bluuebunny/crossref_metadata_2025 huggingface dataset:
Spontaneous Development of Liver Tumors in the Absence of the Bile Acid Receptor Farnesoid X Receptor
Authors: Yang Fan , Huang Xiongfei , Yi Tangsheng , Yen Yun , Moore David D. , Huang Wendong
Published: February 2007

Farnesoid X receptor (FXR, NR1H4) is a member of the nuclear hormone receptor superfamily, which plays an essential role in regulating bile acid, lipid, and glucose homeostasis. Both male and female FXR−/− mice spontaneously developed liver tumors; however, no other tumors were developed after 15 months of age. In contrast, no liver tumors were observed in wild-type mice of the same age. Histologic analyses confirm that tumors were hepatocellular adenoma and carcinoma. Although there was no obvious tumor at ages 9 to 12 months, FXR−/− livers displayed prominent liver injury and inflammation. Strong labeling of apoptotic hepatocytes and liver damage–induced compensatory regeneration were observed. Deregulation of genes involved in bile acid homeostasis in FXR−/− mice was consistent with abnormal levels of bile acids presented in serum and liver. Genes involved in inflammation and cell cycle were up-regulated in aging FXR−/− mice but not in wild-type controls. Increasing the bile acid levels by feeding mice with a 0.2% cholic acid diet strongly promoted N-nitrosodiethylamine–initiated liver tumorigenesis, whereas lowering bile acid pool in FXR−/− mice by a 2% cholestyramine feeding significantly reduced the malignant lesions. Our results suggest an intriguing link between metabolic regulation and hepatocarcinogenesis. [Cancer Res 2007;67(3):863–7]
Knockdown of XAB2 Enhances All-Trans Retinoic Acid–Induced Cellular Differentiation in All-Trans Retinoic Acid–Sensitive and –Resistant Cancer Cells
Authors: Ohnuma-Ishikawa Kumiko , Morio Tomohiro , Yamada Takayuki , Sugawara Yuji , Ono Makoto , Nagasawa Masayuki , Yasuda Akio , Morimoto Chikao , Ohnuma Kei , Dang Nam H. , Hosoi Hajime , Verdin Eric , Mizutani Shuki
Published: February 2007

Xeroderma pigmentosum group A (XPA)–binding protein 2 (XAB2) is composed of 855 amino acids, contains 15 tetratricopeptide repeat motifs, and associates with Cockayne syndrome group A and B proteins and RNA polymerase II, as well as XPA. In vitro and in vivo studies showed that XAB2 is involved in pre-mRNA splicing, transcription, and transcription-coupled DNA repair, leading to preimplantation lethality, and is essential for mouse embryogenesis. Retinoids are effective for the treatment of preneoplastic diseases including xeroderma pigmentosum and other dermatologic diseases such as photoaging. We therefore focused on defining the effect of XAB2 on cellular differentiation in the presence of ATRA treatment. In the present study, we showed that overexpression of XAB2 inhibited ATRA-induced cellular differentiation in human rhabdomyosarcoma cell line, and that knockdown of XAB2 by small interfering RNA (siRNA) increased ATRA-sensitive cellular differentiation in the human promyelocytic leukemia cell line HL60 at both physiologic (10−9–10−8 mol/L) and therapeutic (10−7 mol/L) concentrations of ATRA. Moreover, we found that XAB2 was associated with retinoic acid receptor α (RARα) and histone deacetylase 3 in the nuclei. Finally, using siRNA against XAB2, we showed that the ATRA-resistant neuroblastoma cell line IMR-32 underwent cellular differentiation induced by ATRA at a therapeutic concentration (10−6 mol/L). These results strongly suggest that XAB2 is a component of the RAR corepressor complex with an inhibitory effect on ATRA-induced cellular differentiation and that XAB2 plays a role in ATRA-mediated cellular differentiation as an important aspect of cancer therapy. [Cancer Res 2007;67(3):1019–29]
DNA Methylation of Tumor Suppressor Genes in Clinical Remission Predicts the Relapse Risk in Acute Myeloid Leukemia
Authors: Agrawal Shuchi , Unterberg Matthias , Koschmieder Steffen , zur Stadt Udo , Brunnberg Uta , Verbeek Walter , Büchner Thomas , Berdel Wolfgang E. , Serve Hubert , Müller-Tidow Carsten
Published: February 2007

Epigenetic changes play an important role in leukemia pathogenesis. DNA methylation is among the most common alterations in leukemia. The potential role of DNA methylation as a biomarker in leukemia is unknown. In addition, the lack of molecular markers precludes minimal residual disease (MRD) estimation for most patients with hematologic malignancies. We analyzed the potential of aberrant DNA promoter methylation as a biomarker for MRD in acute leukemias. Quantitative real-time PCR methods with bisulfite-modified DNA were established to quantify MRD based on estrogen receptor α (ERα) and/or p15INK4B methylation. Methylation analyses were done in >370 DNA specimens from 180 acute leukemia patients and controls. Methylation of ERα and/or p15INK4B occurred frequently and specifically in acute leukemia but not in healthy controls or in nonmalignant hematologic diseases. Aberrant DNA methylation was detectable in >20% of leukemia patients during clinical remission. In pediatric acute lymphoblastic leukemia, methylation levels during clinical remission correlated closely with T-cell receptor/immunoglobulin MRD levels (r = +0.7, P < 0.01) and were associated with subsequent relapse. In acute myelogenous leukemia patients in clinical remission, increased methylation levels were associated with a high relapse risk and significantly reduced relapse-free survival (P = 0.003). Many patients with acute leukemia in clinical remission harbor increased levels of aberrant DNA methylation. Analysis of methylation MRD might be used as a novel biomarker for leukemia patients' relapse risk. [Cancer Res 2007;67(3):1370–7]
Growth Factor Stimulation Reduces Residual Quiescent Chronic Myelogenous Leukemia Progenitors Remaining after Imatinib Treatment
Authors: Holtz Melissa , Forman Stephen J. , Bhatia Ravi
Published: February 2007

