bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monoclonal Antibody Blockade of the Human Eag1 Potassium Channel Function Exerts Antitumor Activity
Authors: Gómez-Varela David , Zwick-Wallasch Esther , Knötgen Hendrik , Sánchez Araceli , Hettmann Thore , Ossipov Dmitri , Weseloh Rüdiger , Contreras-Jurado Constanza , Rothe Mike , Stühmer Walter , Pardo Luis A. 
Published: August 2007

AbstractThe potassium channel ether à go-go has been directly linked to cellular proliferation and transformation, although its physiologic role(s) are as of yet unknown. The specific blockade of human Eag1 (hEag1) may not only allow the dissection of the role of the channel in distinct physiologic processes, but because of the implication of hEag1 in tumor biology, it may also offer an opportunity for the treatment of cancer. However, members of the potassium channel superfamily are structurally very similar to one another, and it has been notoriously difficult to obtain specific blockers for any given channel. Here, we describe and validate the first rational design of a monoclonal antibody that selectively inhibits a potassium current in intact cells. Specifically blocking hEag1 function using this antibody inhibits tumor cell growth both in vitro and in vivo. Our data provide a proof of concept that enables the generation of functional antagonistic monoclonal antibodies against ion channels with therapeutic potential. The particular antibody described here, as well as the technique developed to make additional functional antibodies to Eag1, makes it possible to evaluate the potential of the channel as a target for cancer therapy. [Cancer Res 2007;67(15):7343–49]
Guggulsterone-Induced Apoptosis in Human Prostate Cancer Cells Is Caused by Reactive Oxygen Intermediate–Dependent Activation of c-Jun NH2-Terminal Kinase
Authors: Singh Shivendra V. , Choi Sunga , Zeng Yan , Hahm Eun-Ryeong , Xiao Dong 
Published: August 2007

AbstractGuggulsterone, a constituent of Indian Ayurvedic medicinal plant Commiphora mukul, causes apoptosis in cancer cells but the sequence of events leading to cell death is poorly understood. We now show that guggulsterone-induced cell death in human prostate cancer cells is caused by reactive oxygen intermediate (ROI)–dependent activation of c-Jun NH2-terminal kinase (JNK). Exposure of PC-3 and LNCaP cells to apoptosis inducing concentrations of guggulsterone resulted in activation of JNK and p38 mitogen-activated protein kinase (p38 MAPK) in both cell lines and activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in LNCaP cells. The guggulsterone-induced apoptosis in PC-3/LNCaP cells was partially but statistically significantly attenuated by pharmacologic inhibition (SP600125) as well as genetic suppression of JNK activation. On the other hand, pharmacologic inhibition of p38 MAPK activation in PC-3 or LNCaP cells (SB202190) and ERK1/2 activation in LNCaP cells (PD98059) did not protect against guggulsterone-induced cell death. The guggulsterone treatment caused generation of ROI in prostate cancer cells but not in a normal prostate epithelial cell line (PrEC), which was also resistant to guggulsterone-mediated JNK activation. The guggulsterone-induced JNK activation as well as cell death in prostate cancer cells was significantly attenuated by overexpression of catalase and superoxide dismutase. In addition, guggulsterone treatment resulted in a decrease in protein level and promoter activity of androgen receptor in LNCaP cells. In conclusion, the present study reveals that the guggulsterone-induced cell death in human prostate cancer cells is regulated by ROI-dependent activation of JNK and guggulsterone inhibits promoter activity of androgen receptor. [Cancer Res 2007;67(15):7439–49]
Profiling Microdissected Epithelium and Stroma to Model Genomic Signatures for Cervical Carcinogenesis Accommodating for Covariates
Authors: Gius David , Funk Margo C. , Chuang Eric Y. , Feng Sheng , Huettner Phyllis C. , Nguyen Loan , Bradbury C. Matthew , Mishra Mark , Gao Shuping , Buttin Barbara M. , Cohn David E. , Powell Matthew A. , Horowitz Neil S. , Whitcomb Bradford P. , Rader Janet S. 
Published: August 2007

