bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cutaneous Human Papillomaviruses Down-regulate AKT1, whereas AKT2 Up-regulation and Activation Associates with Tumors
Authors: O'Shaughnessy Ryan F.L. , Akgũl Baki , Storey Alan , Pfister Herbert , Harwood Catherine A. , Byrne Carolyn 
Published: September 2007

Abstract
Epithelial tumorigenesis has been linked to AKT up-regulation. Human papillomaviruses (HPV) cause anogenital cancers and anogenital HPV infection up-regulates AKT activity. Mounting evidence points to a role for cutaneous HPVs as etiologic factors in skin tumorigenesis. High-risk cutaneous β HPVs have been linked to carcinogenesis in immunosuppressed patients, and high-risk cutaneous HPV8 genes enhance tumorigenesis in transgenic mice. We find that, in contrast to anogenital HPVs, cutaneous HPV8 early genes down-regulate epidermal AKT activity by down-regulating AKT1 isoform levels. This down-regulation occurs before papilloma formation or tumorigenesis and leads to cutaneous differentiation changes that may weaken the epidermal squame for viral release. We find that, in viral warts (papillomas) and HPV gene-induced epidermal tumors, AKT activity can be activated focally by up-regulation and phosphorylation of the AKT2 isoform. In squamous cell carcinomas (SCC), AKT1 down-regulation is also common, consistent with a viral influence, whereas AKT2 up-regulation is widespread. Activation of up-regulated AKT2 by serine phosphorylation associates with high-grade tumors. Our data suggest that AKT2 up-regulation is characteristic of SCC and that coincident AKT2 activation through serine phosphorylation correlates with malignancy. These findings highlight differences between the effects of anogenital and cutaneous HPV on epithelial AKT activity and furthermore show that AKT isoforms can behave differently during epidermal tumorigenesis. These findings also suggest AKT2 as a possible therapeutic tumor target in SCC. [Cancer Res 2007;67(17):8207–15]
Activation of Double-Stranded RNA–Dependent Protein Kinase, A New Pathway by Which Human Polynucleotide Phosphorylase (hPNPaseold-35) Induces Apoptosis
Authors: Sarkar Devanand , Park Eun Sook , Barber Glen N. , Fisher Paul B. 
Published: September 2007

Abstract
Human polynucleotide phosphorylase (hPNPaseold-35) is a type I IFN-inducible 3′,5′ exoribonuclease that mediates mRNA degradation. In melanoma cells, slow and sustained overexpression of hPNPaseold-35 induces G1 cell cycle arrest ultimately culminating in apoptosis, whereas rapid overexpression of hPNPaseold-35 directly promotes apoptosis without cell cycle changes. These observations imply that inhibition of cell cycle progression and induction of apoptosis by hPNPaseold-35 involve multiple intracellular targets and signaling pathways. We now provide evidence that the apoptosis-inducing activity of hPNPaseold-35 is mediated by activation of double-stranded RNA–dependent protein kinase (PKR). Activation of PKR by hPNPaseold-35 precedes phosphorylation of eukaryotic initiation factor-2α and induction of growth arrest and DNA damage-inducible gene 153 (GADD153) that culminates in the shutdown of protein synthesis and apoptosis. Activation of PKR by hPNPaseold-35 also instigates down-regulation of the antiapoptotic protein Bcl-xL. A dominant-negative inhibitor of PKR, as well as GADD153 antisense or bcl-xL overexpression, effectively inhibits apoptosis induction by hPNPaseold-35. These studies elucidate a novel pathway by which an evolutionary conserved RNA-metabolizing enzyme, hPNPaseold-35, regulates cell growth and viability. [Cancer Res 2007;67(17):7948–53]
Side Population Cells Isolated from Mesenchymal Neoplasms Have Tumor Initiating Potential
Authors: Wu Colleen , Wei Qingxia , Utomo Velani , Nadesan Puviindran , Whetstone Heather , Kandel Rita , Wunder Jay S. , Alman Benjamin A. 
Published: September 2007

