin-dependent human breast tumors. Such a model could potentially be used to screen for safer antiprogestins, antiangiogenic agents, or for compounds that reactivate mutant p53 and prevent progestin-dependent progression of breast disease. [Cancer Res 2007;67(20):9929–36]
Chemoprevention of Familial Adenomatous Polyposis by Natural Dietary Compounds Sulforaphane and Dibenzoylmethane Alone and in Combination in ApcMin/+ Mouse
Authors: Shen Guoxiang , Khor Tin Oo , Hu Rong , Yu Siwang , Nair Sujit , Ho Chi-Tang , Reddy Bandaru S. , Huang Mou-Tuan , Newmark Harold L. , Kong Ah-Ng Tony 
Published: October 2007

Abstract
Cancer chemopreventive agent sulforaphane (SFN) and dibenzoylmethane (DBM) showed antitumorigenesis effects in several rodent carcinogenesis models. In this study, we investigated the cancer chemopreventive effects and the underlying molecular mechanisms of dietary administration of SFN and DBM alone or in combination in the ApcMin/+ mice model. Male ApcMin/+ mice (12 per group) at age of 5 weeks were given control AIN-76A diet, diets containing 600 ppm SFN and 1.0% DBM, or a combination of 300 ppm SFN and 0.5% DBM for 10 weeks. Mice were then sacrificed, and tumor numbers and size were examined. Microarray analysis, Western blotting, ELISA, and immunohistochemical staining were done to investigate the underlying molecular mechanisms of cancer chemopreventive effects of SFN and DBM. Dietary administrations of SFN and DBM alone or in combination significantly inhibited the development of intestinal adenomas by 48% (P = 0.002), 50% (P = 0.001), and 57% (P &lt; 0.001), respectively. Dietary administration of 600 ppm SFN and 1.0% DBM also reduced colon tumor numbers by 80% (P = 0.016) and 60% (P = 0.103), respectively, whereas the combination of SFN and DBM treatment blocked the colon tumor development (P = 0.002). Both SFN and DBM treatments resulted in decreased levels of prostaglandin E2 or leukotriene B4 in intestinal polyps or apparently normal mucosa. Treatments also led to the inhibition of cell survival and growth-related signaling pathways (such as Akt and extracellular signal-regulated kinase) or biomarkers (such as cyclooxygenase-2, proliferating cell nuclear antigen, cleaved caspases, cyclin D1, and p21). In conclusion, our results showed that both SFN and DBM alone as well as their combination are potent natural dietary compounds for chemoprevention of gastrointestinal cancers. [Cancer Res 2007;67(20):9937–44]
Selective Role of an NH2-Terminal WxxLF Motif for Aberrant Androgen Receptor Activation in Androgen Depletion–Independent Prostate Cancer Cells
Authors: Dehm Scott M. , Regan Kevin M. , Schmidt Lucy J. , Tindall Donald J. 
Published: October 2007

Abstract
Systemic prostate cancer therapy requires androgen ablation, which inhibits the production or action of androgens. Prostate cancer ultimately relapses during androgen ablation, and an androgen depletion-independent (ADI) phenotype emerges. Aberrant androgen receptor (AR) activation underlies therapy resistance at this stage of the disease, and mounting evidence implicates the large and highly disordered AR NH2-terminal domain (NTD) as a key mediator of this activity. In this study, we investigated the role of the NTD transactivation unit 5 (TAU5) domain in mediating AR transcriptional activity in cell-based models of prostate cancer progression. AR replacement and Gal4-based promoter tethering experiments revealed that AR TAU5 had a dichotomous function, inhibiting ligand-dependent AR activity in androgen-dependent prostate cancer cells, while enhancing ligand-independent AR activity in ADI prostate cancer cells. Molecular dissection of TAU5 showed that a WxxLF motif was fully responsible for its ligand-independent activity. Mechanistically, WxxLF did not rely on an interaction with the AR ligand-binding domain to mediate ligand-independent AR activity. Rather, WxxLF functioned as an autonomous transactivation domain. These data show that ligand-dependent and ligand-independent AR activation rely on fundamentally distinct mechanisms, and define WxxLF as the major transactivation motif within the AR TAU5 domain. [Cancer Res 2007;67(20):10067–77]
Selective Inhibition of Growth ofTuberous Sclerosis Complex 2–Null Cells by Atorvastatin Is Associated with Impaired Rheb and Rho GTPase Function and Reduced mTOR/S6 Kinase Activity
Authors: Finlay Geraldine A. , Malhowski Amy J. , Liu Yingling , Fanburg Barry L. , Kwiatkowski David J. , Toksoz Deniz 
Published: October 2007

