bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Melanoma Cytolysis by Combined Inhibition of Mammalian Target of Rapamycin and Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor-2
Authors: Molhoek Kerrington R. , Griesemann Heinrich , Shu Jianfen , Gershenwald Jeffrey E. , Brautigan David L. , Slingluff Craig L. 
Published: June 2008

AbstractVascular endothelial growth factor (VEGF) plays a vital role in tumor angiogenesis. VEGF is produced by human melanomas, and the VEGF receptor 2 (VEGFR-2) is expressed by most advanced stage melanomas, suggesting the possibility of an autocrine loop. Here, we show that bevacizumab, an anti-VEGF antibody, inhibits proliferation of VEGFR-2+ melanoma cell lines by an average of 41%; however, it failed to inhibit proliferation of VEGFR-2neg melanoma cell lines. The growth inhibitory effect of bevacizumab was eliminated by VEGFR-2 knockdown with small interfering RNA, showing that VEGF autocrine growth in melanoma is mediated through VEGFR-2. However, bevacizumab inhibition of autocrine signals did not completely inhibit cell proliferation nor cause cell death. Cell survival is mediated partially through mammalian target of rapamycin (mTOR), which is inhibited by rapamycin. Combination of bevacizumab with rapamycin caused loss of half of the VEGFR-2+ melanoma cells, but no reduction in the number of VEGFR-2neg melanoma cells. The results show (a) an autocrine growth loop active in VEGFR-2+ melanoma, (b) a nonangiogenic mechanism for inhibition of melanoma by blocking autocrine VEGFR-2 activation, and (c) a possible therapeutic role for combination of inhibitors of mTOR plus VEGF in selected melanomas. [Cancer Res 2008;68(11):4392–7]
RAP80 Responds to DNA Damage Induced by Both Ionizing Radiation and UV Irradiation and Is Phosphorylated at Ser205
Authors: Yan Jun , Yang Xiao-Ping , Kim Yong-Sik , Jetten Anton M. 
Published: June 2008

Abstract
Receptor-associated protein (RAP80), a nuclear protein containing two ubiquitin-interacting motifs (UIM), was recently found to be associated with breast cancer-1 (BRCA1) and to translocate to ionizing radiation–induced foci (IRIF). In this study, we show that the BRCT mutant of BRCA1, R1699W, which is associated with increased risk of breast cancer, is unable to interact with RAP80. Previously, we showed that ataxia-telangiectasia mutated protein kinase (ATM) can phosphorylate RAP80 in vitro at Ser205, but whether this site is a target of ATM in whole cells was not established. To address this question, we generated an anti-RAP80Ser205P antibody that specifically recognizes RAP80 phosphorylated at Ser205. Our data show that RAP80 becomes phosphorylated at Ser205 in cells exposed to ionizing irradiation and that RAP80Ser205P translocates to IRIF. We show that this phosphorylation is mediated by ATM and does not require a functional BRCA1. The phosphorylation occurs within 5 minutes after irradiation, long before the translocation of RAP80 to IRIF. In addition, we show that UV irradiation induces translocation of RAP80 to DNA damage foci that colocalize with γ-H2AX. We further show that this translocation is also dependent on the UIMs of RAP80 and that the UV-induced phosphorylation of RAP80 at Ser205 is mediated by ATM- and RAD3-related kinase, not ATM. These findings suggest that RAP80 has a more general role in different types of DNA damage responses. [Cancer Res 2008;68(11):4269–76]
Is Tumor Growth Sustained by Rare Cancer Stem Cells or Dominant Clones?
Authors: Adams Jerry M. , Strasser Andreas 
Published: June 2008

Abstract
A key issue for cancer biology and therapy is whether the relentless growth of a tumor is driven by a substantial proportion of its cells or exclusively by a rare subpopulation, commonly termed “cancer stem cells.” Support for the cancer stem cell model has been stimulated by experiments in which human tumor cells were transplanted into immunodeficient mice. Most notably, in human acute myeloid leukemia, only a minute proportion of the cells, displaying a defined phenotype, could seed leukemia in mice. Xenotransplantation, however, may fail to reveal many tumor growth–sustaining cells because the foreign microenvironment precludes essential interactions with support cells. In studies that instead have transplanted mouse leukemias and lymphomas into syngeneic animals, most of the tumors seem to be maintained by the dominant cell population, and only a few types of mouse leukemia seem to be sustained by a minor tumor growth–sustaining subpopulation. The collective evidence suggests that various tumors may span the spectrum between the extremes represented by the two models. If tumor growth can indeed be sustained either by rare cancer stem cells or dominant clones or both, as current evidence suggests, curative therapy for many types of tumors will most likely require targeting all the tumor cell populations. [Cancer Res 2008;68(11):4018–21]
β1 Integrin Inhibition Dramatically Enhances Radiotherapy Efficacy in Human Breast Cancer Xenografts
Authors: Park Catherine C. , Zhang Hui J. , Yao Evelyn S. , Park Chong J. , Bissell Mina J. 
Published: June 2008

