bluuebunny/crossref_metadata_2025_split huggingface dataset:
Down-regulation of PU.1 by Methylation of Distal Regulatory Elements and the Promoter Is Required for Myeloma Cell Growth
Authors: Tatetsu Hiro , Ueno Shikiko , Hata Hiroyuki , Yamada Yasuhiro , Takeya Motohiro , Mitsuya Hiroaki , Tenen Daniel G. , Okuno Yutaka 
Published: June 2007

Abstract
The transcription factor PU.1 is essential for myeloid and B-cell development. Down-regulation of PU.1 by disruption of its 14-kb 5′ upstream regulatory element induced acute myeloid leukemia, T-cell lymphoma, and chronic lymphocytic leukemia–like disease in murine models. In the present study, we found that PU.1 was down-regulated in the majority of human myeloma cell lines and a subset of freshly isolated myeloma cells, in contrast to relatively high expression of PU.1 in normal plasma cells. Patients in this low PU.1 expression subset may have a poor prognosis. In human myeloma cell lines, the 17-kb 5′ upstream enhancer and the promoter region of the PU.1 gene were highly methylated, and this is consistent with disappearance of DNase I–hypersensitive sites in these regions. To elucidate the significance of down-regulation of PU.1, we generated stable myeloma cell lines with an inducible PU.1 expression system. Exogenous expression of PU.1 in PU.1 null myeloma cell lines, U266 and KMS12PE, induced complete growth arrest and cell death. Up-regulation of PU.1 by 5-aza-2′-deoxycytidine also induced growth arrest of KMS12PE and KHM11 myeloma cells. These data suggest that down-regulation of PU.1 is an essential step for the survival of a subset of myeloma cells and that up-regulation of PU.1 by demethylation agents or other types of agents may represent a new therapeutic strategy for treatment of multiple myeloma patients. [Cancer Res 2007;67(11):5328–36]
Mel-18 Acts as a Tumor Suppressor by Repressing Bmi-1 Expression and Down-regulating Akt Activity in Breast Cancer Cells
Authors: Guo Wei-Jian , Zeng Mu-Sheng , Yadav Ajay , Song Li-Bing , Guo Bao-Hong , Band Vimla , Dimri Goberdhan P. 
Published: June 2007

Abstract
The Bmi-1 oncogene is overexpressed in a number of malignancies including breast cancer. In addition to Bmi-1, mammalian cells also express four other polycomb group (PcG) proteins that are closely related to Bmi-1. Virtually nothing is known about the role of these PcG proteins in oncogenesis. We have recently reported that Mel-18, a Bmi-1–related PcG protein, negatively regulates Bmi-1 expression, and that its expression negatively correlates with Bmi-1 in proliferating and senescing human fibroblasts. Here, we report that the expression of Bmi-1 and Mel-18 inversely correlates in a number of breast cancer cell lines and in a significant number of breast tumor samples. Overexpression of Mel-18 results in repression of Bmi-1 and reduction of the transformed phenotype in malignant breast cancer cells. Furthermore, the repression of Bmi-1 by Mel-18 is accompanied by the reduction of Akt/protein kinase B (PKB) activity in breast cancer cells. Similarly, Bmi-1 knockdown using RNA interference approach results in down-regulation of Akt/PKB activity and reduction in transformed phenotype of MCF7 cells. Importantly, we show that overexpression of constitutively active Akt overrides tumor-suppressive effect of Mel-18 overexpression and the knockdown of Bmi-1 expression. Thus, our studies suggest that Mel-18 and Bmi-1 may regulate the Akt pathway in breast cancer cells, and that Mel-18 functions as a tumor suppressor by repressing the expression of Bmi-1 and consequently down-regulating Akt activity. [Cancer Res 2007;67(11):5083–9]
Plasma Folate, Vitamin B6, Vitamin B12, and Homocysteine and Pancreatic Cancer Risk in Four Large Cohorts
Authors: Schernhammer Eva , Wolpin Brian , Rifai Nader , Cochrane Barbara , Manson Jo Ann , Ma Jing , Giovannucci Ed , Thomson Cynthia , Stampfer Meir J. , Fuchs Charles 
Published: June 2007

