bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thymosin β4 Is a Determinant of the Transformed Phenotype and Invasiveness of S-Adenosylmethionine Decarboxylase–Transfected Fibroblasts
Authors: Nummela Pirjo , Yin Miao , Kielosto Mari , Leaner Virna , Birrer Michael J. , Hölttä Erkki 
Published: January 2006

Abstract
S-adenosylmethionine decarboxylase (AdoMetDC) is a key enzyme in the synthesis of polyamines essential for cell growth and proliferation. Its overexpression induces the transformation of murine fibroblasts in both sense and antisense orientations, yielding highly invasive tumors in nude mice. These cell lines hence provide a good model to study cell invasion. Here, the gene expression profiles of these cells were compared with their normal counterpart by microarray analyses (Incyte Genomics, Palo Alto, CA, and Affymetrix, Santa Clara, CA). Up-regulation of the actin sequestering molecule thymosin β4 was the most prominent change in both cell lines. Tetracycline-inducible expression of thymosin β4 antisense RNA caused a partial reversal of the transformed phenotype. Further, reversal of transformation by dominant-negative mutant of c-Jun (TAM67) caused reduction in thymosin β4 mRNA. Interestingly, a sponge toxin, latrunculin A, which inhibits the binding of thymosin β4 to actin, was found to profoundly affect the morphology and proliferation of the AdoMetDC transformants and to block their invasion in three-dimensional Matrigel. Thus, thymosin β4 is a determinant of AdoMetDC-induced transformed phenotype and invasiveness. Up-regulation of thymosin β4 was also found in ras-transformed fibroblasts and metastatic human melanoma cells. These data encourage testing latrunculin A–like and other agents interfering with thymosin β4 for treatment of thymosin β4–overexpressing tumors with high invasive and metastatic potential. (Cancer Res 2006; 66(2): 701-12)
Protein Kinase C-δ and Mitogen-Activated Protein/Extracellular Signal–Regulated Kinase-1 Control GLI Activation in Hedgehog Signaling
Authors: Riobo Natalia A. , Haines Gwendolyn M. , Emerson Charles P. 
Published: January 2006

Abstract
One third of all lethal cancers are associated with excessive activation of the Hedgehog (HH) pathway by mutations of its signaling components or by increased responsiveness of cells to the HH ligand. HH signaling through the GLI transcription factors leads to increased cell proliferation by up-regulation of the extracellular regulated kinase (ERK) pathway and by expression of S phase cyclins. In this study, we have tested the hypothesis that the HH pathway can integrate ERK signaling to modulate the activity of GLI. Using NIH 3T3 cells, we show that phorbol esters, acting through protein kinase C-δ (PKCδ) and mitogen-activated protein/extracellular signal–regulated kinase-1 (MEK-1), fully stimulate the transcriptional activity of endogenous and overexpressed GLI proteins, as assessed by GLI-luciferase reporter assays, and induce the expression of endogenous GLI1 and PTCH-1 target genes, as assessed by reverse transcription-PCR. Moreover, activation of GLI elicited by Sonic Hedgehog also requires PKCδ and MEK-1 function. Remarkably, coexpression of activated MEK-1 and GLI1 or GLI2 induced a 10-fold synergistic increase in GLI-luciferase activity that was totally blocked by PD98059. The NH2-terminal region of GLI1 (amino acids 1-130) is required for sensing the ERK pathway, as deletion of this domain produces active GLI1 protein with greatly reduced response to activation by MEK-1. Basic fibroblast growth factor activation of the ERK pathway also stimulated GLI1 activity through its NH2-terminal domain. Our results identify PKCδ and MEK-1 as essential, positive regulators of GLI-mediated HH signaling. Furthermore, our findings suggest that tumors with deregulated HH and ERK synergize to stimulate cell proliferation pathways. (Cancer Res 2006; 66(2): 839-45)
Chaperoning Function of Stress Protein grp170, a Member of the hsp70 Superfamily, Is Responsible for its Immunoadjuvant Activity
Authors: Park Jun-Eui , Facciponte John , Chen Xing , MacDonald Ian , Repasky Elizabeth A. , Manjili Masoud H. , Wang Xiang-Yang , Subjeck John R. 
Published: January 2006