The BCR/ABL tyrosine kinase inhibitor imatinib mesylate is highly effective in the treatment of chronic myelogenous leukemia (CML) but fails to eliminate all leukemia cells. Residual leukemia stem and progenitor cells persist in imatinib-responsive patients and may be a potential source of relapse. Previous studies indicate that imatinib preferentially targets dividing cells, and nondividing progenitor cells are resistant to imatinib-mediated apoptosis. We investigated whether growth factor stimulation of progenitor proliferation could reduce the number of residual nondividing cells remaining after imatinib treatment. CML and normal CD34+ cells were labeled with 5-(and 6-)-carboxyfluorescein diacetate succinimidyl ester (CFSE) to track cell division and cultured in low or high concentrations of growth factor to determine effects of growth factor stimulation on nondividing cells. High growth factor concentrations significantly enhanced CML proliferation with or without imatinib treatment and significantly reduced the number of viable, nondividing CFSE bright cells remaining after imatinib exposure. Stimulation with high growth factor before imatinib treatment further reduced the number of residual nondividing CML CD34+ cells. Importantly, clinically achievable concentrations of granulocyte macrophage colony-stimulating factor alone or in combination with granulocyte colony-stimulating factor also significantly reduced nondividing CML CD34+ cells. These results support the potential efficacy of growth factor stimulation in reducing the residual leukemia progenitor population in imatinib-treated patients. [Cancer Res 2007;67(3):1113–20]
DNAX Accessory Molecule-1 Mediated Recognition of Freshly Isolated Ovarian Carcinoma by Resting Natural Killer Cells
Authors: Carlsten Mattias , Björkström Niklas K. , Norell Håkan , Bryceson Yenan , van Hall Thorbald , Baumann Bettina C. , Hanson Mikael , Schedvins Kjell , Kiessling Rolf , Ljunggren Hans-Gustaf , Malmberg Karl-Johan
Published: February 2007

Although natural killer (NK) cells are well known for their ability to kill tumors, few studies have addressed the interactions between resting (nonactivated) NK cells and freshly isolated human tumors. Here, we show that human leukocyte antigen class Ilow tumor cells isolated directly from patients with advanced ovarian carcinoma trigger degranulation by resting allogeneic NK cells. This was paralleled by induction of granzyme B and caspase-6 activities in the tumor cells and significant tumor cell lysis. Ovarian carcinoma cells displayed ubiquitous expression of the DNAX accessory molecule-1 (DNAM-1) ligand PVR and sparse/heterogeneous expression of the NKG2D ligands MICA/MICB and ULBP1, ULBP2, and ULBP3. In line with the NK receptor ligand expression profiles, antibody-mediated blockade of activating receptor pathways revealed a dominant role for DNAM-1 and a complementary contribution of NKG2D signaling in tumor cell recognition. These results show that resting NK cells are capable of directly recognizing freshly isolated human tumor cells and identify ovarian carcinoma as a potential target for adoptive NK cell–based immunotherapy. [Cancer Res 2007;67(3):1317–25]
Bcl-2 Protects Endothelial Cells against γ-Radiation via a Raf-MEK-ERK-Survivin Signaling Pathway That Is Independent of Cytochrome c Release
Authors: Kumar Pawan , Coltas Ila K. , Kumar Bhavna , Chepeha Douglas B. , Bradford Carol R. , Polverini Peter J.
Published: February 2007

The Bcl-2 oncoprotein is a potent inhibitor of apoptosis and is overexpressed in a wide variety of malignancies. Until recently, it was generally accepted that Bcl-2 primarily mediates its antiapoptotic function by regulating cytochrome c release from mitochondria. However, more recent studies have shown that Bcl-2 is present on several intracellular membranes and mitochondria may not be the only site where Bcl-2 exercises its survival function. In this study, we investigated if Bcl-2 can protect endothelial cells against γ-radiation by a cytochrome c–independent signaling pathway. Human dermal microvascular endothelial cells (HDMEC), when exposed to γ-radiation, exhibited a time-dependent activation of caspase-3 that was associated with increased cytochrome c release from mitochondria. Bcl-2 expression in endothelial cells (HDMEC-Bcl-2) significantly inhibited irradiation-induced caspase-3 activation. However, Bcl-2–mediated inhibition of caspase-3 was significantly reversed by inhibition of the Raf-mitogen-activated protein kinase (MAPK)/extracellular signal–regulated kinase (ERK) kinase (MEK)-ERK pathway. Interestingly, caspase-3 activation in HDMEC-Bcl-2 cells was not associated with cytochrome c release. We also observed that endothelial cell Bcl-2 expression significantly increased the expression of survivin and murine double minute-2 (Mdm2) via the Raf-MEK-ERK pathway. Endothelial cells expressing Bcl-2 also inhibited γ-radiation–induced activation of p38 MAPK and p53 accumulation. Inhibition of p53 accumulation in HDMEC-Bcl-2 could be due to the enhanced expression of Mdm2 in these cells. Taken together, these results show three mechanisms by which Bcl-2 may mediate endothelial cell cytoprotection independently of cytochrome c release: (a) increased survivin expression, (b) inhibition of p53 accumulation, and (c) inhibition of p38 MAPK. [Cancer Res 2007;67(3):1193–202]
Antiadhesive Effects of GRN163L—An Oligonucleotide N3′→P5′ Thio-Phosphoramidate Targeting Telomerase
Authors: Jackson Shalmica R. , Zhu Chun-Hong , Paulson Vera , Watkins Linda , Dikmen Z. Gunnur , Gryaznov Sergei M. , Wright Woodring E. , Shay Jerry W.
Published: February 2007