Abstract
This study is the first comprehensive, integrated approach to examine grade-specific changes in gene expression along the entire neoplastic spectrum of cervical intraepithelial neoplasia (CIN) in the process of cervical carcinogenesis. This was accomplished by identifying gene expression signatures of disease progression using cDNA microarrays to analyze RNA from laser-captured microdissected epithelium and underlying stroma from normal cervix, graded CINs, cancer, and patient-matched normal cervical tissues. A separate set of samples were subsequently validated using a linear mixed model that is ideal to control for interpatient gene expression profile variation, such as age and race. These validated genes were ultimately used to propose a genomically based model of the early events in cervical neoplastic transformation. In this model, the CIN 1 transition coincides with a proproliferative/immunosuppression gene signature in the epithelium that probably represents the epithelial response to human papillomavirus infection. The CIN 2 transition coincides with a proangiogenic signature, suggesting a cooperative signaling interaction between stroma and tumor cells. Finally, the CIN 3 and squamous cell carcinoma antigen transition coincide with a proinvasive gene signature that may be a response to epithelial tumor cell overcrowding. This work strongly suggests that premalignant cells experience a series of microenvironmental stresses at the epithelium/stroma cell interface that must be overcome to progress into a transformed phenotype and identifies the order of these events in vivo and their association with specific CIN transitions. [Cancer Res 2007;67(15):7113–23]
Sequential Loss of Tumor Vessel Pericytes and Endothelial Cells after Inhibition of Platelet-Derived Growth Factor B by Selective Aptamer AX102
Authors: Sennino Barbara , Falcón Beverly L. , McCauley Dilara , Le Tom , McCauley Thomas , Kurz Jeffrey C. , Haskell Amy , Epstein David M. , McDonald Donald M. 
Published: August 2007

Abstract
Inhibition of platelet derived growth factor (PDGF) can increase the efficacy of other cancer therapeutics, but the cellular mechanism is incompletely understood. We examined the cellular effects on tumor vasculature of a novel DNA oligonucleotide aptamer (AX102) that selectively binds PDGF-B. Treatment with AX102 led to progressive reduction of pericytes, identified by PDGF receptor β, NG2, desmin, or α-smooth muscle actin immunoreactivity, in Lewis lung carcinomas. The decrease ranged from 35% at 2 days, 63% at 7 days, to 85% at 28 days. Most tumor vessels that lacked pericytes at 7 days subsequently regressed. Overall tumor vascularity decreased 79% over 28 days, without a corresponding decrease in tumor size. Regression of pericytes and endothelial cells led to empty basement membrane sleeves, which were visible at 7 days, but only 54% remained at 28 days. PDGF-B inhibition had a less pronounced effect on pancreatic islet tumors in RIP-Tag2 transgenic mice, where pericytes decreased 47%, vascularity decreased 38%, and basement membrane sleeves decreased 21% over 28 days. Taken together, these findings show that inhibition of PDGF-B signaling can lead to regression of tumor vessels, but the magnitude is tumor specific and does not necessarily retard tumor growth. Loss of pericytes in tumors is an expected direct consequence of PDGF-B blockade, but reduced tumor vascularity is likely to be secondary to pericyte regression. [Cancer Res 2007;67(15):7358–67]
Enhanced Peritoneal Ovarian Tumor Dissemination by Tissue Transglutaminase
Authors: Satpathy Minati , Cao Liyun , Pincheira Roxana , Emerson Robert , Bigsby Robert , Nakshatri Harikrishna , Matei Daniela 
Published: August 2007

AbstractTissue transglutaminase (TG2) is involved in Ca2+-dependent aggregation and polymerization of proteins. We previously reported that TG2 mRNA is up-regulated in epithelial ovarian cancer (EOC) cells compared with normal ovarian epithelium. Here, we show overexpression of the TG2 protein in ovarian cancer cells and tumors and its secretion in ascites fluid and define its role in EOC. By stable knockdown and overexpression, we show that TG2 enhances EOC cell adhesion to fibronectin and directional cell migration. This phenotype is preserved in vivo, where the pattern of tumor dissemination in the peritoneal space is dependent on TG2 expression levels. TG2 knockdown diminishes dissemination of tumors on the peritoneal surface and mesentery in an i.p. ovarian xenograft model. This phenotype is associated with deficient β1 integrin-fibronectin interaction, leading to weaker anchorage of cancer cells to the peritoneal matrix. Highly expressed in ovarian tumors, TG2 facilitates i.p. tumor dissemination by enhancing cell adhesion to the extracellular matrix and modulating β1 integrin subunit expression. [Cancer Res 2007;67(15):7194–202]
Identification of Pax5 as a Target of MTA1 in B-Cell Lymphomas
Authors: Balasenthil Seetharaman , Gururaj Anupama E. , Talukder Amjad H. , Bagheri-Yarmand Rozita , Arrington Ty , Haas Brian J. , Braisted John C. , Kim Insun , Lee Norman H. , Kumar Rakesh 
Published: August 2007

