bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tissue Inhibitor of Metalloproteinase-3 via Oncolytic Herpesvirus Inhibits Tumor Growth and Vascular Progenitors
Authors: Mahller Yonatan Y. , Vaikunth Sachin S. , Ripberger Maria C. , Baird William H. , Saeki Yoshinaga , Cancelas Jose A. , Crombleholme Timothy M. , Cripe Timothy P. 
Published: February 2008

Abstract
Malignant solid tumors remain a significant clinical challenge, necessitating innovative therapeutic approaches. Oncolytic viral therapy is a nonmutagenic, biological anticancer therapeutic shown to be effective against human cancer in early studies. Because matrix metalloproteinases (MMP) play important roles in the pathogenesis and progression of cancer, we sought to determine if “arming” an oncolytic herpes simplex virus (oHSV) with an MMP-antagonizing transgene would increase virus-mediated antitumor efficacy. We generated oHSVs that express human tissue inhibitor of metalloproteinases 3 (TIMP3) or firefly luciferase and designated them rQT3 and rQLuc, respectively. We evaluated the antitumor efficacy of these viruses against neuroblastoma and malignant peripheral nerve sheath tumor (MPNST) xenografts. Relative to rQLuc, rQT3-infected primary human MPNST and neuroblastoma cells exhibited equivalent virus replication but increased cytotoxicity and reduced MMP activity. In vivo, rQT3-treated tumors showed delayed tumor growth, increased peak levels of infectious virus, immature collagen extracellular matrix, and reduced tumor vascular density. Remarkably, rQT3 treatment reduced circulating endothelial progenitors, suggesting virus-mediated antivasculogenesis. We conclude that rQT3 enhanced antitumor efficacy through multiple mechanisms, including direct cytotoxicity, elevated virus titer, and reduced tumor neovascularization. These findings support the further development of combined TIMP-3 and oncolytic virotherapy for cancer. [Cancer Res 2008;68(4):1170–9]
The Differential Role of L1 in Ovarian Carcinoma and Normal Ovarian Surface Epithelium
Authors: Zecchini Silvia , Bianchi Marco , Colombo Nicoletta , Fasani Roberta , Goisis Giovanni , Casadio Chiara , Viale Giuseppe , Liu Jinsong , Herlyn Meenhard , Godwin Andrew K. , Nuciforo Paolo G. , Cavallaro Ugo 
Published: February 2008

Abstract
Epithelial ovarian carcinoma (EOC) arises from the ovarian surface epithelium (OSE), a monolayer of poorly differentiated epithelial cells that lines the ovary. The molecular mechanisms underlying EOC invasion into the surrounding stroma and dissemination to the peritoneum and to retroperitoneal lymph nodes are still unclear. Here, we analyzed the expression and the functional role of the cell adhesion molecule L1 during EOC development. In patient-derived samples, L1 was expressed both in OSE and in a subset of EOC, in the latter being mostly restricted to the invasive areas of the tumors. The expression of L1 correlated significantly with poor outcome and with unfavorable clinicopathologic features of the disease. The peculiar expression pattern of L1 in normal OSE and invasive EOC raised the possibility that this adhesion molecule serves a different function in nontransformed versus neoplastic ovarian epithelial cells. Indeed, we showed that in OSE cells L1 supports cell-cell adhesion and enhances apoptosis, whereas it has no effect on cell proliferation and invasion. In contrast, L1 inhibits cell-cell adhesion and apoptosis in ovarian carcinoma cells, where it promotes malignancy-related properties, such as cell proliferation, Erk1/2-dependent and phosphoinositide 3-kinase–dependent invasion, and transendothelial migration. Interestingly, a crosstalk with the fibroblast growth factor receptor signaling is implicated in the promalignant function of L1 in tumor cells. Our findings point to L1 as an EOC biomarker correlating with poor prognosis, and highlight a switch in L1 function associated to the neoplastic transformation of ovarian epithelial cells, thus implicating L1 as a potential therapeutic target. [Cancer Res 2008;68(4):1110–8]
Acetyl-Keto-β-Boswellic Acid Induces Apoptosis through a Death Receptor 5–Mediated Pathway in Prostate Cancer Cells
Authors: Lu Min , Xia Lijuan , Hua Huiming , Jing Yongkui 
Published: February 2008