AbstractWhen used as vaccines, tumor-derived stress proteins can elicit antitumor immune responses. For members of the hsp70 superfamily, like grp170, this seems to be due to (a) the chaperoning of antigenic peptide by the stress protein and (b) the binding of the stress protein to receptor(s) on antigen-presenting cells (APC) and subsequent antigen presentation. This suggests that domains exist on the stress protein for each function. In this study, we determine the ability of grp170 and its structural domains to (a) bind to and present melanoma-associated antigen gp100 to the immune system and (b) to bind to receptors on APCs. A direct correlation between chaperone function, binding to APCs in a receptor-like manner, and antitumor immunity was observed. Two mutants that share no common sequence, yet are both effective in their antitumor activities, compete with one another for APC binding. Studies of other members of the hsp70 superfamily, hsp110 and hsp70, or their domain deletion mutants, further confirmed that APC binding segregates with chaperoning function and not sequence. Therefore, these studies suggest that molecular chaperoning is involved in stress protein interactions with APCs, antigen binding, and in eliciting antitumor immunity, thus bridging this ancient function of stress proteins in prokaryotes to their ability to elicit immunity in higher organisms. (Cancer Res 2006; 66(2): 1161-8)
DNA Methylation Alterations in the Pancreatic Juice of Patients with Suspected Pancreatic Disease
Authors: Matsubayashi Hiroyuki , Canto Marcia , Sato Norihiro , Klein Alison , Abe Tadayoshi , Yamashita Keishi , Yeo Charles J. , Kalloo Anthony , Hruban Ralph , Goggins Michael 
Published: January 2006

AbstractMolecular markers of pancreatic neoplasia could aid in the evaluation of visible pancreatic lesions and indicate neoplasia invisible to imaging. We evaluated methylation-specific PCR (MSP) assays that detect aberrantly methylated DNA for their use as markers of pancreatic neoplasia. Methylation analysis was done on pancreatic juice collected endoscopically or surgically from 155 individuals with suspected pancreatic disease: 56 patients had pancreatic ductal adenocarcinoma, 17 had intraductal papillary mucinous neoplasms, 26 had symptomatic chronic pancreatitis, 12 controls lacked evidence of pancreatic disease, and 44 were asymptomatic individuals at increased risk of developing familial pancreatic cancer undergoing screening for pancreatic neoplasia. Pancreatic juice DNA was analyzed for promoter methylation using conventional MSP assays for 17 genes. For six genes, pancreatic juice methylation was quantified using real-time quantitative MSP (QMSP; Cyclin D2, FOXE1, NPTX2, ppENK, p16, and TFPI2). Quantifying pancreatic juice methylation using QMSP with a cutoff of &gt;1% methylated DNA could better predict pancreatic cancer than detecting methylation using conventional MSP. In the endoscopic group, 9 of 11 patients with pancreatic cancer, but none of 64 individuals without neoplasia had ≥1% methylation for two or more of the best five QMSP assays (82% sensitivity and 100% specificity; P &lt; 0.0001). The prevalence of pancreatic juice methylation in patients with chronic pancreatitis was less than in patients with pancreatic cancer but higher than in controls and similar to high-risk individuals. The detection and quantification of aberrantly methylated DNA in pancreatic juice is a promising approach to the diagnosis of pancreatic cancer. (Cancer Res 2006; 66(2): 1208-17)
Combined Inhibitory Effects of Curcumin and Phenethyl Isothiocyanate on the Growth of Human PC-3 Prostate Xenografts in Immunodeficient Mice
Authors: Khor Tin Oo , Keum Young-Sam , Lin Wen , Kim Jung-Hwan , Hu Rong , Shen Guoxiang , Xu Changjiang , Gopalakrishnan Avanthika , Reddy Bandaru , Zheng Xi , Conney Allan H. , Kong Ah-Ng Tony 
Published: January 2006