We determined previously that a novel human telomerase RNA (hTR) antagonist, GRN163L, inhibited the tumorigenic potential of A549-luciferase (A549-luc) lung cancer cells in vitro and in vivo. Further studies revealed that A549-luc cells were also morphologically altered by GRN163L. A549-luc cells treated before cell attachment with a single dose of GRN163L only weakly attached to the substrate and remained rounded, whereas control mismatch-treated cells exhibited typical epitheloid appearance and adhesion properties. These morphologic changes were independent of hTR expression and telomerase inhibition and were unrelated to telomere length. This effect is dependent on the molecular properties of the lipid moiety, the phosphorothioate backbone, and the presence of triplet-G sequences within the GRN163L structure. Altered adhesion was manifested by a 50% reduction in rapid cellular attachment and a 3-fold decrease in total cell spreading surface area. Administration of a single dose of GRN163L (15 mg/kg) at the time of cell inoculation, using an in vivo model of lung cancer metastasis, resulted in significant reductions in tumor burden at days 13, 20, and 27 of tumor progression. Thus, the potent antimetastatic effects of GRN163L may be related, in part, to the antiadhesive effects of this novel cancer therapeutic conferred via specific structural determinants and that these effects are independent of telomerase inhibition or telomere shortening. [Cancer Res 2007;67(3):1121–9]
Tbx3 Is a Downstream Target of the Wnt/β-Catenin Pathway and a Critical Mediator of β-Catenin Survival Functions in Liver Cancer
Authors: Renard Claire-Angélique , Labalette Charlotte , Armengol Carolina , Cougot Delphine , Wei Yu , Cairo Stefano , Pineau Pascal , Neuveut Christine , de Reyniès Aurélien , Dejean Anne , Perret Christine , Buendia Marie-Annick
Published: February 2007

Tbx3 encodes a transcriptional repressor that is important for diverse patterning events during development, and Tbx3 mutation in humans causes the ulnar-mammary syndrome. Here, we describe the identification of Tbx3 in array-based search for genes downstream Wnt/β-catenin that are implicated in liver tumorigenesis. Overexpression of Tbx3 is closely associated with the mutational status of β-catenin in murine liver tumors induced by Myc as well as in human hepatocellular carcinomas and hepatoblastomas. Moreover, Tbx3 transcription is activated by ectopic expression of β-catenin in mouse liver and in human tumor cell lines. Evidence that Tbx3 transcription is directly regulated by β-catenin is provided by chromatin immunoprecipitation and reporter assays. Although HepG2 cells stably transfected with Tbx3 display moderately enhanced growth rate, the dominant negative mutant Tbx3-Y149S drastically inhibits hepatoma cell growth in vitro and in vivo. Moreover, small interfering RNAs (siRNA) directed against Tbx3 inhibit anchorage-independent growth of liver and colon carcinoma cells. We further show that inhibition of Tbx3 expression by specific siRNAs blocks β-catenin–mediated cell survival and renders cells sensitive to doxorubicin-induced apoptosis. Conversely, ectopic expression of Tbx3 inhibits apoptosis induced by β-catenin depletion. Marked overexpression of Tbx3 in a subset of hepatoblastomas is associated with chemotherapy-resistant phenotype and unfavorable patient outcome. These results reveal an unsuspected role of Tbx3 as a mediator of β-catenin activities on cell proliferation and survival and as an important player in liver tumorigenesis. [Cancer Res 2007;67(3):901–10]
RASSF1C, an Isoform of the Tumor Suppressor RASSF1A, Promotes the Accumulation of β-Catenin by Interacting with βTrCP
Authors: Estrabaud Emilie , Lassot Irina , Blot Guillaume , Le Rouzic Erwann , Tanchou Valérie , Quemeneur Eric , Daviet Laurent , Margottin-Goguet Florence , Benarous Richard
Published: February 2007

The Ras-association domain family 1 (RASSF1) gene has seven different isoforms; isoform A is a tumor-suppressor gene (RASSF1A). The promoter of RASSF1A is inactivated in many cancers, whereas the expression of another major isoform, RASSF1C, is not affected. Here, we show that RASSF1C, but not RASSF1A, interacts with βTrCP. Binding of RASSF1C to βTrCP involves serine 18 and serine 19 of the SS18GYXS19 motif present in RASSF1C but not in RASSF1A. This motif is reminiscent of the canonical phosphorylation motif recognized by βTrCP; however, surprisingly, the association between RASSF1C and βTrCP does not occur via the βTrCP substrate binding domain, the WD40 repeats. Overexpression of RASSF1C, but not of RASSF1A, resulted in accumulation and transcriptional activation of the β-catenin oncogene, due to inhibition of its βTrCP-mediated degradation. Silencing of RASSF1A by small interfering RNA was sufficient for β-catenin to accumulate, whereas silencing of both RASSF1A and RASSF1C had no effect. Thus, RASSF1A and RASSF1C have opposite effects on β-catenin degradation. Our results suggest that RASSF1C expression in the absence of RASSF1A could play a role in tumorigenesis. [Cancer Res 2007;67(3):1054–61]
Ability to Acquire Drug Resistance Arises Early during the Tumorigenesis Process
Authors: Yagüe Ernesto , Arance Ana , Kubitza Loïc , O'Hare Michael , Jat Parmjit , Ogilvie Caroline M. , Hart Ian R. , Higgins Christopher F. , Raguz Selina
Published: February 2007