Abstract
Previously, we have shown that metastasis-associated protein 1 (MTA1) overexpression in transgenic mice was accompanied by high incidence of spontaneous B-cell lymphomas including diffuse large B-cell lymphomas (DLBCL). To understand the molecular basis of lymphoma in MTA1-transgenic (MTA1-TG) mice, we wished to identify a putative MTA1 target with a causal role in B-cell lymphogenesis. Using chromatin immunoprecipitation assays, we identified paired box gene 5 (Pax5), a molecule previously implicated in B-cell lymphogenesis, as a potential downstream effector of MTA1. Lymphomas from MTA1-TG mice also showed up-regulation of Pax5. We also found that MTA1 acetylated on Lys626 interacted with p300 histone acetyltransferase, and that acetylated MTA1 was recruited to the Pax5 promoter to stimulate Pax5 transcription. Global gene profiling identified down-regulation of a set of genes, including those downstream of Pax5 and directly implicated in the B-cell lymphogenesis. Significance of these murine studies was established by evidence showing a widespread up-regulation of both MTA1 and Pax5 in DLBCL from humans. These observations provide in vivo genetic evidence for a role of MTA1 in lymphomagenesis. [Cancer Res 2007;67(15):7132–8]
Down-regulation of the Sodium/Iodide Symporter Explains 131I-Induced Thyroid Stunning
Authors: Nordén Madeleine M. , Larsson Fredrik , Tedelind Sofia , Carlsson Therese , Lundh Charlotta , Forssell-Aronsson Eva , Nilsson Mikael 
Published: August 2007

Abstract
131I radiation therapy of differentiated thyroid cancer may be compromised by thyroid stunning (i.e., a paradoxical inhibition of radioiodine uptake caused by radiation from a pretherapeutic diagnostic examination). The stunning mechanism is yet uncharacterized at the molecular level. We therefore investigated whether the expression of the sodium/iodide symporter (NIS) gene is changed by irradiation using 131I. Confluent porcine thyroid cells on filter were stimulated with thyroid-stimulating hormone (TSH; 1 milliunit/mL) or insulin-like growth factor-I (IGF-I; 10 ng/mL) and simultaneously exposed to 131I in the culture medium for 48 h, porcine NIS mRNA was quantified by real-time reverse transcription-PCR using 18S as reference, and transepithelial iodide transport was monitored using 125I− as tracer. TSH increased the NIS expression &gt;100-fold after 48 h and 5- to 20-fold after prolonged stimulation. IGF-I enhanced the NIS transcription at most 15-fold but not until 5 to 7 days. 131I irradiation (7.5 Gy) decreased both TSH-stimulated and IGF-I–stimulated NIS transcription by 60% to 90% at all investigated time points. TSH and IGF-I stimulated NIS synergistically 15- to 60-fold after 5 days. NIS expression was reduced by 131I also in costimulated cells, but the transcription level remained higher than in nonirradiated cells stimulated with TSH alone. Changes in NIS mRNA always correlated with altered 125I− transport in cultures with corresponding treatments. It is concluded that down-regulation of NIS is the likely explanation of 131I-induced thyroid stunning. Enhanced NIS expression by synergistically acting agents (TSH and IGF-I) partly prevents the loss of iodide transport expected from a given absorbed dose, suggesting that thyroid stunning might be pharmacologically treatable. [Cancer Res 2007;67(15):7512–17]
Combined Natural Killer T-Cell–Based Immunotherapy Eradicates Established Tumors in Mice
Authors: Teng Michele W.L. , Westwood Jennifer A. , Darcy Phillip K. , Sharkey Janelle , Tsuji Moriya , Franck Richard W. , Porcelli Steven A. , Besra Gurdyal S. , Takeda Kazuyoshi , Yagita Hideo , Kershaw Michael H. , Smyth Mark J. 
Published: August 2007