Abstract
Earlier studies using prostate cancer cells in culture showed that phenethyl isothiocyanate (PEITC) and curcumin have significant chemopreventive and possibly chemotherapeutic effects. However, their in vivo effects are still lacking. Hence, this study was undertaken to determine the possible in vivo efficacy of prostate cancer-prevention as well as cancer-therapeutic treatment by PEITC and curcumin alone or in combination. We evaluated the effects on tumor growth in vivo, using NCr immunodeficient (nu/nu) mice bearing s.c. xenografts of PC-3 human prostate cancer cells. Molecular biomarkers representing proliferation and apoptosis were determined. Continued i.p. injection of curcumin or PEITC (6 and 5 μmol; thrice a week for 28 days), beginning a day before tumor implantation significantly retarded the growth of PC-3 xenografts. Combination of i.p. administration of PEITC (2.5 μmol) and curcumin (3 μmol) showed stronger growth-inhibitory effects. Next, we evaluated the cancer-therapeutic potential of curcumin and PEITC in mice with well-established tumors, and the results showed that PEITC or curcumin alone had little effect, whereas combination of curcumin and PEITC significantly reduced the growth of PC-3 xenografts. Immunohistochemistry staining and Western blot analysis revealed that the inhibition of Akt and nuclear factor-κB signaling pathways could contribute to the inhibition of cell proliferation and induction of apoptosis. Taken together, our results show that PEITC and curcumin alone or in combination possess significant cancer-preventive activities in the PC-3 prostate tumor xenografts. Furthermore, we found that combination of PEITC and curcumin could be effective in the cancer-therapeutic treatment of prostate cancers. (Cancer Res 2006; 66(2): 613-21)
Angiostatin Is Directly Cytotoxic to Tumor Cells at Low Extracellular pH: A Mechanism Dependent on Cell Surface–Associated ATP Synthase
Authors: Chi Sulene L. , Pizzo Salvatore V. 
Published: January 2006

Abstract
Angiostatin, a proteolytic fragment of plasminogen, is a potent angiogenesis inhibitor able to suppress tumor growth and metastasis through inhibition of endothelial cell proliferation and migration. Previously, we showed that angiostatin binds and inhibits F1Fo ATP synthase on the endothelial cell surface and that anti-ATP synthase antibodies reduce endothelial cell proliferation. ATP synthase also occurs on the extracellular surface of a variety of cancer cells, where its function is as yet unknown. Here, we report that ATP synthase is present and active on the tumor cell surface, and angiostatin, or antibody directed against the catalytic β-subunit of ATP synthase, inhibits the activity of the synthase. We show that tumor cell surface ATP synthase is more active at low extracellular pH (pHe). Low pHe is a unique characteristic of the tumor microenvironment. Although the mechanism of action of angiostatin has not been fully elucidated, angiostatin treatment in combination with acidosis decreases the intracellular pH (pHi) of endothelial cells, leading to cell death. We also find that, at low pHe, angiostatin and anti-β-subunit antibody induce intracellular acidification of A549 cells, as well as a direct cytotoxicity that is absent in tumor cells with low levels of extracellular ATP synthase. These results establish angiostatin as an antitumorigenic and antiangiogenic agent through a mechanism implicating tumor cell surface ATP synthase. Furthermore, these data provide evidence that extracellular ATP synthase plays a role in regulating pHi in cells challenged by acidosis. (Cancer Res 2006; 66(2): 875-82)
Deregulation of the HOXA10 Homeobox Gene in Endometrial Carcinoma: Role in Epithelial-Mesenchymal Transition
Authors: Yoshida Hiroyuki , Broaddus Russell , Cheng Wenjun , Xie SuSu , Naora Honami 
Published: January 2006