AbstractInactivating mutations in the tuberous sclerosis complex 2 (TSC2) gene, which encodes tuberin, result in the development of TSC and lymphangioleiomyomatosis (LAM). The tumor suppressor effect of tuberin lies in its GTPase-activating protein activity toward Ras homologue enriched in brain (Rheb), a Ras GTPase superfamily member. The statins, 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, have pleiotropic effects which may involve interference with the isoprenylation of Ras and Rho GTPases. We show that atorvastatin selectively inhibits the proliferation of Tsc2−/− mouse embryo fibroblasts and ELT-3 smooth muscle cells in response to serum and estrogen, and under serum-free conditions. The isoprenoids farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) significantly reverse atorvastatin-induced inhibition of Tsc2−/− cell growth, suggesting that atorvastatin dually targets a farnesylated protein, such as Rheb, and a geranylgeranylated protein, such as Rho, both of which have elevated activity in Tsc2−/− cells. Atorvastatin reduced Rheb isoprenylation, GTP loading, and membrane localization. Atorvastatin also inhibited the constitutive phosphorylation of mammalian target of rapamycin, S6 kinase, and S6 found in Tsc2−/− cells in an FPP-reversible manner and attenuated the high levels of phosphorylated S6 in Tsc2-heterozygous mice. Atorvastatin, but not rapamycin, attenuated the increased levels of activated RhoA in Tsc2−/− cells, and this was reversed by GGPP. These results suggest that atorvastatin may inhibit both rapamycin-sensitive and rapamycin-insensitive mechanisms of tuberin-null cell growth, likely via Rheb and Rho inhibition, respectively. Atorvastatin may have potential therapeutic benefit in TSC syndromes, including LAM. [Cancer Res 2007;67(20):9878–86]
Autophagy Is Activated in Colorectal Cancer Cells and Contributes to the Tolerance to Nutrient Deprivation
Authors: Sato Kazunori , Tsuchihara Katsuya , Fujii Satoshi , Sugiyama Masanori , Goya Tomoyuki , Atomi Yutaka , Ueno Takashi , Ochiai Atsushi , Esumi Hiroyasu 
Published: October 2007

Abstract
Several types of cancer cells, including colorectal cancer–derived cell lines, show austerity, the resistance to nutrient starvation, but exactly how cancer cells obtain energy sources under conditions in which their external nutrient supply is extremely limited remains to be clarified. Because autophagy is a catabolic process by which cells supply amino acids from self-digested organelles, cancer cells are likely to use autophagy to obtain amino acids as alternative energy sources. Amino acid deprivation-induced autophagy was assessed in DLD-1 and other colorectal cancer–derived cell lines. The autophagosome-incorporated LC3-II protein level increased after treatment with a combination of autolysosome inhibitors, which interferes with the consumption of autophagosomes. Autophagosome formation was also morphologically confirmed using ectopically expressed green fluorescent protein-LC3 fusion proteins in DLD-1 and SW480 cells. These data suggest that autophagosomes were actively produced and promptly consumed in colorectal cancer cells under nutrient starvation. Autolysosome inhibitors and 3-methyl adenine, which suppresses autophagosome formation, remarkably enhanced apoptosis under amino acid–deprived and glucose-deprived condition. Similar results were obtained in the cells with decreased ATG7 level by the RNA interference. These data suggest that autophagy is pivotal for the survival of colorectal cancer cells that have acquired austerity. Furthermore, autophagosome formation was seen only in the tumor cells but not in the adjacent noncancerous epithelial cells of colorectal cancer specimens. Taken together, autophagy is activated in colorectal cancers in vitro and in vivo, and autophagy may contribute to the survival of the cancer cells in their microenvironment. [Cancer Res 2007;67(20):9677–84]
Derivation of Stable Microarray Cancer-Differentiating Signatures Using Consensus Scoring of Multiple Random Sampling and Gene-Ranking Consistency Evaluation
Authors: Tang Zhi Qun , Han Lian Yi , Lin Hong Huang , Cui Juan , Jia Jia , Low Boon Chuan , Li Bao Wen , Chen Yu Zong 
Published: October 2007