Abstract
Although many cancers are maintained by tumor-initiating cells, this has not been shown for mesenchymal tumors, in part due to the lack of unique surface markers that identify mesenchymal progenitors. An alternative technique to isolate stem-like cells is to isolate side population (SP) cells based on efflux of Hoechst 33342 dye. We examined 29 mesenchymal tumors ranging from benign to high-grade sarcomas and identified SP cells in all but six samples. There was a positive correlation between the percentage of SP cells and the grade of the tumor. SP cells preferentially formed tumors when grafted into immunodeficient mice, and only cells from tumors that developed from the SP cells had the ability to initiate tumor formation upon serial transplantation. Although SP cells are able to efflux rhodamine dye in addition to Hoechst 33342, we found that the ability to efflux rhodamine dye did not identify a population of cells enriched for tumor-initiating capacity. Here, we identify a subpopulation of cells within a broad range of benign and malignant mesenchymal tumors with tumor-initiating capacity. In addition, our data suggest that the proportion of SP cells could be used as a prognostic factor and that therapeutically targeting this subpopulation of cells could be used to improve patient outcome. [Cancer Res 2007;67(17):8216–22]
γ-Secretase Inhibitor Prevents Notch3 Activation and Reduces Proliferation in Human Lung Cancers
Authors: Konishi Jun , Kawaguchi Keiko S. , Vo Huan , Haruki Nobuhiro , Gonzalez Adriana , Carbone David P. , Dang Thao P. 
Published: September 2007

Abstract
Notch receptors are key regulators of development by controlling cell-fate determination in many multicellular organisms. Genes that are important for normal differentiation play a role in cancer when their normal functions became dysregulated. Notch signaling has been shown to promote and maintain survival of many types of cancers, and we previously have shown that Notch3 plays an important role in lung cancer. In this study, we showed that a high percentage of lung cancer lines expressed Jagged1, Notch receptors, and their transcriptional target genes (HES1, Hey1), suggesting that the Notch pathway plays an important role in lung cancer biology. Thus, inhibition of Notch receptor activation represents a compelling treatment strategy. Notch activation requires proteolytic cleavage of the receptor by γ-secretase protein complex. In this study, we determined the ability of MRK-003, a γ-secretase inhibitor, to inhibit Notch3 signaling, growth, and apoptosis of lung cancer cell lines in vitro and in vivo using mouse xenograft models. We also found that MRK-003 inhibited Notch3 signaling, reduced tumor cell proliferation, inhibited serum independence, and induced apoptosis. This drug had no effect when Notch3 expression was knocked down using small interfering RNA (siRNA), suggesting that the observed effects were mediated by specific action on this receptor. In conclusion, these results support the hypothesis that inhibition of Notch activation using a γ-secretase inhibitor represents a potential new approach for the targeted therapy of lung cancer. [Cancer Res 2007;67(17):8051–7]
Use of Reverse Genetics to Enhance the Oncolytic Properties of Newcastle Disease Virus
Authors: Vigil Adam , Park Man-Seong , Martinez Osvaldo , Chua Mark A. , Xiao Sa , Cros Jerome F. , Martínez-Sobrido Luis , Woo Savio L.C. , García-Sastre Adolfo 
Published: September 2007

Abstract
Naturally occurring strains of Newcastle disease virus (NDV) have shown oncolytic therapeutic efficacy in preclinical studies and are currently in clinical trials. Here, we have evaluated the possibility to enhance the cancer therapeutic potential of NDV by means of reverse genetics. Mice bearing s.c. implanted CT26 tumors were treated with intratumoral (i.t.) injections of a recombinant NDV modified to contain a highly fusogenic F protein. These treated mice exhibited significant reduction in tumor development compared with mice treated with the unmodified virus. Furthermore, mice in a CT26 metastatic tumor model treated with an i.v. injection of the genetically engineered NDV exhibited prolonged survival compared with wild-type control virus. In addition, we examined whether the oncolytic properties of NDV could be improved by expression of immunostimulatory molecules. In this regard, we engineered several NDVs to express granulocyte macrophage colony-stimulating factor, IFN-γ, interleukin 2 (IL-2), or tumor necrosis factor α, and evaluated their therapeutic potential in an immunocompetent colon carcinoma tumor model. Mice bearing s.c. CT26 tumors treated with i.t. injections of recombinant NDV expressing IL-2 showed dramatic reductions in tumor growth, with a majority of the mice undergoing complete and long-lasting remission. Our data show the use of reverse genetics to develop enhanced recombinant NDV vectors as effective therapeutic agents for cancer treatment. [Cancer Res 2007;67(17):8285–92]
Tumor-Associated Tn-MUC1 Glycoform Is Internalized through the Macrophage Galactose-Type C-Type Lectin and Delivered to the HLA Class I and II Compartments in Dendritic Cells
Authors: Napoletano Chiara , Rughetti Aurelia , Agervig Tarp Mads P. , Coleman Julia , Bennett Eric P. , Picco Gianfranco , Sale Patrizio , Denda-Nagai Kaori , Irimura Tatsuro , Mandel Ulla , Clausen Henrik , Frati Luigi , Taylor-Papadimitriou Joyce , Burchell Joy , Nuti Marianna 
Published: September 2007