Abstract
Homeobox genes encode transcription factors that control cell differentiation and play essential roles in developmental patterning. Increasing evidence indicates that many homeobox genes are aberrantly expressed in cancers, and that their deregulation significantly contributes to tumor progression. The homeobox gene HOXA10 controls uterine organogenesis during embryonic development and functional endometrial differentiation in the adult. We investigated whether HOXA10 expression is deregulated in endometrial carcinomas, and how counteracting this aberrant expression modifies tumor behavior. We found that down-regulation of HOXA10 expression in endometrial carcinomas strongly correlates with increased tumor grade and is associated with methylation of the HOXA10 promoter. Enforced expression of HOXA10 in endometrial carcinoma cells inhibited invasive behavior in vitro and tumor dissemination in nude mice. The inhibitory effect of HOXA10 on invasive behavior was attributable at least in part to the ability of HOXA10 to induce expression of the epithelial cell adhesion molecule E-cadherin by down-regulating expression of Snail, a repressor of E-cadherin gene transcription. These findings reveal a novel role for HOXA10 deregulation in the progression of endometrial carcinoma by promoting epithelial-mesenchymal transition. (Cancer Res 2006; 66(2): 889-97)
Tumor Cell Lines Expressing the Proteasome Subunit Isoform LMP7E1 Exhibit Immunoproteasome Deficiency
Authors: Heink Sylvia , Fricke Benjamin , Ludwig Daniela , Kloetzel Peter-M. , Krüger Elke 
Published: January 2006

Abstract
The immune system can recognize antigenic peptides derived from tumors by their presentation on MHC class I complexes to CTLs. Immunoproteasomes (i20S) can substantially enhance the MHC class I peptide repertoire, making down-regulation of i20S an important strategy of tumor cells in manipulating immune surveillance. Here, we report that human cancer cells express the nonfunctional immunosubunit-variant LMP7E1, in addition to, or instead of LMP7E2, in response to IFN-γ. This preferential expression of LMP7E1 and the consequent down-regulation of LMP7E2 results in i20S deficiency. The molecular explanation for this phenomenon is the incapacity of LMP7E1 to interact efficiently with the proteasome maturation protein, which regularly recruits LMP7E2 into nascent i20S precursor complexes. In contrast to previous reports, i20S formation in these cancer cells cannot be restored by IFN-γ treatment. However, expression of LMP7E2 in these cells restores the i20S-deficient phenotype. Thus, our data describe a novel mechanism that contributes to the process of oncogenesis. (Cancer Res 2006; 66(2):649-52)
OSI-930: A Novel Selective Inhibitor of Kit and Kinase Insert Domain Receptor Tyrosine Kinases with Antitumor Activity in Mouse Xenograft Models
Authors: Garton Andrew J. , Crew Andrew P.A. , Franklin Maryland , Cooke Andrew R. , Wynne Graham M. , Castaldo Linda , Kahler Jennifer , Winski Shannon L. , Franks April , Brown Eric N. , Bittner Mark A. , Keily John F. , Briner Paul , Hidden Chris , Srebernak Mary C. , Pirrit Carrie , O'Connor Matthew , Chan Anna , Vulevic Bojana , Henninger Dwight , Hart Karen , Sennello Regina , Li An-Hu , Zhang Tao , Richardson Frank , Emerson David L. , Castelhano Arlindo L. , Arnold Lee D. , Gibson Neil W. 
Published: January 2006

