bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nordihydroguaiaretic Acid Inhibits an Activated Fibroblast Growth Factor Receptor 3 Mutant and Blocks Downstream Signaling in Multiple Myeloma Cells
Authors: Meyer April N. , McAndrew Christopher W. , Donoghue Daniel J. 
Published: September 2008

AbstractActivating mutations within fibroblast growth factor receptor 3 (FGFR3), a receptor tyrosine kinase, are responsible for human skeletal dysplasias including achondroplasia and the neonatal lethal syndromes, Thanatophoric Dysplasia (TD) type I and II. Several of these same FGFR3 mutations have also been identified somatically in human cancers, including multiple myeloma, bladder carcinoma, and cervical cancer. Based on reports that strongly activated mutants of FGFR3 such as the TDII (K650E) mutant signal preferentially from within the secretory pathway, the inhibitory properties of nordihydroguaiartic acid (NDGA), which blocks protein transport through the Golgi, were investigated. NDGA was able to inhibit FGFR3 autophosphorylation both in vitro and in vivo. In addition, signaling molecules downstream of FGFR3 activation such as signal transducers and activators of transcription (STAT)1, STAT3, and mitogen-activated protein kinase (MAPK) were inhibited by NDGA treatment. Using HEK293 cells expressing activated FGFR3-TDII, together with several multiple myeloma cell lines expressing activated forms of FGFR3, NDGA generally resulted in a decrease in MAPK activation by 1 hour, and resulted in increased apoptosis over 24 hours. The effects of NDGA on activated FGFR3 derivatives targeted either to the plasma membrane or the cytoplasm were also examined. These results suggest that inhibitory small molecules such as NDGA that target a specific subcellular compartment may be beneficial in the inhibition of activated receptors such as FGFR3 that signal from the same compartment. [Cancer Res 2008;68(18):7362–70]
Interaction of Muc2 and Apc on Wnt Signaling and in Intestinal Tumorigenesis: Potential Role of Chronic Inflammation
Authors: Yang Kan , Popova Natalia V. , Yang Wan Cai , Lozonschi Ioanna , Tadesse Selam , Kent Scott , Bancroft Laura , Matise Ilze , Cormier Robert T. , Scherer Stefan J. , Edelmann Winfried , Lipkin Martin , Augenlicht Leonard , Velcich Anna 
Published: September 2008

Abstract
Somatic mutations of the adenomatous polyposis coli (APC) gene are initiating events in the majority of sporadic colon cancers. A common characteristic of such tumors is reduction in the number of goblet cells that produce the mucin MUC2, the principal component of intestinal mucus. Consistent with these observations, we showed that Muc2 deficiency results in the spontaneous development of tumors along the entire gastrointestinal tract, independently of deregulated Wnt signaling. To dissect the complex interaction between Muc2 and Apc in intestinal tumorigenesis and to elucidate the mechanisms of tumor formation in Muc2−/− mice, we crossed the Muc2−/− mouse with two mouse models, Apc1638N/+ and ApcMin/+, each of which carries an inactivated Apc allele. The introduction of mutant Muc2 into Apc1638N/+ and ApcMin/+ mice greatly increased transformation induced by the Apc mutation and significantly shifted tumor development toward the colon as a function of Muc2 gene dosage. Furthermore, we showed that in compound double mutant mice, deregulation of Wnt signaling was the dominant mechanism of tumor formation. The increased tumor burden in the distal colon of Muc2/Apc double mutant mice was similar to the phenotype observed in ApcMin/+ mice that are challenged to mount an inflammatory response, and consistent with this, gene expression profiles of epithelial cells from flat mucosa of Muc2-deficient mice suggested that Muc2 deficiency was associated with low levels of subclinical chronic inflammation. We hypothesize that Muc2−/− tumors develop through an inflammation-related pathway that is distinct from and can complement mechanisms of tumorigenesis in Apc+/− mice. [Cancer Res 2008;68(18):7313–22]
Multimodal Control of Cdc25A by Nitrosative Stress
Authors: Tomko Robert J. , Lazo John S. 
Published: September 2008