Resistance to chemotherapy is one of the principal causes of cancer mortality and is generally considered a late event in tumor progression. Although cellular models of drug resistance have been useful in identifying the molecules responsible for conferring drug resistance, most of these cellular models are derived from cell lines isolated from patients at a late stage in cancer progression. To ask at which stage in the tumorigenic progression does the cell gain the ability to acquire drug resistance, we generated a series of pretumorigenic and tumorigenic cells from human embryonic skin fibroblasts by introducing, sequentially, the catalytic subunit of telomerase, SV40 large T and small T oncoproteins, and an oncogenic form of ras. We show that the ability to acquire multidrug resistance (MDR) can arise before the malignant transformation stage. The minimal set of changes necessary to obtain pretumorigenic drug-resistant cells is expression of telomerase and inactivation of p53 and pRb. Thus, the pathways inactivated during tumorigenesis also confer the ability to acquire drug resistance. Microarray and functional studies of drug-resistant pretumorigenic cells indicate that the drug efflux pump P-glycoprotein is responsible for the MDR phenotype in this pretumorigenic cell model. [Cancer Res 2007;67(3):1130–7]
Depleting Intratumoral CD4+CD25+ Regulatory T Cells via FasL Protein Transfer Enhances the Therapeutic Efficacy of Adoptive T Cell Transfer
Authors: Chen Aoshuang , Liu Shanrong , Park David , Kang Youmin , Zheng Guoxing
Published: February 2007

One strategy for improving adoptive therapy is preconditioning the host immune environment by depleting CD4+CD25+ regulatory T cells (Treg) suppressive to antitumor responses. Given that Treg increase, or selectively accumulate, within tumors and are sensitive to FasL-mediated apoptosis, we test here the hypothesis that inducing apoptosis of intratumoral Treg using FasL may improve adoptive T cell therapy. We show that FasL applied intratumorally via protein transfer decreases intratumoral Treg via inducing apoptosis in these cells. Significantly, we show that the use of FasL prior to the infusion of tumor-reactive CD8+ T cells enhances the therapeutic efficacy of adoptive T cell transfer against established tumors, which is mediated by persistent, systemic antitumor immunity. Intratumoral FasL protein transfer also results in neutrophil infiltration of tumor. However, we show that intratumoral immunodepletion of neutrophils does not abolish the effect of FasL on adoptive transfer. Rather, the effect of FasL is completely abolished by cotransfer of Treg, isolated from the tumor-draining lymph nodes. Hence, our study shows for the first time that using FasL to predeplete intratumoral Treg provides a useful means for optimizing adoptive therapy. [Cancer Res 2007;67(3):1291–8]
Demethylation-Linked Activation of Urokinase Plasminogen Activator Is Involved in Progression of Prostate Cancer
Authors: Pulukuri Sai Murali Krishna , Estes Norman , Patel Jitendra , Rao Jasti S.
Published: February 2007

Increased expression of urokinase plasminogen activator (uPA) has been reported in various malignancies including prostate cancer. However, the mechanism by which uPA is abnormally expressed in prostate cancer remains elusive. Here, we show that uPA is aberrantly expressed in a high percentage of human prostate cancer tissues but rarely expressed either in tumor-matched nonneoplastic adjacent tissues or benign prostatic hyperplasia samples. This aberrant expression is associated with cancer-linked demethylation of the uPA promoter. Furthermore, treatment with demethylation inhibitor S-adenosylmethionine or stable expression of uPA short hairpin RNA significantly inhibits uPA expression and tumor cell invasion in vitro and tumor growth and incidence of lung metastasis in vivo. Collectively, these findings strongly suggest that DNA demethylation is a common mechanism underlying the abnormal expression of uPA and is a critical contributing factor to the malignant progression of human prostate tumors. [Cancer Res 2007;67(3):930–9]
Modulation of Telomerase Promoter Tumor Selectivity in the Context of Oncolytic Adenoviruses
Authors: Bilsland Alan E. , Merron Andrew , Vassaux Georges , Keith W. Nicol
Published: February 2007

The telomerase RNA (hTR) and reverse transcriptase (hTERT) promoters are active in most cancer cells, but not in normal cells, and are useful for transcriptional targeting in gene therapy models. Telomerase-specific conditionally replicating adenoviruses (CRAd) are attractive vectors because they should selectively lyse tumor cells. Here, we compare CRAds, in which either the hTR or hTERT promoter controls expression of the adenovirus E1A gene. In replication-defective reporter adenoviruses, the hTR promoter was up to 57-fold stronger in cancer cells than normal cells and up to 49-fold stronger than hTERT. In normal cells, hTERT promoter activity was essentially absent. Doses of telomerase-specific CRAds between 1.8 and 28 infectious units per cell efficiently killed cancer cells, but normal cells required higher doses. However, CRAd DNA replication and E1A expression were detected in both cancer and normal cells. Overall, tumor specificity of the CRAds was limited compared with nonreplicating vectors. Surprisingly, both CRAds expressed similar E1A levels and functional behavior, despite known differentials between hTR and hTERT promoter activities, suggesting that the promoters are deregulated. Rapid amplification of cDNA ends analysis of hTR-/hTERT-E1A transcripts ruled out cryptic transcription from the vector backbone. Blocking E1A translation partially restored the hTR-/hTERT-E1A mRNA differential, evidencing feedback regulation by E1A. [Cancer Res 2007;67(3):1299–307]
Human T-Cell Leukemia Virus Oncoprotein Tax Represses Nuclear Receptor–Dependent Transcription by Targeting Coactivator TAX1BP1
Authors: Chin King-Tung , Chun Abel C.S. , Ching Yick-Pang , Jeang Kuan-Teh , Jin Dong-Yan
Published: February 2007