Abstract
β1 Integrin signaling has been shown to mediate cellular resistance to apoptosis after exposure to ionizing radiation (IR). Other signaling molecules that increase resistance include Akt, which promotes cell survival downstream of β1 integrin signaling. We previously showed that β1 integrin inhibitory antibodies (e.g., AIIB2) enhance apoptosis and decrease growth in human breast cancer cells in three-dimensional laminin-rich extracellular matrix (lrECM) cultures and in vivo. Here, we asked whether AIIB2 could synergize with IR to modify Akt-mediated IR resistance. We used three-dimensional lrECM cultures to test the optimal combination of AIIB2 with IR treatment of two breast cancer cell lines, MCF-7 and HMT3522-T4-2, as well as T4-2 myr-Akt breast cancer colonies or HMT3522-S-1, which form normal organotypic structures in three-dimensional lrECM. Colonies were assayed for apoptosis and β1 integrin/Akt signaling pathways were evaluated using Western blot. In addition, mice bearing MCF-7 xenografts were used to validate the findings in three-dimensional lrECM. We report that AIIB2 increased apoptosis optimally post-IR by down-regulating Akt in breast cancer colonies in three-dimensional lrECM. In vivo, addition of AIIB2 after IR significantly enhanced tumor growth inhibition and apoptosis compared with either treatment alone. Remarkably, the degree of tumor growth inhibition using AIIB2 plus 2 Gy radiation was similar to that of 8 Gy alone. We previously showed that AIIB2 had no discernible toxicity in mice; here, its addition allowed for a significant reduction in the IR dose that was necessary to achieve comparable growth inhibition and apoptosis in breast cancer xenografts in vivo. [Cancer Res 2008;68(11):4398–405]
Molecular Signature of MT1-MMP: Transactivation of the Downstream Universal Gene Network in Cancer
Authors: Rozanov Dmitri V. , Savinov Alexei Y. , Williams Roy , Liu Kang , Golubkov Vladislav S. , Krajewski Stan , Strongin Alex Y. 
Published: June 2008

Abstract
Invasion-promoting MT1-MMP is directly linked to tumorigenesis and metastasis. Our studies led us to identify those genes, the expression of which is universally linked to MT1-MMP in multiple tumor types. Genome-wide expression profiling of MT1-MMP–overexpressing versus MT1-MMP–silenced cancer cells and a further data mining analysis of the preexisting expression database of 190 human tumors of 14 cancer types led us to identify 11 genes, the expression of which correlated firmly and universally with that of MT1-MMP (P &lt; 0.00001). These genes included regulators of energy metabolism (NNT), trafficking and membrane fusion (SLCO2A1 and ANXA7), signaling and transcription (NR3C1, JAG1, PI3Kδ, and CK2α), chromatin rearrangement (SMARCA1), cell division (STK38/NDR1), apoptosis (DAPK1), and mRNA splicing (SNRPB2). Our subsequent extensive analysis of cultured cells, tumor xenografts, and cancer patient biopsies supported our data mining. Our results suggest that transcriptional reprogramming of the specific downstream genes, which themselves are associated with tumorigenesis, represents a distinctive “molecular signature” of the proteolytically active MT1-MMP. We suggest that the transactivation activity of MT1-MMP contributes to the promigratory cell phenotype, which is induced by this tumorigenic proteinase. The activated downstream gene network then begins functioning in unison with MT1-MMP to rework the signaling, transport, cell division, energy metabolism, and other critical cell functions and to commit the cell to migration, invasion, and, consequently, tumorigenesis. [Cancer Res 2008;68(11):4086–96]
Inhibition of Gastric Cancer Invasion and Metastasis by PLA2G2A, a Novel β-Catenin/TCF Target Gene
Authors: Ganesan Kumaresan , Ivanova Tatiana , Wu Yonghui , Rajasegaran Vikneswari , Wu Jeanie , Lee Ming Hui , Yu Kun , Rha Sun Young , Chung Hyun Cheol , Ylstra Bauke , Meijer Gerrit , Lian Kon Oi , Grabsch Heike , Tan Patrick 
Published: June 2008