Abstract
Cdc25A propels cell cycle progression, is overexpressed in numerous human cancers, and possesses oncogenic and antiapoptotic activities. Reactive oxygen species, such as hydrogen peroxide, regulate Cdc25A, but the physiologic and pathologic effects of nitric oxide (•NO) and •NO-derived reactive species are not well defined. Herein, we report novel independent mechanisms governing Cdc25A in response to nitrosative insult. We observed direct and rapid inhibition of Cdc25A phosphatase activity after in vitro treatment with the low molecular mass cell-permeable S-nitrosothiol S-nitrosocysteine ethyl ester (SNCEE). In addition, treatment of cancer cells with SNCEE induced nitrosative stress and decreased Cdc25A protein levels in a time-dependent and concentration-dependent manner. Similarly, iNOS-derived •NO was sufficient to suppress Cdc25A expression, consistent with its role in mediating nitrosative stress. Whereas a decrease in Cdc25A half-life was not observed in response to SNCEE, we found the translational regulator eukaryotic initiation factor 2α (eIF2α) was hyperphosphorylated and total protein translation was decreased with kinetics consistent with Cdc25A loss. Inhibition of eIF2α decreased Cdc25A levels, supporting the hypothesis that SNCEE suppressed Cdc25A translation through inhibition of eIF2α. Nitrosative stress decreased the Cdc25A-bound fraction of apoptosis signal-regulating kinase-1 (ASK-1) and sensitized cells to apoptosis induced by the ASK-1–activating chemotherapeutic cis-diaminedichloroplatinum (II), suggesting that nitrosative stress–induced suppression of Cdc25A primed cells for ASK-1–dependent apoptosis. Together these data reveal novel •NO-dependent enzymatic and translational mechanisms controlling Cdc25A, and implicate Cdc25A as a mediator of •NO-dependent apoptotic signaling. [Cancer Res 2008;68(18):7457–65]
Quantitative Molecular Magnetic Resonance Imaging of Tumor Angiogenesis Using cNGR-Labeled Paramagnetic Quantum Dots
Authors: Oostendorp Marlies , Douma Kim , Hackeng Tilman M. , Dirksen Anouk , Post Mark J. , van Zandvoort Marc A.M.J. , Backes Walter H. 
Published: September 2008

Abstract
The objective of this study was to develop and apply cyclic Asn-Gly-Arg (cNGR)-labeled paramagnetic quantum dots (cNGR-pQDs) for the noninvasive assessment of tumor angiogenic activity using quantitative in vivo molecular magnetic resonance imaging (MRI). cNGR was previously shown to colocalize with CD13, an aminopeptidase that is highly overexpressed on angiogenic tumor endothelium. Because angiogenesis is important for tumor growth and metastatization, its in vivo detection and quantification may allow objective diagnosis of tumor status and evaluation of treatment response. I.v. injection of cNGR-pQDs in tumor-bearing mice resulted in increased quantitative contrast, comprising increased longitudinal relaxation rate and decreased proton visibility, in the tumor rim but not in tumor core or muscle tissue. This showed that cNGR-pQDs allow in vivo quantification and accurate localization of angiogenic activity. MRI results were validated using ex vivo two-photon laser scanning microscopy (TPLSM), which showed that cNGR-pQDs were primarily located on the surface of tumor endothelial cells and to a lesser extent in the vessel lumen. In contrast, unlabeled pQDs were not or only sparsely detected with both MRI and TPLSM, supporting a high specificity of cNGR-pQDs for angiogenic tumor vasculature. [Cancer Res 2008;68(18):7676–83]
CYR61 and αVβ5 Integrin Cooperate to Promote Invasion and Metastasis of Tumors Growing in Preirradiated Stroma
Authors: Monnier Yan , Farmer Pierre , Bieler Gregory , Imaizumi Natsuko , Sengstag Thierry , Alghisi Gian Carlo , Stehle Jean-Christophe , Ciarloni Laura , Andrejevic-Blant Snezana , Moeckli Raphael , Mirimanoff René-Olivier , Goodman Simon L. , Delorenzi Mauro , Rüegg Curzio 
Published: September 2008