Human T-cell leukemia virus type 1 oncoprotein Tax is a transcriptional regulator that interacts with a large number of host cell factors. Here, we report the novel characterization of the interaction of Tax with a human cell protein named Tax1-binding protein 1 (TAX1BP1). We show that TAX1BP1 is a nuclear receptor coactivator that forms a complex with the glucocorticoid receptor. TAX1BP1 and Tax colocalize into intranuclear speckles that partially overlap with but are not identical to the PML oncogenic domains. Tax binds TAX1BP1 directly, induces the dissociation of TAX1BP1 from the glucocorticoid receptor–containing protein complex, and represses the coactivator function of TAX1BP1. Genetic knockout of Tax1bp1 in mice abrogates the influence of Tax on the activation of nuclear receptors. We propose that Tax-TAX1BP1 interaction mechanistically explains the previously reported repression of nuclear receptor activity by Tax. [Cancer Res 2007;67(3):1072–81]
Tamoxifen Induces Oxidative Stress and Mitochondrial Apoptosis via Stimulating Mitochondrial Nitric Oxide Synthase
Authors: Nazarewicz Rafal R. , Zenebe Woineshet J. , Parihar Arti , Larson Sarah K. , Alidema Enver , Choi Jiho , Ghafourifar Pedram
Published: February 2007

Tamoxifen is an anticancer drug that induces oxidative stress and apoptosis via mitochondria-dependent and nitric oxide (NO)–dependent pathways. The present report shows that tamoxifen increases intramitochondrial ionized Ca2+ concentration and stimulates mitochondrial NO synthase (mtNOS) activity in the mitochondria from rat liver and human breast cancer MCF-7 cells. By stimulating mtNOS, tamoxifen hampers mitochondrial respiration, releases cytochrome c, elevates mitochondrial lipid peroxidation, increases protein tyrosine nitration of certain mitochondrial proteins, decreases the catalytic activity of succinyl-CoA:3-oxoacid CoA-transferase, and induces aggregation of mitochondria. The present report suggests a critical role for mtNOS in apoptosis induced by tamoxifen. [Cancer Res 2007;67(3):1282–90]
The Type III Transforming Growth Factor-β Receptor as a Novel Tumor Suppressor Gene in Prostate Cancer
Authors: Turley Ryan S. , Finger Elizabeth C. , Hempel Nadine , How Tam , Fields Timothy A. , Blobe Gerard C.
Published: February 2007

The transforming growth factor-β (TGF-β) signaling pathway has an important role in regulating normal prostate epithelium, inhibiting proliferation, differentiation, and both androgen deprivation–induced and androgen-independent apoptosis. During prostate cancer formation, most prostate cancer cells become resistant to these homeostatic effects of TGF-β. Although the loss of expression of either the type I (TβRI) or type II (TβRII) TGF-β receptor has been documented in ∼30% of prostate cancers, most prostate cancers become TGF-β resistant without mutation or deletion of TβRI, TβRII, or Smads2, 3, and 4, and thus, the mechanism of resistance remains to be defined. Here, we show that type III TGF-β receptor (TβRIII or betaglycan) expression is decreased or lost in the majority of human prostate cancers as compared with benign prostate tissue at both the mRNA and protein level. Loss of TβRIII expression correlates with advancing tumor stage and a higher probability of prostate-specific antigen (PSA) recurrence, suggesting a role in prostate cancer progression. The loss of TβRIII expression is mediated by the loss of heterozygosity at the TGFBR3 genomic locus and epigenetic regulation of the TβRIII promoter. Functionally, restoring TβRIII expression in prostate cancer cells potently decreases cell motility and cell invasion through Matrigel in vitro and prostate tumorigenicity in vivo. Taken together, these studies define the loss of TβRIII expression as a common event in human prostate cancer and suggest that this loss is important for prostate cancer progression through effects on cell motility, invasiveness, and tumorigenicity. [Cancer Res 2007;67(3):1090–8]
BRCA1 Ubiquitinates RPB8 in Response to DNA Damage
Authors: Wu Wenwen , Nishikawa Hiroyuki , Hayami Ryosuke , Sato Ko , Honda Akeri , Aratani Satoko , Nakajima Toshihiro , Fukuda Mamoru , Ohta Tomohiko
Published: February 2007

The breast and ovarian tumor suppressor BRCA1 catalyzes untraditional polyubiquitin chains that could be a signal for processes other than proteolysis. However, despite intense investigations, the mechanisms regulated by the enzyme activity remain only partially understood. Here, we report that BRCA1-BARD1 mediates polyubiquitination of RPB8, a common subunit of RNA polymerases, in response to DNA damage. A proteomics screen identified RPB8 as a protein modified after epirubicin treatment in BRCA1-dependent manner. RPB8 interacted with BRCA1-BARD1 and was polyubiquitinated by BRCA1-BARD1 in vivo and in vitro. BRCA1-BARD1 did not destabilize RPB8 in vivo but rather caused an increase in the amount of soluble RPB8. Importantly, RPB8 was polyubiquitinated immediately after UV irradiation in a manner sensitive to BRCA1 knockdown by RNA interference. Substitution of five lysine residues of RPB8 with arginine residues abolished its ability to be ubiquitinated while preserving its polymerase activity. HeLa cell lines stably expressing this ubiquitin-resistant form of RPB8 exhibited UV hypersensitivity accompanied by up-regulated caspase activity. Our findings suggest that ubiquitination of a common subunit of RNA polymerases is a mechanism underlying BRCA1-dependent cell survival after DNA damage. [Cancer Res 2007;67(3):951–8]
Breast Cancer: Should Gastrointestinal Bacteria Be on Our Radar Screen?
Authors: Rao Varada P. , Poutahidis Theofilos , Fox James G. , Erdman Susan E.
Published: February 2007

Anti-inflammatory drugs and antibiotics alter the risk of breast cancer in women, but roles for bacteria and inflammation in breast malignancies are poorly understood. A recent study in mice suggests that intestinal bacteria can trigger mammary carcinoma. The mechanisms involved in this effect suggest that dysregulated host immune responses to enteric bacteria can influence the development of extraintestinal cancers, highlighting the opportunities for prevention and treatment aimed at promoting intestinal homeostasis. [Cancer Res 2007;67(3):847–50]
Pten Loss in the Mouse Thyroid Causes Goiter and Follicular Adenomas: Insights into Thyroid Function and Cowden Disease Pathogenesis
Authors: Yeager Nicole , Klein-Szanto Andres , Kimura Shioko , Di Cristofano Antonio
Published: February 2007