Abstract
Microarrays have been explored for deriving molecular signatures to determine disease outcomes, mechanisms, targets, and treatment strategies. Although exhibiting good predictive performance, some derived signatures are unstable due to noises arising from measurement variability and biological differences. Improvements in measurement, annotation, and signature selection methods have been proposed. We explored a new signature selection method that incorporates consensus scoring of multiple random sampling and multistep evaluation of gene-ranking consistency for maximally avoiding erroneous elimination of predictor genes. This method was tested by using a well-studied 62-sample colon cancer data set and two other cancer data sets (86-sample lung adenocarcinoma and 60-sample hepatocellular carcinoma). For the colon cancer data set, the derived signatures of 20 sampling sets, composed of 10,000 training test sets, are fairly stable with 80% of top 50 and 69% to 93% of all predictor genes shared by all 20 signatures. These shared predictor genes include 48 cancer-related and 16 cancer-implicated genes, as well as 50% of the previously derived predictor genes. The derived signatures outperform all previously derived signatures in predicting colon cancer outcomes from an independent data set collected from the Stanford Microarray Database. Our method showed similar performance for the other two data sets, suggesting its usefulness in deriving stable signatures for biomarker and target discovery. [Cancer Res 2007;67(20):9996–10003]
Control of Androgen Receptor Signaling in Prostate Cancer by the Cochaperone Small Glutamine–Rich Tetratricopeptide Repeat Containing Protein α
Authors: Buchanan Grant , Ricciardelli Carmela , Harris Jonathan M. , Prescott Jennifer , Yu Zoe Chiao-Li , Jia Li , Butler Lisa M. , Marshall Villis R. , Scher Howard I. , Gerald William L. , Coetzee Gerhard A. , Tilley Wayne D. 
Published: October 2007

Abstract
Although the androgen receptor (AR) is accepted as the major determinant of prostate cancer cell survival throughout disease progression, it is currently unclear how the receptor sustains genomic signaling under conditions of systemic androgen ablation. Here, we show that the evolutionarily conserved Hsp70/Hsp90 cochaperone, small glutamine–rich tetratricopeptide repeat containing protein α (αSGT), interacts with the hinge region of the human AR in yeast and mammalian cells. Overexpression and RNA interference revealed that αSGT acts to (a) promote cytoplasmic compartmentalization of the AR, thereby silencing the receptors basal/ligand-independent transcriptional activity, (b) regulate the sensitivity of receptor signaling by androgens, and (c) limit the capacity of noncanonical ligands to induce AR agonist activity. Immunofluorescence, coactivator, and chromatin immunoprecipitation analyses strongly suggest that these effects of αSGT on AR function are mediated by interaction in the cytoplasm and are distinct from the receptors response to classic coregulators. Quantitative immunohistochemical analysis of αSGT and AR levels in a cohort of 32 primary and 64 metastatic human prostate cancers revealed dysregulation in the level of both proteins during disease progression. The significantly higher AR/αSGT ratio in metastatic samples is consistent with the sensitization of prostate tumor cells to androgen signaling with disease progression, particularly in a low-hormone environment. These findings implicate αSGT as a molecular rheostat of in vivo signaling competence by the AR, and provide new insight into the determinants of androgen sensitivity during prostate cancer progression. [Cancer Res 2007;67(20):10087–96]
Transcriptional Regulation of Human Protease-Activated Receptor 1: A Role for the Early Growth Response-1 Protein in Prostate Cancer
Authors: Salah Zaidoun , Maoz Myriam , Pizov Gallina , Bar-Shavit Rachel 
Published: October 2007