Abstract
OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain receptor (KDR), which is currently being evaluated in clinical studies. OSI-930 selectively inhibits Kit and KDR with similar potency in intact cells and also inhibits these targets in vivo following oral dosing. We have investigated the relationships between the potency observed in cell-based assays in vitro, the plasma exposure levels achieved following oral dosing, the time course of target inhibition in vivo, and antitumor activity of OSI-930 in tumor xenograft models. In the mutant Kit–expressing HMC-1 xenograft model, prolonged inhibition of Kit was achieved at oral doses between 10 and 50 mg/kg and this dose range was associated with antitumor activity. Similarly, prolonged inhibition of wild-type Kit in the NCI-H526 xenograft model was observed at oral doses of 100 to 200 mg/kg, which was the dose level associated with significant antitumor activity in this model as well as in the majority of other xenograft models tested. The data suggest that antitumor activity of OSI-930 in mouse xenograft models is observed at dose levels that maintain a significant level of inhibition of the molecular targets of OSI-930 for a prolonged period. Furthermore, pharmacokinetic evaluation of the plasma exposure levels of OSI-930 at these effective dose levels provides an estimate of the target plasma concentrations that may be required to achieve prolonged inhibition of Kit and KDR in humans and which would therefore be expected to yield a therapeutic benefit in future clinical evaluations of OSI-930. (Cancer Res 2006; 66(2): 1015-24)
Critical Roles for Polymerase ζ in Cellular Tolerance to Nitric Oxide–Induced DNA Damage
Authors: Wu Xiaohua , Takenaka Katsuya , Sonoda Eiichiro , Hochegger Helfrid , Kawanishi Shosuke , Kawamoto Takuo , Takeda Shunichi , Yamazoe Mitsuyoshi 
Published: January 2006

Abstract
Nitric oxide (NO), a signal transmitter involved in inflammation and regulation of smooth muscle and neurons, seems to cause mutagenesis, but its mechanisms have remained elusive. To gain an insight into NO-induced genotoxicity, we analyzed the effect of NO on a panel of chicken DT40 clones deficient in DNA repair pathways, including base and nucleotide excision repair, double-strand break repair, and translesion DNA synthesis (TLS). Our results show that cells deficient in Rev1 and Rev3, a subunit essential for DNA polymerase ζ (Polζ), are hypersensitive to killing by two chemical NO donors, spermine NONOate and S-nitroso-N-acetyl-penicillamine. Mitotic chromosomal analysis indicates that the hypersensitivity is caused by a significant increase in the level of induced chromosomal breaks. The data reveal the critical role of TLS polymerases in cellular tolerance to NO-induced DNA damage and suggest the contribution of these error-prone polymerases to accumulation of single base substitutions. (Cancer Res 2006; 66(2): 748-54)
Cranking the Immunologic Engine with Chemotherapy: Using Context to Drive Tumor Antigen Cross-Presentation towards Useful Antitumor Immunity
Authors: van der Most Robbert G. , Currie Andrew , Robinson Bruce W.S. , Lake Richard A. 
Published: January 2006

AbstractThis review shows how tumor antigen cross-presentation is affected by the major therapeutic modalities including chemotherapy, radiotherapy, and surgery. We argue that this process could affect the way that a tumor works as its own cellular vaccine, and that it is differentially modulated by the choice of treatment. (Cancer Res 2006; 66(2): 601-4)
The P2X7 Receptor Sustains the Growth of Human Neuroblastoma Cells through a Substance P–Dependent Mechanism
Authors: Raffaghello Lizzia , Chiozzi Paola , Falzoni Simonetta , Di Virgilio Francesco , Pistoia Vito 
Published: January 2006

AbstractP2X7 is a receptor for extracellular nucleotides expressed by different normal cell types. P2X7 triggering may result in stimulation of cell proliferation or induction of apoptosis depending on the level of activation. P2X7 expression and function in B-cell chronic lymphocytic leukemia has been shown to correlate with disease severity. Here, we have asked the question of whether P2X7 is expressed and functional in neuroblastoma, a pediatric tumor of neuroectodermal origin. P2X7 was detected both in primary neuroblastoma tumors and in neuroblastoma cell lines. In the latter cells, P2X7 stimulation by ATP was found to trigger (a) increased intracellular calcium fluxes, (b) plasma membrane depolarization, and (c) formation of a nonselective plasma membrane permeable pore. In contrast to the usual response typically observed in the majority of cell types, P2X7 in vitro stimulation did not induce caspase-3 activation or apoptosis of neuroblastoma cells but rather supported their proliferation. Growth stimulation was partially due to substance P release from nucleotide-activated neuroblastoma cells. Therefore, neuroblastoma cells seem to have molded P2X7 function to their advantage in two ways (i.e., by silencing P2X7 proapoptotic activity and by coupling P2X7 stimulation to release of locally acting trophic factors). (Cancer Res 2006; 66(2): 907-14)
Prostaglandin E2 Impairs CD4+ T Cell Activation by Inhibition of lck: Implications in Hodgkin's Lymphoma
Authors: Chemnitz Jens M. , Driesen Julia , Classen Sabine , Riley James L. , Debey Svenja , Beyer Marc , Popov Alexey , Zander Thomas , Schultze Joachim L. 
Published: January 2006