Inactivation and silencing of the tumor suppressor PTEN are found in many different epithelial tumors, including thyroid neoplasia. Cowden Disease patients, who harbor germ-line PTEN mutations, often display thyroid abnormalities, including multinodular goiter and follicular adenomas, and are at increased risk of thyroid cancer. To gain insights into the role PTEN plays in thyroid function and disease, we have generated a mouse strain, in which Cre-mediated recombination is used to specifically delete Pten in the thyrocytes. We found that Pten mutant mice develop diffuse goiter characterized by extremely enlarged follicles, in the presence of normal thyroid-stimulating hormone and T4 hormone levels. Loss of Pten resulted in a significant increase in the thyrocyte proliferative index, which was more prominent in the female mice, and in increased cell density in the female thyroid glands. Surprisingly, goitrogen treatment did not cause a substantial increase of the mutant thyroid size and increased only to some extent the proliferation index of the female thyrocytes, suggesting that a relevant part of the thyroid-stimulating hormone–induced proliferation signals are funneled through the phosphatidylinositol-3-kinase (PI3K)/Akt cascade. Although complete loss of Pten was not sufficient to cause invasive tumors, over two thirds of the mutant females developed follicular adenomas by 10 months of age, showing that loss of Pten renders the thyroid highly susceptible to neoplastic transformation through mechanisms that include increased thyrocyte proliferation. Our findings show that constitutive activation of the PI3K/Akt cascade is sufficient to stimulate continuous autonomous growth and provide novel clues to the pathogenesis of Cowden Disease and sporadic nontoxic goiter. [Cancer Res 2007;67(3):959–66]
Establishment of a New Interleukin-6 (IL-6) Receptor Inhibitor Applicable to the Gene Therapy for IL-6–Dependent Tumor
Authors: Yoshio-Hoshino Naoko , Adachi Yasuo , Aoki Chieko , Pereboev Alexander , Curiel David T. , Nishimoto Norihiro
Published: February 2007

Interleukin-6 (IL-6) is a key molecule involved in the pathogenesis of several inflammatory diseases and malignancies. Treatments that inhibit IL-6 mitigate the clinical conditions of such diseases. Here, we report on the development of a new receptor inhibitor of IL-6 (NRI) by genetically engineering tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody which specifically blocks IL-6 signaling. This NRI consists of VH and VL of tocilizumab in a single-chain fragment format dimerized by fusing to the Fc portion of human immunoglobulin G1. The binding activity to IL-6 receptor and the biological activity of the purified NRI were found to be similar to those of parental tocilizumab. Because NRI is encoded on a single gene, it is easily applicable to a gene delivery system using virus vehicles. We administered an adenovirus vector encoding NRI to mouse i.p. and monitored the serum NRI level and growth reduction property on S6B45, an IL-6–dependent multiple myeloma cell line, in vivo. Adequate amount of the serum NRI level to exert anti-IL-6 action could be obtained by the NRI gene introduction combined with adenovirus gene delivery, and this treatment inhibited the in vivo S6B45 cell growth significantly. These findings indicate that NRI is a promising agent applicable to the therapeutic gene delivery approach for IL-6–driven diseases. [Cancer Res 2007;67(3):871–5]
Differential Patterns of MicroRNA Expression in Neuroblastoma Are Correlated with Prognosis, Differentiation, and Apoptosis
Authors: Chen Yongxin , Stallings Raymond L.
Published: February 2007

Neuroblastoma accounts for 15% of pediatric cancer deaths, and although a few protein-coding genes, such as MYCN, are involved with aggressive pathogenicity, the identification of novel biological targets for therapeutic intervention is still a necessary prerequisite for improving patient survival. Expression profiling of 157 microRNA (miRNA) loci in 35 primary neuroblastoma tumors indicates that 32 loci are differentially expressed in favorable and unfavorable tumor subtypes, indicating a potential role of miRNAs in neuroblastoma pathogenesis. Many of these loci are significantly underexpressed in tumors with MYCN amplification, which have particularly poor prognoses. Interestingly, we found that miRNA expression levels substantially change in a MYCN-amplified cell line following exposure to retinoic acid, a compound which is well known for causing reductions in MYCN expression and for inducing neuroblastoma cell lines to undergo neuronal differentiation. We also show that small interfering RNA inhibition of MYCN by itself causes similar alterations in the expression of miRNA loci. In vitro functional studies of one locus, miR-184, indicate that it plays a significant role in apoptosis. The association of experimentally induced alterations of miRNA expression in neuroblastoma cell lines with differentiation or apoptosis leads us to conclude that these loci play important roles in neuroblastoma pathogenesis. We further suggest that MYCN may mediate a tumorigenic effect, in part, through directly or indirectly regulating the expression of miRNAs that are involved with neural cell differentiation and/or apoptosis, warranting substantial further studies of miRNAs as potential therapeutic targets. [Cancer Res 2007;67(3):976–83]
Therapy-Induced Tumor Immunosurveillance Involves IFN-Producing Killer Dendritic Cells
Authors: Ullrich Evelyn , Bonmort Mathieu , Mignot Grégoire , Chaput Nathalie , Taieb Julien , Ménard Cédric , Viaud Sophie , Tursz Thomas , Kroemer Guido , Zitvogel Laurence
Published: February 2007

A unique class of IFN-producing killer dendritic cells (IKDC) resembling natural killer cells has been defined that can recognize and lyse tumor cells through a tumor necrosis factor–related apoptosis-inducing ligand–dependent mechanism. IKDC may mediate the host-dependent antitumor activity of Gleevec/STI571 and other therapeutics that can inhibit the c-kit tyrosine kinase. IKDC represent an important new component of the innate immune system responding to cancer. [Cancer Res 2007;67(3):851–3]
Risks for Familial and Contralateral Breast Cancer Interact Multiplicatively and Cause a High Risk
Authors: Hemminki Kari , Ji Jianguang , Försti Asta
Published: February 2007