Abstract
Transcriptional regulation plays a central role in the molecular pathways underlying preferential cancer growth and metastasis. In the present study, we investigated the regulation of human protease-activated receptor 1 (hPar1) gene overexpression in the malignant androgen hormone-resistant phase. We found increased hPar1 RNA chain elongation and no change in message stability in cells with high levels of PAR1 expression, indicating that increased transcription is largely responsible for the overexpression of hPar1 in prostate tumor progression. Enforced expression of early growth response-1 (Egr-1) plasmid markedly enhanced luciferase activity driven by the hPar1 promoter. The neuroendocrine peptide bombesin significantly induced hPar1 expression and increased the ability of the cells to invade Matrigel, an effect abolished by expression of hPar1 small interfering RNA, showing the importance of hPAR1 in invasion. Bombesin also markedly enhanced Egr-1 binding to the hPar1 promoter in vivo and in vitro. These data suggest that bombesin enhances Egr-1 expression leading to increased hPar1 transcription, thereby increasing PAR1 expression and function. Immunohistostaining of prostate tissue biopsy specimens revealed a direct correlation between the degree of prostate cancer malignancy, PAR1 expression, and EGR-1 expression. Altogether, we show that transcriptional regulation of hPar1 in the aggressive hormone-resistant prostate cancer stage is controlled in part by the transcription factor Egr-1 and may play a central role in invasiveness, an important indicator of malignancy. [Cancer Res 2007;67(20):9835–43]
Lin-7C/VELI3/MALS-3: An Essential Component in Metastasis of Human Squamous Cell Carcinoma
Authors: Onda Takeshi , Uzawa Katsuhiro , Nakashima Dai , Saito Kengo , Iwadate Yasuo , Seki Naohiko , Shibahara Takahiko , Tanzawa Hideki 
Published: October 2007

Abstract
Using proteomic selection, functional verification, and clinical validation, we identified specific down-regulation of Lin-7C/VELI3/MALS-3 (Lin-7C), which marks oral squamous cell carcinoma (OSCC) metastasis. Despite a rarity of sequence variations in the Lin-7C gene in both primary OSCC and OSCC-derived cells, a high prevalence of hypermethylation was detected in the CpG island region that strongly correlated with its down-regulation. Inducible Lin-7C mRNA by experimental demethylation was found in all OSCC cells tested. Overexpression of the Lin-7C gene in an OSCC cell clone does not contribute to underproliferation but results in a noninvasive phenotype with elevated β-catenin expression. Experimental metastases in multiple organs of immunodeficient mice were inhibited in cells expressing Lin-7C. Finally, the Lin-7C expression status in primary tumors afforded significantly (P &lt; 0.001) high accuracy for predicting lymph node metastasis. These results establish Lin-7C as a novel target of early detection, prevention, and therapy for OSCC metastasis. [Cancer Res 2007;67(20):9643–8]
Genetic Determinants of Mitochondrial Response to Arsenic in YeastSaccharomyces cerevisiae
Authors: Vujcic Marija , Shroff Meghna , Singh Keshav K. 
Published: October 2007

AbstractWe have used yeast Saccharomyces cerevisiae as a tool to identify the importance of mitochondrial processes involved in arsenic-induced carcinogenicity in humans. We screened 466 single-gene knockout strains of yeast S. cerevisiae known to be involved in biogenesis of mitochondria for sodium arsenite (AsIII) and sodium arsenate (AsV) sensitivity. We identified 72 arsenite-sensitive and 81 arsenate-sensitive mutants. We categorized the identified mutants based on the various mitochondrial processes, including nucleic acid metabolism, oxidative phosphorylation, protein synthesis, and vacuolar acidification. We have identified 65 human orthologues to proteins involved in arsenite sensitivity and 3 human orthologues to arsenite resistance. Furthermore, 23 human orthologues to arsenate sensitivity and 20 human orthologues to arsenate-resistant proteins, including MSH3, COX10, GCSH, PPOX, and MTHFD1, were also identified. Using PathwayAssist software, we did cellular network analysis between identified mitochondrial proteins. Three types of interactions, (a) protein-protein interactions, (b) common transcriptional regulators, and (c) common target genes, were identified. We found that RTG (retrograde) genes involved in mitochondria-to-nucleus signaling regulate both arsenite sensitivity and resistance. Furthermore, our study revealed that ABF1, a multifunctional transcriptional factor, regulates genes involved in both arsenite and arsenate sensitivity and resistance. However, REB1 and RAP1 transcriptional regulators were common to only arsenate- and arsenite-sensitive genes, respectively. These studies indicate that multiple pathways involved in mitochondrial biogenesis protect yeast S. cerevisiae from arsenic-induced toxicity. Together, our studies suggest that evolutionary conserved mitochondrial networks identified in yeast S. cerevisiae must play an important role in arsenic-induced carcinogenesis in humans. [Cancer Res 2007;67(20):9740–9]