AbstractAcetyl-keto-β-boswellic acid (AKBA), a triterpenoid isolated from Boswellia carterri Birdw and Boswellia serrata, has been found to inhibit tumor cell growth and to induce apoptosis. The apoptotic effects and the mechanisms of action of AKBA were studied in LNCaP and PC-3 human prostate cancer cells. AKBA induced apoptosis in both cell lines at concentrations above 10 μg/mL. AKBA-induced apoptosis was correlated with the activation of caspase-3 and caspase-8 as well as with poly(ADP)ribose polymerase (PARP) cleavage. The activation of caspase-8 was correlated with increased levels of death receptor (DR) 5 but not of Fas or DR4. AKBA-induced apoptosis, caspase-8 activation, and PARP cleavage were inhibited by knocking down DR5 using a small hairpin RNA. AKBA treatment increased the levels of CAAT/enhancer binding protein homologous protein (CHOP) and activated a DR5 promoter reporter but did not activate a DR5 promoter reporter with the mutant CHOP binding site. These results suggest that AKBA induces apoptosis in prostate cancer cells through a DR5-mediated pathway, which probably involves the induced expression of CHOP. [Cancer Res 2008;68(4):1180–6]
Integrated Genomic Profiling of Chronic Lymphocytic Leukemia Identifies Subtypes of Deletion 13q14
Authors: Ouillette Peter , Erba Harry , Kujawski Lisa , Kaminski Mark , Shedden Kerby , Malek Sami N. 
Published: February 2008

Abstract
Chronic lymphocytic leukemia (CLL) is a biologically heterogeneous illness with a variable clinical course. Loss of chromosomal material on chromosome 13 at cytoband 13q14 is the most frequent genetic abnormality in CLL, but the molecular aberrations underlying del13q14 in CLL remain incompletely characterized. We analyzed 171 CLL cases for loss of heterozygosity and subchromosomal copy loss on chromosome 13 in DNA from fluorescence-activated cell sorting–sorted CD19+ cells and paired buccal cells using the Affymetrix XbaI 50k SNP array platform. The resulting high-resolution genomic maps, together with array-based measurements of expression levels of RNA in CLL cases with and without del13q14 and quantitative PCR–based expression analysis of selected genes, support the following conclusions: (a) del13q14 is heterogeneous and composed of multiple subtypes, with deletion of Rb or the miR15a/miR16 loci serving as anatomic landmarks, respectively; (b) del13q14 type Ia deletions are relatively uniform in length and extend from breakpoints close to the miR15a/miR16 cluster to a newly identified telomeric breakpoint cluster at the ∼50.2 to 50.5 Mb physical position; (c) LATS2 RNA levels are ∼2.6-fold to 2.8-fold lower in cases with del13q14 type I that do not delete Rb, as opposed to del13q14 type II or all other CLL cases; (d) PHLPP RNA is absent in ∼50% of CLL cases with del13q14; and (e) ∼15% of CLL cases display marked reductions in miR15a/miR16 expression that are often but not invariably associated with bi-allelic miR15a/miR16 loss. These data should aid future investigations into biological differences imparted on CLL by different del13q14 subtypes. [Cancer Res 2008;68(4):1012–21]
Pten Inactivation Accelerates Oncogenic K-ras–Initiated Tumorigenesis in a Mouse Model of Lung Cancer
Authors: Iwanaga Kentaro , Yang Yanan , Raso Maria Gabriela , Ma Lijiang , Hanna Amy E. , Thilaganathan Nishan , Moghaddam Seyed , Evans Christopher M. , Li Huaiguang , Cai Wei-Wen , Sato Mitsuo , Minna John D. , Wu Hong , Creighton Chad J. , Demayo Francesco J. , Wistuba Ignacio I. , Kurie Jonathan M. 
Published: February 2008