The reasons for the high risk of contralateral breast cancer are not understood, although polygenic mechanisms have been suggested to be involved. The nationwide Swedish Family-Cancer Database was used to examine the interaction of the risks for contralateral and familial cancer. Relative risks were separately determined for contralateral and familial breast cancers, and these were tested for additive and multiplicative interactions. The Database contained information on 102,176 first breast cancers. Familial risk for breast cancer was 1.76 and the risk for contralateral breast cancer was 3.40, or 5.80 when extrapolated to two breasts. When women had a family history, the risk for contralateral breast cancer was remarkably high, 5.48, or 9.96 when the risk was extrapolated to two breasts, almost identical with 10.21, which was predicted by the multiplicative model. Although the data do not rule out polygenic mechanisms, they suggest that epigenetic imprinting events may be involved for the contralateral breast cancer. [Cancer Res 2007;67(3):868–70]
Deregulated CDC25A Expression Promotes Mammary Tumorigenesis with Genomic Instability
Authors: Ray Dipankar , Terao Yasuhisa , Fuhrken Peter G. , Ma Zhi-Qing , DeMayo Francesco J. , Christov Konstantin , Heerema Nyla A. , Franks Roberta , Tsai Sophia Y. , Papoutsakis Eleftherios T. , Kiyokawa Hiroaki
Published: February 2007

Checkpoint pathways help cells maintain genomic integrity, delaying cell cycle progression in response to various risks of fidelity, such as genotoxic stresses, compromised DNA replication, and impaired spindle control. Cancer cells frequently exhibit genomic instability, and recent studies showed that checkpoint pathways are likely to serve as a tumor-suppressive barrier in vivo. The cell cycle–promoting phosphatase CDC25A is an activator of cyclin-dependent kinases and one of the downstream targets for the CHK1-mediated checkpoint pathway. Whereas CDC25A overexpression is observed in various human cancer tissues, it has not been determined whether deregulated CDC25A expression triggers or promotes tumorigenesis in vivo. Here, we show that transgenic expression of CDC25A cooperates markedly with oncogenic ras or neu in murine mammary tumorigenesis. MMTV-CDC25A transgenic mice exhibit alveolar hyperplasia in the mammary tissue but do not develop spontaneous mammary tumors. The MMTV-CDC25A transgene markedly shortens latency of tumorigenesis in MMTV-ras mice. The MMTV-CDC25A transgene also accelerates tumor growth in MMTV-neu mice with apparent cell cycle miscoordination. CDC25A-overexpressing tumors, which invade more aggressively, exhibit various chromosomal aberrations on fragile regions, including the mouse counterpart of human 1p31-36, according to array-based comparative genomic hybridization and karyotyping. The chromosomal aberrations account for substantial changes in gene expression profile rendered by transgenic expression of CDC25A, including down-regulation of Trp73. These data indicate that deregulated control of cellular CDC25A levels leads to in vivo genomic instability, which cooperates with the neu-ras oncogenic pathway in mammary tumorigenesis. [Cancer Res 2007;67(3):984–91]
Culture and Cognitive Development: Giyoo Hatano’s Insights and the Questions They Open
Authors: Goodnow Jacqueline J. , Peterson Candi , Lawrence Jeanette A.
Published: February 2007

To bring out Giyoo Hatano’s contributions to the understanding of culture and cognitive development, we note first his special style – thoughtful, inventive, and always focused on central issues and on combining theory with data – and then, for three areas, some of the conceptual advances he proposed. The areas have to do with ties between cognitive and social development (links between skills and identity provide the selected advance), the nature of expertise (adaptive expertise is the selected advance), and the place of what is ‘naturally given’ (selected is the emphasis on specifying what is biologically given, what is culturally ready-to-hand, and their interconnections). He will be missed both as a scholar and a person.
Conceptual Change and Education
Authors: Vosniadou Stella
Published: February 2007

In order to understand the advanced, scientific concepts of the various disciplines, students cannot rely on the simple memorization of facts. They must learn how to restructure their naive, intuitive theories based on everyday experience and lay culture. In other words, they must undergo profound conceptual change. This type of conceptual change cannot be achieved without systematic instruction that takes into consideration both individual, constructivist and sociocultural factors. Teachers must find ways to enhance individual students’ motivation by creating a social classroom environment that supports the creation of intentional learners who can engage in the deep and enduring comprehension activities required for the revision of conceptual knowledge.
Intercultural Adaptive Expertise: Explicit and Implicit Lessons from Dr. Hatano
Authors: Lin Xiaodong , Schwartz Daniel L. , Bransford John
Published: February 2007

Giyoo Hatano was an international scholar – an adaptive expert himself. His creative methodologies and theoretical insights have enriched the work of researchers in many countries. How Hatano lived his life and treated others provides enriching insights as well. In this essay, we focus on ‘adaptive expertise’, one of Giyoo Hatano’s major contributions to the field. We explore both the explicit information he provided about adaptive expertise and the implicit information gleaned from how he lived his life and collaborated with people around the world. By describing Giyoo Hatano’s own qualities as an intercultural adaptive expert, we can begin to explore conditions for promoting those qualities.
What Is Important for Ultrasound Evaluation of Occult Metastatic Lymph Nodes in Laryngeal Cancer: Size, Shape, Vascularity or Cytological Findings?
Authors: Čvorović L. , Milutinović Z. , Štrbac M. , Markovski S.
Published: February 2007