Abstract
Folate deficiency induces DNA breaks and may alter cellular capacity for mutation and epigenetic methylation. Few studies have examined the influence of one-carbon nutrients on pancreatic cancer risk, although recent studies suggest a potential protective effect for one-carbon nutrients from food sources, but not from supplements. We conducted a prospective nested case-control study to examine plasma concentrations of folate, vitamin B6 [whose main circulating form is pyridoxal-5′-phosphate (PLP)], vitamin B12, and homocysteine in relationship to pancreatic cancer, using four large prospective cohorts. Multivariable adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression. All statistical tests were two sided. Among 208 cases and 623 controls, we observed no association between folate, PLP, vitamin B12, or homocysteine and pancreatic cancer risk. Comparing the highest to lowest quartiles of plasma concentration, the ORs were 1.20 (95% CI, 0.76–1.91) for folate, 0.80 (95% CI, 0.51–1.25) for B6, 0.91 (95% CI, 0.57–1.46) for B12, and 1.43 (95% CI, 0.90–2.28) for homocysteine. In analyses restricted to nonusers of multivitamins, we observe a modest inverse trend between folate, PLP, and B12 and pancreatic cancer risk. In contrast, no such inverse associations were observed among study subjects who reported multivitamin supplement use. Among all participants, plasma levels of folate, B6, B12, and homocysteine were not associated with a significant reduction in the risk of pancreatic cancer. Among participants who obtain these factors exclusively through dietary sources, there may be an inverse relation between circulating folate, B6, and B12 and risk. [Cancer Res 2007;67(11):5553–60]
Epigenetically Controlled Fibroblast Growth Factor Receptor 2 Signaling Imposes on the RAS/BRAF/Mitogen-Activated Protein Kinase Pathway to Modulate Thyroid Cancer Progression
Authors: Kondo Tetsuo , Zheng Lei , Liu Wei , Kurebayashi Junichi , Asa Sylvia L. , Ezzat Shereen 
Published: June 2007

Abstract
Fibroblast growth factor (FGF) signals play fundamental roles in development and tumorigenesis. Thyroid cancer is an example of a tumor with nonoverlapping genetic mutations that up-regulate mitogen-activated protein kinase (MAPK). Here, we show that FGF receptor 1 (FGFR1), which is expressed mainly in neoplastic thyroid cells, propagates MAPK activation and promotes tumor progression. In contrast, FGFR2 is down-regulated in neoplastic thyroid cells through DNA promoter methylation. Reexpression of FGFR2 competes with FGFR1 for the immediate substrate FGFR substrate 2 to impede signaling upstream of the BRAF/MAPK pathway. These data unmask an epigenetically controlled FGFR2 signal that imposes precisely on the intragenically modified BRAF/MAPK pathway to modulate thyroid cancer behavior. [Cancer Res 2007;67(11):5461–70]
Whole-Body Subcellular Multicolor Imaging of Tumor-Host Interaction and Drug Response in Real Time
Authors: Yang Meng , Jiang Ping , Hoffman Robert M. 
Published: June 2007