Abstract
Phosphatase and tensin homologue deleted from chromosome 10 (Pten) is expressed aberrantly in non–small cell lung cancer cells, but the role of Pten in lung neoplasia has not been fully elucidated. In this study, we used a genetic approach to inactivate Pten in the bronchial epithelium of mice. Although, by itself, Pten inactivation had no discernible effect on bronchial epithelial histology, it accelerated lung tumorigenesis initiated by oncogenic K-ras, causing more rapid lethality than that induced by oncogenic K-ras alone (8 weeks versus 24 weeks of median duration of survival, respectively). Lung tumors arose in K-ras mutant, Pten-deficient mice that rapidly obstructed bronchial lumina and replaced alveolar spaces. Relative to K-ras mutant tumors, the K-ras mutant, Pten-deficient tumors exhibited more advanced histologic severity and more prominent inflammation and vascularity. Thus, Pten inactivation cooperated with oncogenic K-ras in promoting lung tumorigenesis. [Cancer Res 2008;68(4):1119–27]
Silencing of HSP90 Cochaperone AHA1 Expression Decreases Client Protein Activation and Increases Cellular Sensitivity to the HSP90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin
Authors: Holmes Joanna L. , Sharp Swee Y. , Hobbs Steve , Workman Paul 
Published: February 2008

Abstract
AHA1 (activator of HSP90 ATPase) is a cochaperone of the ATP-dependent molecular chaperone, HSP90, which is involved in the maturation, stabilization/degradation, and function of oncogenic proteins. HSP90 operates in a multimeric complex driven by the binding and hydrolysis of ATP. Treatment of cells with the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) results in the degradation of client proteins via the ubiquitin-proteasome pathway. As AHA1 increases the ATPase activity of HSP90, we hypothesized that modulation of AHA1 expression could influence the activity of client proteins and/or the cellular response to 17-AAG. We show that the basal expression of AHA1 is different across a panel of human cancer cell lines, and that treatment with 17-AAG resulted in sustained AHA1 up-regulation. Increasing the expression of AHA1 did not affect the sensitivity to 17-AAG, but did increase C-RAF activity and the levels of phosphorylated MEK1/2 and ERK1/2 without affecting total levels of these proteins or of client proteins C-RAF, ERBB2, or CDK4. Conversely, small interfering RNA–selective knockdown of &gt;80% of AHA1 expression decreased C-RAF activity and reduced the levels of MEK1/2 and ERK1/2 phosphorylation. Moreover, the AHA1 knockdown resulted in a significant (P &lt; 0.05) increase in sensitivity to 17-AAG, due in part to a 2- to 3-fold increase in apoptosis. These results show that the reduction of AHA1 levels could decrease the phosphorylation of key signal transduction proteins, and for the first time, separate the activation and stabilization functions of HSP90. Furthermore, AHA1 knockdown could sensitize cancer cells to 17-AAG. We conclude that modulation of AHA1 might be a potential therapeutic strategy to increase sensitivity to HSP90 inhibitors. [Cancer Res 2008;68(4):1187–97]
Negative Feedback Regulation of IFN-γ Pathway by IFN Regulatory Factor 2 in Esophageal Cancers
Authors: Wang Yan , Liu Dongping , Chen Pingping , Koeffler H. Phillip , Tong Xiangjun , Xie Dong 
Published: February 2008