Abstract
Radiotherapy is widely used to treat human cancer. Patients locally recurring after radiotherapy, however, have increased risk of metastatic progression and poor prognosis. The clinical management of postradiation recurrences remains an unresolved issue. Tumors growing in preirradiated tissues have an increased fraction of hypoxic cells and are more metastatic, a condition known as tumor bed effect. The transcription factor hypoxia inducible factor (HIF)-1 promotes invasion and metastasis of hypoxic tumors, but its role in the tumor bed effect has not been reported. Here, we show that tumor cells derived from SCCVII and HCT116 tumors growing in a preirradiated bed, or selected in vitro through repeated cycles of severe hypoxia, retain invasive and metastatic capacities when returned to normoxia. HIF activity, although facilitating metastatic spreading of tumors growing in a preirradiated bed, is not essential. Through gene expression profiling and gain- and loss-of-function experiments, we identified the matricellular protein CYR61 and αVβ5 integrin as proteins cooperating to mediate these effects. The anti-αV integrin monoclonal antibody 17E6 and the small molecular αVβ3/αVβ5 integrin inhibitor EMD121974 suppressed invasion and metastasis induced by CYR61 and attenuated metastasis of tumors growing within a preirradiated field. These results represent a conceptual advance to the understanding of the tumor bed effect and identify CYR61 and αVβ5 integrin as proteins that cooperate to mediate metastasis. They also identify αV integrin inhibition as a potential therapeutic approach for preventing metastasis in patients at risk for postradiation recurrences. [Cancer Res 2008;68(18):7323–31]
Epigenetic Silencing of Cell Adhesion Molecule 1 in Different Cancer Progenitor Cells of Transgenic c-Myc and c-Raf Mouse Lung Tumors
Authors: Reamon-Buettner Stella Marie , Borlak Juergen 
Published: September 2008

Abstract
Understanding molecular mechanisms underlying lung cancer is a prerequisite toward treatment. To enable mechanistic investigations into the epigenetic regulation of the tumor suppressor gene cell adhesion molecule 1 (Cadm1) in lung cancer progenitor cells, we developed 10 cell lines from single, spontaneously transformed lung tumor cells isolated from c-Myc and c-Raf double-transgenic mice. Specifically, we investigated Cadm1 promoter hypermethylation, which was significantly induced in transgenic transformed cells. Analysis of 69 CpGs displayed differential methylation pattern between and within progenitor cell lines, and the degree of methylation correlated well with transcriptional repression. Indeed, restoration of Cadm1 gene expression was achieved by treatment with the experimental demethylating drug 5-aza-2′-deoxycytidine. Furthermore, methylation of core CpGs in the binding sites of Sp1, Sp3, and zinc finger 5 along the promoter region of Cadm1 abrogated DNA-protein binding. Treatment with mithramycin A, an inhibitor of Sp1 or Sp3 binding, resulted in reduction of Cadm1 gene expression, therefore suggesting a potential role of Sp1/Sp3 in Cadm1 regulation. Identifying molecular rules for the epigenetic control of tumor suppressor genes enables mechanistic insights into lung cancer growth and opportunities for novel therapies. [Cancer Res 2008;68(18):7587–96]
Prevention of Both Direct and Cross-Priming of Antitumor CD8+ T-Cell Responses following Overproduction of Prostaglandin E2 by Tumor CellsIn vivo
Authors: Ahmadi Maryam , Emery David C. , Morgan David J. 
Published: September 2008