Abstract
To noninvasively image cancer cell/stromal cell interaction in the tumor microenvironment and drug response at the cellular level in live animals in real time, we developed a new imageable three-color animal model. The model consists of green fluorescent protein (GFP)–expressing mice transplanted with dual-color cancer cells labeled with GFP in the nucleus and red fluorescent protein in the cytoplasm. The Olympus IV100 Laser Scanning Microscope, with ultra-narrow microscope objectives (“stick objectives”), is used for three-color whole-body imaging of the two-color cancer cells interacting with the GFP-expressing stromal cells. In this model, drug response of both cancer and stromal cells in the intact live animal is also imaged in real time. Various in vivo phenomena of tumor-host interaction and cellular dynamics were imaged, including mitotic and apoptotic tumor cells, stromal cells interacting with the tumor cells, tumor vasculature, and tumor blood flow. This new model system enables the first cellular and subcellular images of unperturbed tumors in the live intact animal. New visible real-time targets for novel anticancer agents are provided in this model, including the color-coded interacting cancer and stromal cells, tumor vasculature, and blood flow. This imageable model should lead to many new insights of in vivo cancer cell biology and to novel drug discovery. [Cancer Res 2007;67(11):5195–200]
Therapeutic Efficacy of Replication-Competent Retrovirus Vector–Mediated Suicide Gene Therapy in a Multifocal Colorectal Cancer Metastasis Model
Authors: Hiraoka Kei , Kimura Takahiro , Logg Christopher R. , Tai Chien-Kuo , Haga Kazunori , Lawson Gregory W. , Kasahara Noriyuki 
Published: June 2007

Abstract
Replication-competent retrovirus (RCR) vectors are intrinsically incapable of infecting quiescent cells and have been shown to achieve highly efficient and tumor-restricted replicative spread and gene transfer in vivo after direct intratumoral injection in a variety of primary cancer models. However, i.v. delivery of RCR vectors expressing therapeutic genes has never previously been tested, particularly in an immunocompetent tumor model. Therefore, in the present study, we sought to test the therapeutic effect of an RCR vector (ACE-CD) carrying the yeast cytosine deaminase (CD) gene, which converts the nontoxic prodrug 5-fluorocytosine (5FC) into the chemotoxin 5-fluorouracil, after delivery by infusion into the locoregional circulation in a multifocal hepatic metastasis model of colon cancer. After confirmation of suicide gene cytotoxicity in vitro, multifocal hepatic tumors were established in syngeneic mice with murine CT26 colorectal cancer cells expressing firefly luciferase (CT26-Luc), and the ACE-CD vector was infused via intrasplenic injection into the portal circulation. Fourteen days after locoregional infusion, systemic administration of 5FC resulted in significant inhibition of bioluminescent signals in mice whose tumors had been infected with RCR but not in control mice. Notably, there was no detectable RCR vector spread to normal liver or bone marrow by quantitative PCR analysis. Our results thus show that locoregional delivery of a suicide gene by RCR vectors infused into the portal circulation results in progressive transduction of multiple tumor foci in the liver, without evidence of spread to adjacent normal parenchyma or extrahepatic tissues, and can achieve significant tumor growth inhibition. [Cancer Res 2007;67(11):5345–53]
Human Macrophages Promote the Motility and Invasiveness of Osteopontin-Knockdown Tumor Cells
Authors: Cheng Jiasen , Huo De-Hua , Kuang Dong-Ming , Yang Jine , Zheng Limin , Zhuang Shi-Mei 
Published: June 2007

AbstractIncreasing evidence indicates that macrophages in tumor stroma can significantly modify the malignant phenotypes of tumors. Osteopontin (OPN) is frequently overexpressed in cancers with high metastatic capacity and, thus, has been considered as a potential therapeutic target. To find out whether macrophages can affect the outcome of OPN-knockdown tumor cells, we used RNA interference (RNAi) to stably silence the OPN expression in the highly invasive human hepatoma cell line SK-Hep-1. Silencing of OPN markedly decreased the motility and invasiveness of the SK-Hep-1 cells. Further studies using this cell model revealed that coculture with human macrophages or macrophage-conditioned medium largely restored the migration and invasion potential of OPN-knockdown tumor cells. Moreover, such macrophage-promoted motility can be effectively blocked either by the addition of OPN-neutralizing antibody to the cocultured medium or by silencing OPN expression in macrophages. These results indicate that macrophage-derived OPN can compensate for the decrease of OPN and thereby restore the metastatic potential of OPN-knockdown tumor cells. Further characterization of the underlying mechanisms disclosed that macrophage-derived OPN exerted its function independently of the actin cytoskeleton rearrangement or the activation of matrix metalloproteinase and Rho families. Our results suggest that there are fine-tuned complex interactions between cancer cells and stroma cells, which may modify the outcome of cancer therapy, and therefore should be considered for the rational design of anticancer strategy. [Cancer Res 2007;67(11):5141–7]
Eradication of Therapy-Resistant Human Prostate Tumors Using a Cancer Terminator Virus
Authors: Sarkar Devanand , Lebedeva Irina V. , Su Zao-zhong , Park Eun-Sook , Chatman Lejuan , Vozhilla Nicollaq , Dent Paul , Curiel David T. , Fisher Paul B. 
Published: June 2007