The assessment of the status of the cervical lymph nodes in patients with a squamous cell carcinoma of the head and neck is still one of the most challenging diagnostic problems. We evaluated ultrasonography criteria with respect to their value for comparative determination of occult metastatic lymph nodes in laryngeal carcinoma. A prospective study was performed in 60 patients with laryngeal squamous cell carcinoma without enlarged neck nodes on CT scan. We used recommended sonography criteria for size, shape and vascularity for distinguishing metastatic and nonmetastatic nodes preoperatively and compared them with cytological and histopathological investigations. Fifty-two of 144 lymph nodes were involved with metastasis on histopathological examination. Respective values for ultrasound-guided fine needle aspiration cytology (USg FNAC) showed high sensitivity, specificity, positive and negative predictive values and accuracy (92, 100, 100, 96, and 97%, respectively). The size, shape and vascularity showed significantly lower values of these statistic parameters. USg FNAC is useful for preoperative evaluation of the neck, as the most reliable, inexpensive and easily available method. It is essential for diagnosis, staging and therapy choices.
Critical Role of Monocyte Chemoattractant Protein-1/CC Chemokine Ligand 2 in the Pathogenesis of Ischemic Cardiomyopathy
Authors: Frangogiannis Nikolaos G. , Dewald Oliver , Xia Ying , Ren Guofeng , Haudek Sandra , Leucker Thorsten , Kraemer Daniela , Taffet George , Rollins Barrett J. , Entman Mark L.
Published: February 2007

Background—

Cardiac interstitial fibrosis plays an important role in the pathogenesis of ischemic cardiomyopathy, contributing to systolic and diastolic dysfunction. We have recently developed a mouse model of fibrotic noninfarctive cardiomyopathy due to brief repetitive myocardial ischemia and reperfusion. In this model, fibrotic changes are preceded by marked and selective induction of the CC chemokine monocyte chemoattractant protein-1 (MCP-1). We hypothesized that MCP-1 may mediate fibrotic remodeling through recruitment of mononuclear cells and direct effects on fibroblasts.

Methods and Results—

Wild-type (WT) and MCP-1-null mice underwent daily 15-minute coronary occlusions followed by reperfusion. Additional WT animals received intraperitoneal injections of a neutralizing anti-MCP-1 antibody after the end of each ischemic episode. Hearts were examined echocardiographically and processed for histological and RNA studies. WT mice undergoing repetitive brief myocardial ischemia and reperfusion protocols exhibited macrophage infiltration after 3 to 5 days and marked interstitial fibrosis in the ischemic area after 7 days, accompanied by ventricular dysfunction. MCP-1-null mice had markedly diminished interstitial fibrosis, lower macrophage infiltration, and attenuated ventricular dysfunction compared with WT animals. MCP-1 neutralization also inhibited interstitial fibrosis, decreasing left ventricular dysfunction and regional hypocontractility. Cardiac myofibroblasts isolated from WT but not from MCP-1-null animals undergoing repetitive myocardial ischemia and reperfusion demonstrated enhanced proliferative capacity. However, MCP-1 stimulation did not induce cardiac myofibroblast proliferation and did not alter expression of fibrosis-associated genes.

Conclusions—

Defective MCP-1 signaling inhibits the development of ischemic fibrotic cardiomyopathy in mice. The profibrotic actions of MCP-1 are associated with decreased macrophage recruitment and may not involve direct effects on cardiac fibroblasts.
Accounting for Fluorine: Production, Use, and Loss
Authors: Villalba Gara , Ayres Robert U. , Schroder Hans
Published: February 2007

Fluorine is an essential element to human health and to the chemical industry. In spite of our dependence on fluorine and fluorine compounds, we have yet to learn to use them wisely. Our fluorine history, which spans about a hundred years, has had negative effects such as hydrofluoric acid pollution caused by aluminum smelters and ozone depletion due to chlorofluorocarbon (CFC) emissions. More recent concerns center on greenhouse effects from CFCs, hydrofluorocarbons (HFCs), and sulfur hexafluoride (SF6). In this article we note also that fluorine is a nonrenewable resource that is nonsubstitutable for many purposes. This article tracks fluorine from sources through conversion processes to end uses, most of which are dissipative. We present a stock‐flow model of the fluorine system. Based on this model we consider some possible measures that could be taken to increase the degree of recovery. To mention one example, a large percentage of the world demand for fluorspar could be supplied by the phosphate rock (fertilizer) industry, which currently dissipates a great deal of recoverable fluorine in waste phospho‐gypsum.
Industrial Symbiosis in the Australian Minerals Industry: The Cases of Kwinana and Gladstone
Authors: van Beers Dick , Bossilkov Albena , Corder Glen , van Berkel Rene
Published: February 2007

The realization of regional synergies in industrial areas with intensive minerals processing provides a significant avenue toward sustainable resource processing. This article provides an overview of past and current synergy developments in two of Australia's major heavy industrial regions, Kwinana (Western Australia) and Gladstone (Queensland), and includes a comparative review and assessment of the drivers, barriers, and trigger events for regional synergies initiatives in both areas. Kwinana and Gladstone compare favorably with well‐known international examples in terms of the current level and maturity of industry involvement and collaboration and the commitment to further explore regional resource synergies. Kwinana stands out with regard to the number, diversity, complexity, and maturity of existing synergies. Gladstone is remarkable with regard to unusually large geographic boundaries and high dominance of one industry sector. Many diverse regional synergy opportunities still appear to exist in both industrial regions (particularly in Kwinana), mostly in three broad areas: water, energy, and inorganic by‐product reuse. To enhance the further development of new regional synergies, the Centre for Sustainable Resource Processing (CSRP), a joint initiative of Australian minerals processing companies, research providers, and government agencies, has undertaken several collaborative projects. These include research to facilitate the process of identifying and evaluating potential synergy opportunities and assistance for the industries with feasibility studies and implementation of selected synergy projects in both regions. The article also reports on the progress to date from this CSRP research.