AbstractDefects in antitumor immune responses have been associated with increased release of prostaglandin E2 (PGE2) as a result of overexpression of cyclooxygenase (COX)-2 by tumors. In this report, we examine the effects of PGE2 on antitumor CD8+ T-cell responses generated both by cross-presenting dendritic cells and by direct priming by tumor cells. Our data show that PGE2 inhibits dendritic cell maturation, resulting in the abortive activation of naive CD8+ T cells, and is dependent on interleukin-10 production by dendritic cells. Interaction of tumor cells with naïve CD8+ T cells in the presence of PGE2 in vitro results in the induction of CD8+ CD28− T cells, which fail to proliferate or exhibit effector function. In vivo, overexpression of COX-2 by tumor cells results in a decrease in number of tumor-infiltrating dendritic cells and confers the ability of tumor cells to metastasize to the tumor draining lymph nodes. [Cancer Res 2008;68(18):7520–9]
Functional Characterization of Filamin A Interacting Protein 1–Like, a Novel Candidate for Antivascular Cancer Therapy
Authors: Kwon Mijung , Hanna Engy , Lorang Dominique , He Mei , Quick John S. , Adem Asha , Stevenson Christina , Chung Joon-Yong , Hewitt Stephen M. , Zudaire Enrique , Esposito Dominic , Cuttitta Frank , Libutti Steven K. 
Published: September 2008

Abstract
Inhibiting angiogenesis has become a major therapeutic strategy for cancer treatment. To identify common intracellular mediators, we previously analyzed gene expression profiles of endothelial cells after treatment with angiogenesis inhibitors. Filamin A interacting protein 1-like (FILIP1L; previously known as down-regulated in ovarian cancer 1) was identified as one of the genes up-regulated in endothelial cells in response to these inhibitors. However, the expression and function of FILIP1L protein is uncharacterized. Here, we provide the first description of the expression and specific subcellular localization of FILIP1L protein in human tissue. Overexpression of FILIP1L resulted in inhibition of cell proliferation and migration and increased apoptosis. In addition, overexpression of FILIP1L truncation mutants showed differential antiproliferative activity. A COOH terminal truncation mutant (FILIP1LΔC103) was more potent than wild-type FILIP1L in mediating this activity. Targeted expression of FILIP1LΔC103 in tumor vasculature inhibited tumor growth in vivo. Overall, these findings suggest that the novel protein FILIP1L may be an important mediator of the effects of angiogenesis inhibitors and that FILIP1L has the potential to be an antivascular reagent for cancer therapy. [Cancer Res 2008;68(18):7332–41]
Regulation of Cyclin D1 RNA Stability by SNIP1
Authors: Bracken Cameron P. , Wall Steven J. , Barré Benjamin , Panov Kostya I. , Ajuh Paul M. , Perkins Neil D. 
Published: September 2008

Abstract
Cyclin D1 expression represents one of the key mitogen-regulated events during the G1 phase of the cell cycle, whereas Cyclin D1 overexpression is frequently associated with human malignancy. Here, we describe a novel mechanism regulating Cyclin D1 levels. We find that SNIP1, previously identified as a regulator of Cyclin D1 expression, does not, as previously thought, primarily function as a transcriptional coactivator for this gene. Rather, SNIP1 plays a critical role in cotranscriptional or posttranscriptional Cyclin D1 mRNA stability. Moreover, we show that the majority of nucleoplasmic SNIP1 is present within a previously undescribed complex containing SkIP, THRAP3, BCLAF1, and Pinin, all proteins with reported roles in RNA processing and transcriptional regulation. We find that this complex, which we have termed the SNIP1/SkIP–associated RNA-processing complex, is coordinately recruited to both the 3′ end of the Cyclin D1 gene and Cyclin D1 RNA. Significantly, SNIP1 is required for the further recruitment of the RNA processing factor U2AF65 to both the Cyclin D1 gene and RNA. This study shows a novel mechanism regulating Cyclin D1 expression and offers new insight into the role of SNIP1 and associated proteins as regulators of proliferation and cancer. [Cancer Res 2008;68(18):7621–8]
Development of Resistance to Targeted Therapies Transforms the Clinically Associated Molecular Profile Subtype of Breast Tumor Xenografts
Authors: Creighton Chad J. , Massarweh Suleiman , Huang Shixia , Tsimelzon Anna , Hilsenbeck Susan G. , Osborne C. Kent , Shou Jiang , Malorni Luca , Schiff Rachel 
Published: September 2008