Abstract
IFN-γ is an antitumor cytokine that inhibits cell proliferation and induces apoptosis after engagement with the IFN-γ receptors (IFNGR) expressed on target cells, whereas IFN regulatory factor 2 (IRF-2) is able to block the effects of IFN-γ by repressing transcription of IFN-γ–induced genes. Thus far, few studies have explored the influences of IFN-γ on human esophageal cancer cells. In the present study, therefore, we investigated in detail the functions of IFN-γ in esophageal cancer cells. The results in clinical samples of human esophageal cancers showed that the level of IFN-γ was increased in tumor tissues and positively correlated with tumor progression and IRF-2 expression, whereas the level of IFNGR1 was decreased and negatively correlated with tumor progression and IRF-2 expression. Consistently, in vitro experiments showed that low concentration of IFN-γ induced the expression of IRF-2 with potential promotion of cell growth, and moreover, IRF-2 was able to suppress IFNGR1 transcription in human esophageal cancer cells by binding a specific motif in IFNGR1 promoter, which lowered the sensitivity of esophageal cancer cells to IFN-γ. Taken together, our results disclosed a new IRF-2–mediated inhibitory mechanism for IFN-γ–induced pathway in esophageal cancer cells: IFN-γ induced IRF-2 up-regulation, then up-regulated IRF-2 decreased endogenous IFNGR1 level, and finally, the loss of IFNGR1 turned to enhance the resistance of esophageal cancer cells to IFN-γ. Accordingly, the results implied that IRF-2 might act as a mediator for the functions of IFN-γ and IFNGR1 in human esophageal cancers. [Cancer Res 2008;68(4):1136–43]
Regulation of Cancer Cell Survival, Migration, and Invasion by Twist: AKT2 Comes to Interplay
Authors: Cheng George Z. , Zhang Weizhou , Wang Lu-Hai 
Published: February 2008

Abstract
Metastasis, the foremost cause of mortality in cancer patients, is increasingly recognized as a coordinated biological process. The multistep process of metastasis posts difficulty in studying its mechanism and molecular basis. Recent works have shown that the basic helix-loop-helix transcriptional factor Twist and the serine/threonine kinase AKT play pivotal roles in tumor development and progression. Our recent study has shown that AKT2 is a transcriptional regulatory target of Twist and acts downstream of Twist to promote cancer cell survival, migration, and invasion. Functional convergence of Twist and AKT2 underscores the importance of this signaling pathway in tumor development and progression and as a potential therapeutic target. [Cancer Res 2008;68(4):957–60]
TREK-1 Is a Novel Molecular Target in Prostate Cancer
Authors: Voloshyna Iryna , Besana Alessandra , Castillo Mireia , Matos Tulio , Weinstein I. Bernard , Mansukhani Mahesh , Robinson Richard B. , Cordon-Cardo Carlos , Feinmark Steven J. 
Published: February 2008

AbstractTREK-1 is a two-pore domain (K2P) potassium channel that carries a leak current that is time- and voltage-independent. Recently, potassium channels have been related to cell proliferation and some K2P family channels, such as TASK-3, have been shown to be overexpressed in specific neoplasms. In this study, we addressed the expression of TREK-1 in prostatic tissues and cell lines, and we have found that this potassium channel is highly expressed in prostate cancer but is not expressed in normal prostate nor in benign prostatic hyperplasia. Furthermore, expression of TREK-1 correlates strongly with the grade and the stage of the disease, suggesting a causal link between channel expression and abnormal cell proliferation. In vitro studies showed that TREK-1 is highly expressed in PC3 and LNCaP prostate cancer cell lines but is not detectable in normal prostate epithelial cells (NPE). In this report, we show that overexpression of TREK-1 in NPE and Chinese hamster ovary (CHO) cells leads to a significant increase in proliferation. Moreover, the increased cell proliferation rate of PC3 cells and TREK-1 overexpressing CHO cells could be reduced when TREK-1 current was reduced by overexpression of a dominant-negative TREK-1 mutant or when cells were exposed to a TREK-1 inhibitor. Taken together, these data suggest that TREK-1 expression is associated with abnormal cell proliferation and may be a novel marker for and a molecular target in prostate cancer. [Cancer Res 2008;68(4):1197–203]
Reconstitution of Nasopharyngeal Carcinoma–Type EBV Infection Induces Tumorigenicity
Authors: Seto Eri , Ooka Tadamasa , Middeldorp Jaap , Takada Kenzo 
Published: February 2008