Abstract
Terminal prostate cancer is refractory to conventional anticancer treatments because of frequent overexpression of antiapoptotic proteins Bcl-2 and/or Bcl-xL. Adenovirus-mediated delivery of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), a secreted cytokine having cancer-selective apoptosis-inducing properties, profoundly inhibits prostate cancer cell growth. However, forced overexpression of Bcl-2 or Bcl-xL renders prostate cancer cells resistant to Ad.mda-7. We constructed a conditionally replication-competent adenovirus in which expression of the adenoviral E1A gene, necessary for replication, is driven by the cancer-specific promoter of progression elevated gene-3 (PEG-3) and which simultaneously expresses mda-7/IL-24 in the E3 region of the adenovirus (Ad.PEG-E1A-mda-7), a cancer terminator virus (CTV). This CTV generates large quantities of MDA-7/IL-24 as a function of adenovirus replication uniquely in cancer cells. Infection of Ad.PEG-E1A-mda-7 (CTV) in normal prostate epithelial cells and parental and Bcl-2– or Bcl-xL–overexpressing prostate cancer cells confirmed cancer cell–selective adenoviral replication, mda-7/IL-24 expression, growth inhibition, and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 (CTV) into xenografts derived from DU-145-Bcl-xL cells in athymic nude mice completely eradicated not only primary tumors but also distant tumors (established in the opposite flank), thereby implementing a cure. These provocative findings advocate potential therapeutic applications of this novel virus for advanced prostate cancer patients with metastatic disease. [Cancer Res 2007;67(11):5434–42]
The Soluble Wnt Receptor Frizzled8CRD-hFc Inhibits the Growth of Teratocarcinomas In vivo
Authors: DeAlmeida Venita I. , Miao Li , Ernst James A. , Koeppen Hartmut , Polakis Paul , Rubinfeld Bonnee 
Published: June 2007

Abstract
Wnt signaling is important for normal cell proliferation and differentiation, and mutations in pathway components are associated with human cancers. Recent studies suggest that altered wnt ligand/receptor interactions might also contribute to human tumorigenesis. Therefore, agents that antagonize wnt signaling at the extracellular level would be attractive therapeutics for these cancers. We have generated a soluble wnt receptor comprising the Frizzled8 cysteine-rich domain (CRD) fused to the human Fc domain (F8CRDhFc) that exhibits favorable pharmacologic properties in vivo. Potent antitumor efficacy was shown using the mouse mammary tumor virus-Wnt1 tumor model under dosing conditions that did not produce detectable toxicity in regenerating tissue compartments. In vitro, F8CRDhFc inhibited autocrine wnt signaling in the teratoma cell lines PA-1, NTera-2, Tera-2, and NCCIT. In vivo, systemic administration of F8CRDhFc significantly retarded the growth of tumor xenografts derived from two of these cell lines, PA-1 and NTera-2. Pharmacodynamic markers of wnt signaling, identified by gene expression analysis of cultured teratoma cells, were also modulated in the tumor xenografts following treatment with F8CRDhFc. Additionally, these markers could be used as indicators of treatment efficacy and might also be useful in identifying patients that would benefit from the therapeutic agent. This is the first report showing the efficacy of a soluble wnt receptor as an antitumor agent and suggests that further development of wnt antagonists will have utility in treating human cancer. [Cancer Res 2007;67(11):5371–9]
HS1-Associated Protein X-1 Regulates Carcinoma Cell Migration and Invasion via Clathrin-Mediated Endocytosis of Integrin αvβ6
Authors: Ramsay Alan G. , Keppler Melanie D. , Jazayeri Mona , Thomas Gareth J. , Parsons Maddy , Violette Shelia , Weinreb Paul , Hart Ian R. , Marshall John F. 
Published: June 2007