Abstract
The effectiveness of therapies targeting specific pathways in breast cancer, such as the estrogen receptor or HER2, is limited because many tumors manifest resistance, either de novo or acquired, during the course of treatment. To investigate molecular mechanisms of resistance, we used two xenograft models of estrogen receptor–positive (ER+) breast cancer, one with and one without HER2 overexpression (MCF7/HER2-18 and MCF7 wt, respectively). Mice with established tumors were assigned to the following treatment groups: estrogen supplementation (E2), estrogen deprivation (ED), ED plus tamoxifen (Tam), all with or without the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (G). Another group received ED plus the antiestrogen fulvestrant (MCF7 wt only). Tumors with acquired or de novo resistance to these endocrine therapies were profiled for gene expression and compared with tumors in the E2 control group. One class of genes underexpressed in endocrine-resistant tumors (relative to E2-treated tumors) were estrogen inducible in vitro and associated with ER+ human breast cancers (luminal subtype). Another class of genes overexpressed in tumors with acquired resistance in both models represented transcriptional targets of HER2 signaling and was associated with ER−/HER2+ human cancers (ERBB2+ subtype). A third class of genes overexpressed in MCF7/HER2-18 tumors exhibiting de novo resistance to tamoxifen was associated with ER+ human cancers but not with estrogen-regulated genes. Thus, in response to various endocrine therapy regimens, these xenograft breast tumors shut down classic estrogen signaling and activate alternative pathways such as HER2 that contribute to treatment resistance. Over time, the molecular phenotype of breast cancer can change. [Cancer Res 2008;68(18):7493–501]
Identification of a Small Molecule with Synthetic Lethality for K-Ras and Protein Kinase C Iota
Authors: Guo Wei , Wu Shuhong , Liu Jinsong , Fang Bingliang 
Published: September 2008

Abstract
K-Ras mutations are frequently found in various cancers and are associated with resistance to treatment or poor prognosis. Similarly, poor outcomes have recently been observed in cancer patients with overexpression of protein kinase C iota (PKCι), an atypical protein kinase C that is activated by oncogenic Ras protein and is required for K-Ras–induced transformation and colonic carcinogenesis in vivo. Thus far, there is no effective agent for treatment of cancers with K-Ras mutations or PKCι overexpression. By synthetic lethality screening, we identified a small compound (designated oncrasin-1) that effectively kills various human lung cancer cells with K-Ras mutations at low or submicromolar concentrations. The cytotoxic effects correlated with apoptosis induction, as was evidenced by increase of apoptotic cells and activation of caspase-3 and caspase-8 upon the treatment of oncrasin-1 in sensitive cells. Treatment with oncrasin-1 also led to abnormal aggregation of PKCι in the nucleus of sensitive cells but not in resistant cells. Furthermore, oncrasin-1–induced apoptosis was blocked by siRNA of K-Ras or PKCι, suggesting that oncrasin-1 is targeted to a novel K-Ras/PKCι pathway. The in vivo administration of oncrasin-1 suppressed the growth of K-ras mutant human lung tumor xenografts by &gt;70% and prolonged the survival of nude mice bearing these tumors, without causing detectable toxicity. Our results indicate that oncrasin-1 or its active analogues could be a novel class of anticancer agents, which effectively kill K-Ras mutant cancer cells. [Cancer Res 2008;68(18):7403–8]
CCN5/WISP-2 Expression in Breast Adenocarcinoma Is Associated with Less Frequent Progression of the Disease and Suppresses the Invasive Phenotypes of Tumor Cells
Authors: Banerjee Snigdha , Dhar Gopal , Haque Inamul , Kambhampati Suman , Mehta Smita , Sengupta Krishanu , Tawfik Ossama , Phillips Teresa A. , Banerjee Sushanta K. 
Published: September 2008