Abstract
Several reports have shown that the EBV-encoded BARF1 gene has oncogenic activity. We have recently reported that BARF1 is expressed as a latent gene in most nasopharyngeal carcinomas (NPC), suggesting that BARF1 may have an important role in NPC oncogenesis. However, we found that when the NPC-derived EBV-negative cell lines, HONE-1 and CNE-1, were infected with EBV in vitro, BARF1 was not expressed, although the expression of other latent genes was identical to that of NPC tumors. Therefore, we generated a recombinant EBV (rEBV) carrying the BARF1 gene (BARF1-rEBV) under the SV40 promoter to reconstitute the NPC-type EBV infection. NPC-derived EBV-negative cell lines were stably infected with either a wild-type rEBV (wild-rEBV) or BARF1-rEBV. The resultant BARF1-rEBV–infected NPC cell clones represented NPC-type EBV expression, and BARF1 expression was similar to that observed in NPC tissues. BARF1-rEBV–infected cell clones grew to a higher cell density and were more resistant to apoptosis than wild-rEBV–infected counterparts. BARF1 protein was quickly secreted into the culture medium, and secreted BARF1 contributed to the increase of cell densities in NPC cells, but it had no effect on resistance to apoptosis. Furthermore, BARF1-rEBV–infected cell clones became tumorigenic in nude mice. These results suggest that BARF1 plays an important role in NPC development. [Cancer Res 2008;68(4):1030–6]
Stroma-Initiated Hedgehog Signaling Takes Center Stage in B-Cell Lymphoma
Authors: Lindemann Ralph K. 
Published: February 2008

Abstract
Hedgehog-mediated signaling has been shown to promote growth and dissemination of solid cancers, most prominently basal cell carcinomas and medulloblastoma. Recent findings indicate that hedgehog signals are also important for tumor growth in hematologic malignancies. Hedgehog ligands secreted by stromal cells could elicit Patched/Smoothened-mediated antiapoptotic signaling in mouse B-cell lymphomas. Inhibition of hedgehog signaling induced apoptosis in lymphoma cells and prolonged survival of lymphoma-bearing mice. Depletion of tumor cells proceeded in the absence of p53 via the mitochondrial apoptotic pathway. These and other recently published data on hedgehog inhibition in cancer cells and their implications will be discussed. [Cancer Res 2008;68(4):961–4]
Use of a Cryptic Splice Site for the Expression of Huntingtin Interacting Protein 1 in Select Normal and Neoplastic Tissues
Authors: Graves Chiron W. , Philips Steven T. , Bradley Sarah V. , Oravecz-Wilson Katherine I. , Li Lina , Gauvin Alice , Ross Theodora S. 
Published: February 2008

Abstract
Huntingtin interacting protein 1 (HIP1) is a 116-kDa endocytic protein, which is necessary for the maintenance of several tissues in vivo as its deficiency leads to degenerative adult phenotypes. HIP1 deficiency also inhibits prostate tumor progression in mice. To better understand how deficiency of HIP1 leads to such phenotypes, we analyzed tumorigenic potential in mice homozygous for a Hip1 mutant allele, designated Hip1Δ3-5, which is predicted to result in a frame-shifted, nonsense mutation in the NH2 terminus of HIP1. In contrast to our previous studies using the Hip1 null allele, an inhibition of tumorigenesis was not observed as a result of the homozygosity of the nonsense Δ3-5 allele. To further examine the contrasting results from the prior Hip1 mutant mice, we cultured tumor cells from homozygous Δ3-5 allele–bearing mice and discovered the presence of a 110-kDa form of HIP1 in tumor cells. Upon sequencing of Hip1 DNA and message from these tumors, we determined that this 110-kDa form of HIP1 is the product of splicing of a cryptic U12-type AT-AC intron. This event results in the insertion of an AG dinucleotide between exons 2 and 6 and restoration of the reading frame. Remarkably, this mutant protein retains its capacity to bind lipids, clathrin, AP2, and epidermal growth factor receptor providing a possible explanation for why tumorigenesis was not altered after this knockout mutation. Our data show how knowledge of the transcript that is produced by a knockout allele can lead to discovery of novel types of molecular compensation at the level of splicing. [Cancer Res 2008;68(4):1064–73]
Construction of Optimized Bispecific Antibodies for Selective Activation of the Death Receptor CD95
Authors: Herrmann Tanja , Große-Hovest Ludger , Otz Tina , Krammer Peter H. , Rammensee Hans-Georg , Jung Gundram 
Published: February 2008