AbstractEnhanced expression levels of integrin αvβ6 have been linked to more aggressive invasive carcinoma cell behavior and poorer clinical prognosis. However, how αvβ6 determines invasion and the dynamics of integrin αvβ6 regulation in tumor cells are poorly understood. We have identified the 35-kDa HS1-associated protein X-1 (HAX-1) protein as a novel binding partner of the β6 cytoplasmic tail using a yeast two-hybrid screen. We show that αvβ6-dependent migration is blocked following small interfering RNA (siRNA)–mediated depletion of HAX-1 in oral squamous cell carcinoma cell lines. Using both siRNA and membrane-permeable peptides, we show that αvβ6-dependent migration and invasion require HAX-1 to bind directly to β6 and thereby regulate clathrin-mediated endocytosis of αvβ6 integrins. Progression of oral cancer is associated with enhanced expression of αvβ6 and HAX-1 proteins in patient tissue. This report establishes that integrin endocytosis is required for αvβ6-dependent carcinoma cell motility and invasion and suggests that this process is an important mechanism in cancer progression. [Cancer Res 2007;67(11):5275–84]
The Peroxisome Proliferator WY-14,643 Promotes Hepatocarcinogenesis Caused by Endogenously Generated Oxidative DNA Base Modifications in Repair-Deficient Csbm/m/Ogg1−/− Mice
Authors: Trapp Christian , Schwarz Michael , Epe Bernd 
Published: June 2007

Abstract
Basal levels of endogenously generated oxidative DNA modifications such as 7,8-dihydro-8-oxoguanine (8-oxoG) are present in apparently all mammalian cells, but their relevance for the generation of spontaneous cancers remains to be established. Both the 8-oxoG levels and the resulting spontaneous mutations are increased in the livers of Csbm/m/Ogg1−/− mice, which are deficient in the repair of 8-oxoG. In order to determine the consequences of these additional oxidative DNA modifications and mutations and thus assess the tumor initiating potency of this type of endogenous DNA damage, we treated Csbm/m/Ogg1−/− mice and repair-proficient controls with the peroxisome proliferator WY-14,643 (0.025% ad libitum), a potent inducer of liver cell proliferation. The treatment did not generate any additional oxidative DNA damage; the elevated levels of 8-oxoG in the Csbm/m/Ogg1−/− mice even decreased. Also, the spontaneous mutation frequencies observed in the lacI gene of BigBlue Csbm/m/Ogg1−/− mice, which were ∼3-fold higher than in the repair-proficient mice, declined by 39% under the treatment, whereas the frequencies in the livers of the repair-proficient animals remained unchanged. Preneoplastic lesions (staining positive or negative for glucose-6-phoshatase) developed in the livers of both wild-type and Csbm/m/Ogg1−/− mice after 30 weeks. Both the numbers and the total volumes of the lesions were ∼6-fold higher in the repair-deficient mice than in the wild-type mice. The results indicate that spontaneous mutations generated from endogenous oxidative DNA base damage efficiently translate into increased tumorigenesis when cell proliferation is stimulated. [Cancer Res 2007;67(11):5156–61]
Myc Goes Global: New Tricks for an Old Oncogene
Authors: Knoepfler Paul S. 
Published: June 2007