AbstractMany tumors, including Hodgkin's lymphoma, are associated with decreased cellular immunity and elevated levels of prostaglandin E2 (PGE2), a known inhibitor of CD4+ T cell activation, suggested to be involved in immune deviation in cancer. To address the molecular mechanisms tumor-derived PGE2 might have on primary human CD4+ T cells, we used a whole genome-based transcriptional approach and show that PGE2 severely limited changes of gene expression induced by signaling through the T cell receptor and CD28. This data suggests an interference of PGE2 at an early step of T cell receptor signaling: indeed, PGE2 stimulation of T cells leads to inactivation of lck and reduced phosphorylation of ZAP70. Antiapoptotic genes escaped PGE2-induced inhibition resulting in partial protection from apoptosis in response to irradiation or Fas-mediated signaling. As a functional consequence, PGE2-treated CD4+ T cells are arrested in the cell cycle associated with up-regulation of the cyclin/cyclin-dependent kinase inhibitor p27kip1. Most importantly, CD4+ T cells in Hodgkin's lymphoma show similar regulation of genes that were altered in vitro by PGE2 in T cells from healthy individuals. These data strongly suggest that PGE2 is an important factor leading to CD4+ T cell impairment observed in Hodgkin's lymphoma. (Cancer Res 2006; 66(2): 1114-22)
In utero Exposure of Mice to Dibenzo[a,l]Pyrene Produces Lymphoma in the Offspring: Role of the Aryl Hydrocarbon Receptor
Authors: Yu Zhen , Loehr Christiane V. , Fischer Kay A. , Louderback Mandy A. , Krueger Sharon K. , Dashwood Roderick H. , Kerkvliet Nancy I. , Pereira Clifford B. , Jennings-Gee Jamie E. , Dance Stephanie T. , Miller Mark Steven , Bailey George S. , Williams David E. 
Published: January 2006

Abstract
Lymphoma and leukemia are the most common cancers in children and young adults; in utero carcinogen exposure may contribute to the etiology of these cancers. A polycyclic aromatic hydrocarbon (PAH), dibenzo[a,l]pyrene (DBP), was given to pregnant mice (15 mg/kg body weight, gavage) on gestation day 17. Significant mortalities in offspring, beginning at 12 weeks of age, were observed due to an aggressive T-cell lymphoblastic lymphoma. Lymphocytes invaded numerous tissues. All mice surviving 10 months, exposed in utero to DBP, exhibited lung tumors; some mice also had liver tumors. To assess the role of the aryl hydrocarbon receptor (AHR) in DBP transplacental cancer, B6129SF1/J (AHRb-1/d, responsive) mice were crossed with strain 129S1/SvIm (AHRd/d, nonresponsive) to determine the effect of maternal and fetal AHR status on carcinogenesis. Offspring born to nonresponsive mothers had greater susceptibility to lymphoma, irrespective of offspring phenotype. However, when the mother was responsive, an AHR-responsive phenotype in offspring increased mortality by 2-fold. In DBP-induced lymphomas, no evidence was found for TP53, β-catenin, or Ki-ras mutations but lung adenomas of mice surviving to 10 months of age had mutations in Ki-ras codons 12 and 13. Lung adenomas exhibited a 50% decrease and a 35-fold increase in expression of Rb and p19/ARF mRNA, respectively. This is the first demonstration that transplacental exposure to an environmental PAH can induce a highly aggressive lymphoma in mice and raises the possibility that PAH exposures to pregnant women could contribute to similar cancers in children and young adults. (Cancer Res 2006; 66(2): 755-62)