AbstractThe type of interaction between tumor-associated antigens and specialized antigen-presenting cells such as dendritic cells (DCs) is critical for the type of immunity that will be generated. MUC1, a highly O-glycosylated mucin, is overexpressed and aberrantly glycosylated in several tumor histotypes. This results in the expression of tumor-associated glycoforms and in MUC1 carrying the tumor-specific glycan Tn (GalNAcα1-O-Ser/Thr). Glycopeptides corresponding to three tandem repeats of MUC1, enzymatically glycosylated with 9 or 15 mol of GalNAc, were shown to specifically bind and to be internalized by immature monocyte-derived DCs (iDCs). Binding required calcium and the GalNAc residue and was competed out by GalNAc polymer and Tn-MUC1 or Tn-MUC2 glycopeptides. The macrophage galactose-type C-type lectin (MGL) receptor expressed on iDCs was shown to be responsible for the binding. Confocal analysis and ELISA done on subcellular fractions of iDCs showed that the Tn-MUC1 glycopeptides colocalized with HLA class I and II compartments after internalization. Importantly, although Tn-MUC1 recombinant protein was bound and internalized by MGL, the glycoprotein entered the HLA class II compartment, but not the HLA class I pathway. These data indicate that MGL expressed on iDCs is an optimal receptor for the internalization of short GalNAcs carrying immunogens to be delivered into HLA class I and II compartments. Such glycopeptides therefore represent a new way of targeting the HLA class I and II pathways of DCs. These results have possible implications in designing cancer vaccines. [Cancer Res 2007;67(17):8358–67]
Real-time Imaging of Tumor-Cell Shedding and Trafficking in Lymphatic Channels
Authors: Hayashi Katsuhiro , Jiang Ping , Yamauchi Kensuke , Yamamoto Norio , Tsuchiya Hiroyuki , Tomita Katsuro , Moossa A.R. , Bouvet Michael , Hoffman Robert M. 
Published: September 2007

Abstract
In the present report, we show real-time imaging of cancer cell trafficking in lymphatic vessels. Cancer cells labeled with both green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm or with GFP only or RFP only were injected into the inguinal lymph node of nude mice. The labeled cancer cells trafficked through lymphatic vessels where they were imaged via a skin flap in real time at the cellular level until they entered the axillary lymph node. The bright fluorescence of the cancer cells and the real-time microscopic imaging capability of the Olympus OV100 small-animal imaging system enabled imaging of the trafficking cancer cells in the lymphatics. Using this imaging strategy, two different cancer cell lines, one expressing GFP and the other expressing RFP, were simultaneously injected in the inguinal lymph node. Fluorescence imaging readily distinguished the two color-coded cell lines and their different abilities to survive in the lymphatic system. Using this imaging technology, we also investigated the role of pressure on tumor-cell shedding into lymphatic vessels. Pressure was generated by placing 25- and 250-g weights for 10 s on the bottom surface of a tumor-bearing footpad. Tumor cell fragments, single cells, and emboli shed from the footpad tumor were easily distinguished with the labeled cells and OV100 imaging system. Increasing pressure on the tumor increased the numbers of shed cells, fragments, and emboli. Pressure also deformed the shed emboli, increasing their maximum major axis. Imaging lymphatic trafficking of cancer cells can reveal critical steps of lymph node metastasis. [Cancer Res 2007;67(17):8223–8]
Integrative Analysis of Genomic Aberrations Associated with Prostate Cancer Progression
Authors: Kim Jung H. , Dhanasekaran Saravana M. , Mehra Rohit , Tomlins Scott A. , Gu Wenjuan , Yu Jianjun , Kumar-Sinha Chandan , Cao Xuhong , Dash Atreya , Wang Lei , Ghosh Debashis , Shedden Kerby , Montie James E. , Rubin Mark A. , Pienta Kenneth J. , Shah Rajal B. , Chinnaiyan Arul M. 
Published: September 2007