Abstract
A rational monoclonal antibody (mAb)-based antitumor therapy approach has previously been shown to eradicate various established experimental and carcinogen-induced tumors in a majority of mice. This therapy comprised an agonistic mAb reactive with tumor necrosis factor–related apoptosis-inducing ligand receptor (DR5), expressed by tumor cells, an agonistic anti-CD40 mAb to mature dendritic cells, and an agonistic anti-4-1BB mAb to costimulate CD8+ T cells. Because agonists of CD40 have been toxic in patients, we were interested in substituting anti-CD40 mAb with other dendritic cell–maturing agents, such as glycolipid ligands recognized by invariant natural killer T (iNKT) cells. Here, we show that CD1d-restricted glycolipid ligands for iNKT cells effectively substitute for anti-CD40 mAb and reject established experimental mouse breast and renal tumors when used in combination with anti-DR5 and anti-4-1BB mAbs (termed “NKTMab” therapy). NKTMab therapy–induced tumor rejection was dependent on CD4+ and CD8+ T cells, NKT cells, and the cytokine IFN-γ. NKTMab therapy containing either α-galactosylceramide (α-GC) or α-C-galactosylceramide (α-c-GC) at high concentrations induced similar rates of tumor rejection in mice; however, toxicity was observed at the highest doses of α-GC (&gt;250 ng/injection), limiting the use of this glycolipid. By contrast, even very low doses of α-c-GC (25 ng/injection) retained considerable antitumor activity when used in combination with anti-DR5/anti-4-1BB, and thus, α-c-GC showed a considerably greater therapeutic index. In summary, sequential tumor cell apoptosis and amplification of dendritic cell function by NKT cell agonists represents an exciting and novel approach for cancer treatment. [Cancer Res 2007;67(15):7495–504]
Cannabinoid Modulation of Kaposi's Sarcoma–Associated Herpesvirus Infection and Transformation
Authors: Zhang Xuefeng , Wang Jian Feng , Kunos George , Groopman Jerome E. 
Published: August 2007

Abstract
Kaposi's sarcoma–associated herpesvirus (KSHV; also named human herpesvirus 8) is necessary but not sufficient for the development of Kaposi's sarcoma. A variety of factors may contribute to the pathogenesis of Kaposi's sarcoma in addition to KSHV. Marijuana is a widely used recreational agent, and Δ9-tetrahydrocannabinol (Δ9-THC), the major active component of marijuana, is prescribed for medicinal use. To evaluate how cannabinoids may affect the pathogenesis of Kaposi's sarcoma, we studied primary human dermal microvascular endothelial cells (HMVEC) exposed to KSHV. There was an increased efficiency of KSHV infection in the presence of low doses of Δ9-THC. We also found that Δ9-THC increased the viral load in KSHV-infected HMVEC through activation of the KSHV lytic switch gene, the open reading frame 50. Furthermore, we observed that Δ9-THC stimulated expression of the KSHV-encoded viral G protein–coupled receptor and Kaposi's sarcoma cell proliferation. Our results indicate that Δ9-THC can enhance KSHV infection and replication and foster KSHV-mediated endothelial transformation. Thus, use of cannabinoids may place individuals at greater risk for the development and progression of Kaposi's sarcoma. [Cancer Res 2007;67(15):7230–7]
Isoobtusilactone A Induces Cell Cycle Arrest and Apoptosis through Reactive Oxygen Species/Apoptosis Signal-Regulating Kinase 1 Signaling Pathway in Human Breast Cancer Cells
Authors: Kuo Po-Lin , Chen Chung-Yi , Hsu Ya-Ling 
Published: August 2007

Abstract
This study is the first to investigate the anticancer effect of isoobtusilactone A (IOA) in two human breast cancer cell lines, MCF-7 and MDA-MB-231. IOA exhibited effective cell growth inhibition by inducing cancer cells to undergo G2-M phase arrest and apoptosis. Further investigation revealed that IOA's inhibition of cell growth was also evident in a nude mice model. Cell cycle blockade was associated with increased levels of p21 and reduced amounts of cyclin B1, cyclin A, cdc2, and cdc25C. IOA also enhanced the levels of inactivated phosphorylated cdc2 and cdc25C. IOA triggered the mitochondrial apoptotic pathway, as indicated by a change in Bax/Bcl-2 ratios, resulting in mitochondrial membrane potential loss, cytochrome c release, and caspase-9 activation. We also found that the generation of reactive oxygen species (ROS) is a critical mediator in IOA-induced cell growth inhibition. Enhancement of ROS by IOA activated apoptosis signal-regulating kinase 1 (ASK1) resulted in the increased activation of c-Jun NH2-terminal kinase and p38. Antioxidants EUK8 and N-acetyl cystenine significantly decreased apoptosis by inhibiting the ASK1 dephosphorylation at Ser967 and subsequently increased the interaction of ASK1 with thioredoxin or 14-3-3 proteins. Moreover, blocking ASK1 by small interfering RNA inhibition completely suppressed IOA-induced apoptosis. Taken together, these results imply a critical role for ROS and ASK1 in IOA's anticancer activity. [Cancer Res 2007;67(15):7406–20]
Combined Yeast β-Glucan and Antitumor Monoclonal Antibody Therapy Requires C5a-Mediated Neutrophil Chemotaxis via Regulation of Decay-Accelerating Factor CD55
Authors: Li Bing , Allendorf Daniel J. , Hansen Richard , Marroquin Jose , Cramer Daniel E. , Harris Claire L. , Yan Jun 
Published: August 2007