Abstract
Myc, a transcription factor commonly deregulated in tumorigenesis, is thought to mediate its diverse cellular effects by altering the expression of specific target genes. However, it has been difficult to gain a precise understanding of how Myc drives cancer because Myc acts rather weakly at many of its target loci, and it has been reported to regulate as many as 10% to 15% of all cellular genes. A new perspective on this issue has been provided by a recent study that revealed Myc can regulate chromatin structure in a global fashion. These findings suggest actions for Myc that extend beyond the traditional concept of a targeted gene regulator. [Cancer Res 2007;67(11):5061–3]
Regression of Early and Intermediate Stages of Colon Cancer by Targeting Multiple Members of the EGFR Family with EGFR-Related Protein
Authors: Schmelz Eva M. , Xu Hu , Sengupta Radha , Du Jianhua , Banerjee Sanjeev , Sarkar Fazlul H. , Rishi Arun K. , Majumdar Adhip P.N. 
Published: June 2007

Abstract
A role of the epidermal growth factor receptor (EGFR) family has been suggested in colon cancer etiology, progression, and/or severity. Our recently identified pan-erbB inhibitor EGFR-related protein (ERRP) targets EGFRs by attenuating their activation and subsequent signaling leading to cellular growth inhibition. In the present study, we evaluated the therapeutic effectiveness of ERRP on early and intermediate stages of colon cancer by examining regression of chemically induced aberrant crypt foci (ACF) in the colon of CF1 mice and intestinal adenomas in APCMin+/− (Min) mice. After formation of ACF or adenomas, the mice were injected (i.p.) with ERRP (50 μg/mouse) for 10 consecutive days. This treatment significantly reduced the number of ACF from 25.0 ± 3.0 (controls) to 14.9 ± 1.6 (ERRP-treated; P = 0.011) and also reduced their size (P &lt; 0.01). In Min mice, ERRP caused the regression of adenomas throughout the small intestine (P &lt; 0.05) and reduced their size (P &lt; 0.001). This could partly be attributed to inhibition of proliferation and stimulation of apoptosis in the intestinal mucosa and was associated with decreased activation of several EGFR family members, suppression of downstream effector nuclear factor κB and down-regulation of cyclooxygenase-2. ERRP-induced attenuation of EGFR activation could be due to increased sequestration of the ligand(s) by ERRP, rendering them unavailable for binding to and activation of the receptor. In conclusion, our data show that ERRP is effective in regressing both early and intermediate intestinal lesions and could be an effective therapeutic agent for colon cancer. [Cancer Res 2007;67(11):5389–96]
Sequential Treatment by Ionizing Radiation and Sodium Arsenite Dramatically Accelerates TRAIL-Mediated Apoptosis of Human Melanoma Cells
Authors: Ivanov Vladimir N. , Zhou Hongning , Hei Tom K. 
Published: June 2007

Abstract
Melanoma is the most lethal form of skin cancer. There is a lack of effective treatments for individuals with advanced disease. Many melanomas exhibit high levels of radioresistance. The direct consequence of γ-irradiation for most melanoma cells is growth arrest at the G2-M phase of cell cycle. However, radiation-induced signaling pathways may affect numerous additional targets in cancer cells. We show in the present study that γ-irradiation, as well as α-particle exposure, dramatically increases the susceptibility of melanoma cells to recombinant tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)-mediated apoptosis via up-regulation of surface TRAIL-receptor 1/receptor 2 (DR4/DR5) levels and to Fas ligand–mediated apoptosis via up-regulation of surface Fas levels. Additionally, increased dynamin-2 expression after irradiation is critically important in the translocation of death receptor to the cell surface. Moreover, sodium arsenite treatment may up-regulate expression of endogenous TRAIL and induces its translocation to cell surface and further down-regulates cFLIP levels in melanoma cells. We have evaluated the effects of sequential γ-irradiation and arsenite treatment of melanoma cells for the induction of death signaling. Such treatment results in an efficient TRAIL-mediated apoptosis via a paracrine mechanism. These data highlight the efficacy of combined modality treatment involving radiation and arsenite in clinical management of this often fatal form of skin cancer. [Cancer Res 2007;67(11):5397–407]