Abstract
Integrative analysis of genomic aberrations in the context of trancriptomic alterations will lead to a more comprehensive perspective on prostate cancer progression. Genome-wide copy number changes were monitored using array comparative genomic hybridization of laser-capture microdissected prostate cancer samples spanning stages of prostate cancer progression, including precursor lesions, clinically localized disease, and metastatic disease. A total of 62 specific cell populations from 38 patients were profiled. Minimal common regions (MCR) of alterations were defined for each sample type, and metastatic samples displayed the most number of alterations. Clinically localized prostate cancer samples with high Gleason grade resembled metastatic samples with respect to the size of altered regions and number of affected genes. A total of 9 out of 13 MCRs in the putative precursor lesion, high-grade prostatic intraepithelial neoplasia (PIN), showed an overlap with prostate cancer cases (amplifications in 3q29, 5q31.3-q32, 6q27, and 8q24.3 and deletions in 6q22.31, 16p12.2, 17q21.2, and 17q21.31), whereas postatrophic hyperplasia (PAH) did not exhibit this overlap. Interestingly, prostate cancers that do not overexpress ETS family members (i.e., gene fusion–negative prostate cancers) harbor differential aberrations in 1q23, 6q16, 6q21, 10q23, and 10q24. Integrative analysis with matched mRNA profiles identified genetic alterations in several proposed candidate genes implicated in prostate cancer progression. [Cancer Res 2007;67(17):8229–39]
HOXA5 Acts Directly Downstream of Retinoic Acid Receptor β and Contributes to Retinoic Acid–Induced Apoptosis and Growth Inhibition
Authors: Chen Hexin , Zhang Huiping , Lee Jishin , Liang Xiaohui , Wu Xinyan , Zhu Tao , Lo Pang-kuo , Zhang Xiaokun , Sukumar Saraswati 
Published: September 2007

Abstract
The promise of retinoids as chemopreventive agents in breast cancer is based on the differentiation and apoptosis induced upon their binding to the retinoic acid (RA) receptor β (RARβ). We have previously shown that HOXA5 induces apoptosis in breast cancer cells. In this study, we investigated whether RA/RARβ and HOXA5 actions intersect to induce apoptosis and differentiation in breast cancer cells. We found that HOXA5 expression can be induced by RA only in RARβ-positive breast cancer cells. We have, for the first time, identified the RA response element in HOXA5, which was found to be located in the 3′ end of the gene. Chromatin immunoprecipitation assays showed that RARβ binds directly to this region in vivo. Overexpression of RARβ strongly enhances RA responsiveness, and knocking down RARβ expression abolishes RA-mediated induction of HOXA5 expression in breast cancer cells. In addition, there is coordinated loss of both HOXA5 and RARβ expression during neoplastic transformation and progression in the breast epithelial cell model, MCF10A. Knockdown of HOXA5 expression partially abrogates retinoid-induced apoptosis and promotes cell survival upon RA treatment. These results strongly suggest that HOXA5 acts directly downstream of RARβ and may contribute to retinoid-induced anticancer and chemopreventive effects. [Cancer Res 2007;67(17):8007–13]
Systemic Delivery of γ134.5-Deleted Herpes Simplex Virus-1 Selectively Targets and Treats Distant Human Xenograft Tumors That Express High MEK Activity
Authors: Veerapong Jula , Bickenbach Kai A. , Shao Michael Y. , Smith Kerrington D. , Posner Mitchell C. , Roizman Bernard , Weichselbaum Ralph R. 
Published: September 2007

Abstract
Δγ134.5 mutant herpes simplex type 1 viruses are under active clinical investigation as oncolytic therapy for cancer. Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) activity has been shown to suppress protein kinase R and thereby confer oncolytic susceptibility to some human tumors by R3616, a virus deleted for both copies of γ134.5. We report that systemic delivery of R3616 can selectively target and destroy human xenograft tumors that overexpress MEK activity compared with tumors that express lower MEK activity. These results suggest systemic delivery of R3616 may be effective in the treatment of some human tumors. [Cancer Res 2007;67(17):8301–6]
Leveraging the Immune System during Chemotherapy: Moving Calreticulin to the Cell Surface Converts Apoptotic Death from “Silent” to Immunogenic
Authors: Obeid Michel , Panaretakis Theocharis , Tesniere Antoine , Joza Nick , Tufi Roberta , Apetoh Lionel , Ghiringhelli François , Zitvogel Laurence , Kroemer Guido 
Published: September 2007