AbstractAdministration of a combination of yeast-derived β-glucan with antitumor monoclonal antibodies (mAb) has significant therapeutic efficacy in a variety of syngeneic murine tumor models. We have now tested this strategy using human carcinomas implanted in immunocompromised severe combined immunodeficient mice. Combined immunotherapy was therapeutically effective in vivo against NCI-H23 human non–small-cell lung carcinomas, but this modality was surprisingly ineffective against SKOV-3 human ovarian carcinomas. Whereas NCI-H23 tumors responded to this combination therapy with increased intratumoral neutrophil infiltration and C5a production, these responses were lacking in treated SKOV-3 tumors. Further results suggested that SKOV-3 tumors were protected by up-regulation of the membrane complement regulatory protein CD55 (decay-accelerating factor). Blockade of CD55 in vitro led to enhanced deposition of C activation product C3b and increased cytotoxicity mediated by β-glucan–primed neutrophils. In vivo, administration of anti-CD55 mAb along with β-glucan and anti–Her-2/neu mAb caused tumor regression and greatly improved long-term survival in animals bearing the previously resistant SKOV-3 tumors. This was accompanied by increased intratumoral neutrophil accumulation and C5a production. We conclude that CD55 suppresses tumor killing by antitumor mAb plus β-glucan therapy (and, perhaps, in other circumstances). These results suggest a critical role for CD55 to regulate iC3b and C5a release and in turn to influence the recruitment of β-glucan–primed neutrophils eliciting killing activity. [Cancer Res 2007;67(15):7421–30]
Tumor Angiogenesis: Cause or Consequence of Cancer?
Authors: Shchors Ksenya , Evan Gerard 
Published: August 2007

AbstractBoth tumors and normal tissues need a blood supply for oxygen, nutrients, and waste removal. However, whereas normal vasculature is hierarchically assembled into efficient networks of arteries, capillaries, and veins, the blood vessels of tumors are a mess—chaotic, leaky, inefficient, and barely making do. Why the difference? Do tumor vessels lack the signals to mature or, instead, is their maturation actively suppressed? What triggers and maintains tumor vasculature? In a recent study using a switchable Myc-driven mouse tumor model, we addressed these fundamental questions. We identified the inflammatory cytokine interleukin-1β as an essential initiating trigger of vascular endothelial growth factor–dependent angiogenesis. Here, we consider how kinetic studies using regulatable forms of Myc or other oncogenes can shed new light on the way tumors initiate and maintain their aberrant blood supplies. [Cancer Res 2007;67(15):7059–61]
Validation and Characterization of Human Kallikrein 11 as a Serum Marker for Diagnosis of Ovarian Carcinoma
Authors: McIntosh Martin W. , Liu Yan , Drescher Charles , Urban Nicole , Diamandis Eleftherios P. 
Published: August 2007

Abstract
Purpose: The serum tumor marker CA 125 is elevated in most clinically advanced ovarian carcinomas, and currently, one of the most promising early detection strategies for ovarian cancer uses CA 125 level in conjunction with imaging. However, CA 125 is elevated in only 50% of early-stage ovarian cancer and is often elevated in women with benign ovarian tumors and other gynecologic diseases. Additional markers may improve on its individual performance if they increase sensitivity and specificity and are less sensitive to other gynecologic conditions. The human kallikrein 11 (hK11) marker has been reported to have favorable predictive value for ovarian cancer, although, by itself, it may be inferior to CA 125.
Experimental Design: We here validate the performance of hK11 on an independent data set and further characterize its behavior in multiple types of controls. We also investigate its behavior when combined with CA 125 to form a composite marker. hK11 had not previously been evaluated on these serum samples. CA 125, hK11, and the composite marker were evaluated for their performance in identifying ovarian cancer and for temporal stability.
Results: hK11 significantly distinguished ovarian cancer cases from healthy controls and is less sensitive to benign ovarian disease than is CA 125.
Conclusion: We conclude that hK11 is a valuable new biomarker for ovarian cancer and its temporal stability implies that it may do even better when used in a longitudinal screening program for early detection.