Abstract
Although previous in vitro studies predicted that CCN5/WISP-2 may act as an anti-invasive gene in breast cancer, the distribution pattern of CCN5 in breast cancer samples is conflicting. Thus, we systematically investigated the CCN5 expression profile in noninvasive and invasive breast tumor samples and its functional relevance in breast cancer progression. The studies showed that CCN5 expression is biphasic, such that in normal samples CCN5 expression is undetectable, whereas its expression is markedly increased in noninvasive breast lesions, including atypical ductal hyperplasia and ductal carcinoma in situ. Further, CCN5 mRNA and protein levels are significantly reduced as the cancer progresses from a noninvasive to invasive type. Additionally, we showed that CCN5 mRNA and protein level was almost undetectable in poorly differentiated cancers compared with the moderately or well-differentiated samples and its expression inversely correlated with lymph node positivity. The result was further supported by evaluating the RNA expression profile in microdissected sections using real-time PCR analysis. Therefore, our data suggest a protective function of CCN5 in noninvasive breast tumor cells. This hypothesis was further supported by our in vitro studies illuminating that CCN5 is a negative regulator of migration and invasion of breast cancer cells, and these events could be regulated by CCN5 through the modulation of the expression of genes essential for an invasive front. These include Snail-E-cadherin signaling and matrix metalloproteinase (MMP)-9 and MMP-2. Collectively, these studies suggest that the protective effect of CCN5 in breast cancer progression may have important therapeutic implications. [Cancer Res 2008;68(18):7606–12]
DNA Vaccination Controls Her-2+ Tumors that Are Refractory to Targeted Therapies
Authors: Whittington Paula J. , Piechocki Marie P. , Heng Henry H. , Jacob Jennifer B. , Jones Richard F. , Back Jessica B. , Wei Wei-Zen 
Published: September 2008

Abstract
Her-2/neu+ tumor cells refractory to antibody or receptor tyrosine kinase inhibitors are emerging in treated patients. To investigate if drug resistant tumors can be controlled by active vaccination, gefitinib and antibody sensitivity of four neu+ BALB/c mouse mammary tumor lines were compared. Significant differences in cell proliferation and Akt phosphorylation were observed. Treatment-induced drug resistance was associated with increased chromosomal aberrations as shown by spectral karyotyping analysis, suggesting changes beyond neu signaling pathways. When mice were immunized with pneuTM encoding the extracellular and transmembrane domains of neu, antibody and T-cell responses were induced, and both drug-sensitive and drug-resistant tumor cells were rejected. In T-cell–depleted mice, drug-sensitive tumors were still rejected by vaccination, but drug-refractory tumors survived in some mice, indicating their resistance to anti-neu antibodies. To further test if T cells alone can mediate tumor rejection, mice were immunized with pcytneu encoding full-length cytoplasmic neu that is rapidly degraded by the proteasome to activate CD8 T cells without inducing antibody response. All test tumors were rejected in pcytneu-immunized mice, regardless of their sensitivity to gefitinib or antibody. Therefore, cytotoxic T lymphocytes activated by the complete repertoire of neu epitopes were effective against all test tumors. These results warrant Her-2 vaccination whether tumor cells are sensitive or resistant to Her-2–targeted drugs or antibody therapy. [Cancer Res 2008;68(18):7502–11]