Abstract
In contrast to prior belief, tumor cell apoptosis is not necessarily silent but can be immunogenic. By tracing how anthracyclines and γ-irradiation trigger immunogenic cell deaths, we found that they were causally connected to the exposure of calreticulin on the tumor cell surface, before apoptosis in the tumor cell itself occurred. Furthermore, we showed that calreticulin exposure was necessary and sufficient to increase proimmunogenic killing by other chemotherapies. Our findings suggest that calreticulin could serve as a biomarker to predict therapy-associated immune responses, and that tactics to expose calreticulin might improve the clinical efficacy of many cancer therapies. [Cancer Res 2007;67(17):7941–4]
Chromosomal Instability and Supernumerary Centrosomes Represent Precursor Defects in a Mouse Model of T-Cell Lymphoma
Authors: van de Wetering Christopher I. , Knudson C. Michael 
Published: September 2007

AbstractA hallmark of carcinogenesis is resistance to cell death. However, recent studies indicate that Bax expression increased apoptosis and promoted oncogenesis. In this study, we hypothesized that Bax promotes tumor formation by increasing chromosomal instability (CIN). Consistent with this hypothesis, spectral karyotype analysis (SKY) of lymphomas derived from Lck-Bax38/1 mice were consistently aneuploid. To determine if CIN precedes tumor formation, quantitative cytogenetic analysis, SKY analysis, and quantitative centrosome staining were done on thymocytes from young premalignant mice. Between 6 and 10 weeks of age, thymi from Bax-expressing mice (either p53+/+ or p53−/−) had an increased percentage of aneuploid cells as well as an increase in cells with supernumerary centrosomes. For 3- to 6-week-old mice, Bax expression increased aneuploidy and supernumerary centrosomes in p53−/− mice but not in p53+/+ animals. Importantly, both aneuploidy and supernumerary centrosomes were attenuated by Bcl-2. Remarkably, SKY analysis showed multiple independent aneuploid populations in the p53−/− Bax-expressing mice between 3 and 6 weeks of age. These results indicate that oligoclonal aneuploidy and supernumerary centrosomes are early hallmarks of Bax-induced lymphoma formation and support a novel link between the Bcl-2 family and CIN. The data provide an attractive model for the paradoxical effects of the Bcl-2 family on carcinogenesis that have been observed in multiple studies of both humans and mice. [Cancer Res 2007;67(17):8081–8]
A Chemical Screen Identifies Anisomycin as an Anoikis Sensitizer That Functions by Decreasing FLIP Protein Synthesis
Authors: Mawji Imtiaz A. , Simpson Craig D. , Gronda Marcela , Williams Moyo A. , Hurren Rose , Henderson Clare J. , Datti Alessandro , Wrana Jeffrey L. , Schimmer Aaron D. 
Published: September 2007

AbstractMalignant epithelial cells with metastatic potential resist apoptosis that normally occurs upon loss of anchorage from the extracellular matrix, a process termed “anoikis.” Resistance to anoikis enables malignant cells to survive in an anchorage-independent manner, which leads to the formation of distant metastases. To understand the regulation of anoikis, we designed, automated, and conducted a high-throughput chemical screen for anoikis sensitizers. PPC-1 anoikis–resistant prostate cancer cells were seeded in hydrogel-coated ultralow binding plates for suspension conditions and standard tissue culture plates to promote adhesion. After seeding, cells were treated with aliquots from a library of previously characterized small molecules, and viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt, assay. From this chemical screen, we identified anisomycin that induced apoptosis in suspension conditions, but was not toxic to these cells grown under adherent conditions. Anisomycin sensitized cells to anoikis by decreasing levels of the caspase-8 inhibitor FLIP and subsequently activating the death receptor pathway of caspase activation. Although anisomycin activated c-Jun-NH2-kinase and p38, these kinases were not functionally important for the effect of anisomycin on anoikis and FLIP. Rather, anisomycin decreased FLIP and sensitized cells to anoikis by inhibiting its protein synthesis. Finally, we showed that anisomycin decreased distal tumor formation in a mouse model of prostate cancer metastases. Thus, a novel chemical screen identified anisomycin as an anoikis sensitizer that acts by decreasing FLIP protein synthesis. Our results suggest that FLIP is a suppressor of anoikis and inhibiting FLIP protein synthesis may be a useful antimetastatic strategy. [Cancer Res 2007;67(17):8307–15]