AbstractWe have previously reported that bispecific antibodies directed to different target antigens on lymphoma cells and to the death receptor CD95/Fas/Apo-1 selectively kill these cells, thus providing an attractive strategy for the selective stimulation of CD95 on the surface of tumor cells. Here, we further explore the general applicability of this approach under more stringent conditions using various bispecific antibodies directed to different target antigens on glioblastoma cells which express relatively low levels of CD95. We found that bispecific CD95 antibodies targeting the neuronal glial antigen-2 induce CD95-mediated apoptosis selectively in glioblastoma cells expressing this target antigen. A recombinant bispecific single-chain antibody was as effective as a chemically hybridized F(ab′)2 fragment with identical specificities. In contrast, a bispecific F(ab′)2 fragment binding to the epidermal growth factor receptor on the glioblastoma cells failed to induce apoptosis. This is most likely due to the exclusively unicellular binding of this particular fragment to target cells expressing both the epidermal growth factor receptor and CD95. If this type of binding in a cis configuration is favored by a particular bispecific antibody, rather than a bicellular binding in trans, effective cross-linking of CD95 does not occur and apoptosis is not induced. To facilitate bicellular binding in a trans configuration, we constructed a bispecific antibody directed to the extracellular matrix protein tenascin. As expected, this reagent was the most effective of all the antibodies tested. The presence of sensitizing reagents such as cycloheximide and various cytostatic drugs further enhanced antibody-mediated killing of the tumor cells. We believe that these results may point the way to a successful application of bispecific CD95 antibodies in experimental tumor therapy. [Cancer Res 2008;68(4):1221–7]
Tumor-Selective Replication of an Oncolytic Adenovirus Carrying Oct-3/4 Response Elements in Murine Metastatic Bladder Cancer Models
Authors: Wu Chao-Liang , Shieh Gia-Shing , Chang Chao-Ching , Yo Yi-Te , Su Chih-Hau , Chang Meng-Ya , Huang Yin-Hui , Wu Pensee , Shiau Ai-Li 
Published: February 2008

AbstractPurpose: Oncolytic adenoviruses are attractive therapeutics for cancer because they selectively replicate in tumors. However, targeting tumor metastasis remains a major challenge for current virotherapy for cancer. Oct-3/4 is specifically expressed in embryonic stem cells and tumor cells. Oct-3/4 highly expressed in cancer cells may be a potential target for cancer therapy. We developed an E1B-55 kDa–deleted adenovirus, designated Ad.9OC, driven by nine copies of Oct-3/4 response element for treating Oct-3/4–expressing metastatic bladder cancer.Experimental Design: We examined the expression of Oct-3/4 in human bladder tumor tissues and bladder cancer cell lines. We also evaluated the cytolytic and antitumor effects of Ad.9OC on bladder cancer cells in vitro and in vivo.Results: Oct-3/4 expression was detected in bladder cancer cell lines, as well as in human bladder tumor tissues. Notably, Oct-3/4 expression was higher in metastatic compared with nonmetastatic bladder cancer cells. Ad.9OC induced higher cytolytic activity in metastatic bladder cancer cells than in their nonmetastatic counterparts, whereas it did not cause cytotoxicity in normal cells. Pharmacologic and short hairpin RNA–mediated Oct-3/4 inhibition rendered bladder cancer cells more resistant to Ad.9OC-induced cytolysis. Replication of Ad.9OC was detected in murine bladder cancer cells and bladder tumor tissues. We also showed the effectiveness of Ad.9OC for treating bladder cancer in subcutaneous, as well as metastatic, bladder tumor models.Conclusions: Ad.9OC may have therapeutic potential for treating Oct-3/4–expressing tumors. Especially, metastatic bladder tumors are good target for Ad.9OC treatment. Because Oct-3/4 is expressed in a broad spectrum of cancers, Ad.9OC may be broadly applicable.