Abstract
Elevated expression of the PLA2G2A phospholipase in gastric cancer (GC) is associated with improved patient survival. To elucidate function and regulation of PLA2G2A in GC, we analyzed a panel of GC cell lines. PLA2G2A was specifically expressed in lines with constitutive Wnt activity, implicating β-catenin–dependent Wnt signaling as a major upstream regulator of PLA2G2A expression. The invasive ability of PLA2G2A-expressing AGS cells was enhanced by PLA2G2A silencing, whereas cellular migration in non–PLA2G2A-expressing N87 cells was inhibited by enforced PLA2G2A expression, indicating that PLA2G2A is both necessary and sufficient to function as an inhibitor of GC invasion in vitro. We provide evidence that antiinvasive effect of PLA2G2A occurs, at least in part, through its ability to inhibit the S100A4 metastasis mediator gene. Consistent with its invasion inhibitor role, PLA2G2A expression was elevated in primary gastric, colon, and prostrate early-stage tumors, but was decreased in metastatic and late-stage tumors. There was a strong association between PLA2G2A promoter methylation status and PLA2G2A expression, suggesting that the loss of PLA2G2A expression in late-stage cancers may be due to epigenetic silencing. Supporting this, among the non–PLA2G2A-expressing lines, pharmacologic inhibition of epigenetic silencing reactivated PLA2G2A in Wnt-active lines, but in non–Wnt-active lines, a combination of Wnt hyperactivation and inhibition of epigenetic silencing were both required for PLA2G2A reactivation. Our results highlight the complexity of PLA2G2A regulation and provide functional evidence for PLA2G2A as an important regulator of invasion and metastasis in GC. [Cancer Res 2008;68(11):4277–86]
Advanced Transmission Raman Spectroscopy: A Promising Tool for Breast Disease Diagnosis
Authors: Stone Nicholas , Matousek Pavel 
Published: June 2008

Abstract
A novel approach to noninvasively probe the composition of endogenous materials concealed deeply within mammalian tissue is presented. The method relies upon transmission Raman spectroscopy and permits the detailed characterization of the chemical composition of the probed volume. The technique has been enhanced by the deployment of chemometric methods and the use of a dielectric optical element at the surface to force escaping photons back into the tissue and, thus, enhance the relatively weak signals from the deeper tissue and its components. This permitted reaching both the clinically relevant depth and sufficient sensitivity in phantoms for the noninvasive identification of the calcification types associated with benign or malignant breast disease. Both calcium hydroxyapatite and calcium oxalate monohydrate have been chemically identified from depths of up to 2.7 cm within a breast phantom made up of porcine tissues. The technique has shown significant potential for probing human breasts to provide complementary data in the early diagnosis of breast cancer. [Cancer Res 2008;68(11):4424–30]
Novel Role of Thromboxane Receptors β Isoform in Bladder Cancer Pathogenesis
Authors: Moussa Omar , Ashton Anthony W. , Fraig Mostafa , Garrett-Mayer Elizabeth , Ghoneim Mohamed A. , Halushka Perry V. , Watson Dennis K. 
Published: June 2008

AbstractThese studies were undertaken to determine the potential role of thromboxane receptors (TP) in bladder cancer. The data reported herein show that expression of the TP-β receptor protein is increased in tissue obtained from patients with bladder cancer and associated with a significantly poorer prognosis (P &lt; 0.005). Bladder cancer cell lines express the TP-β isoform, unlike immortalized nontransformed urothelial cells (SV-HUC) that express only the TP-α isoform. TP-β receptor expression, but not TP-α, promoted cell proliferation, migration, and invasion in vitro, and also resulted in malignant transformation of SV-HUC cells in vivo. Agonist-mediated phosphorylation of extracellular signal-regulated kinase and FAK was dependent on the expression of TP-β. Furthermore, TP-β mediated multiple biological effects by signaling through either G-protein α subunit 12 or β-arrestin 2. Treatment of mice with the TP receptor antagonist GR32191, alone or in combination with cisplatin, significantly delayed tumor onset and prolonged survival of mice transplanted with TCC-SUP bladder cancer cells compared with vehicle or cisplatin alone. These results support the model that the TP-β receptor isoform plays a unique role in bladder cancer progression and its expression may have predictive value and provide a novel therapeutic target. [Cancer Res 2008;68(11):4097–104]
Paired Toll-like Receptor Agonists Enhance Vaccine Therapy through Induction of Interleukin-12
Authors: Zheng Rongxiu , Cohen Peter A. , Paustian Christopher A. , Johnson Terrence D. , Lee Walter T. , Shu Suyu , Koski Gary K. 
Published: June 2008

Abstract
Minimal requirements for generating effective immunity include the delivery of antigenic (signal 1) and costimulatory (signal 2) signals to T lymphocytes. Recently, a class of third signals, often delivered by antigen-presenting dendritic cells, has been shown to greatly enhance immune responses, especially against tumors. Among signal 3 factors, interleukin (IL)-12 is particularly effective and can be conditionally induced by agonists of Toll-like transmembrane receptors (TLR). In this study, we assessed the therapeutic effect of adjuvant TLR agonist administration upon the capacity of dendritic cell (DC)-tumor electrofusion hybrids to eradicate established MCA205 sarcomas in syngeneic mice. Paired, but not solitary combinations of polyinosine:polycytadilic acid (P[I:C]; TLR3 agonist) and CpG DNA (ODN1826l; TLR9 agonist) stimulated IL-12 secretion from DCs in vitro and synergized with vaccination to achieve potent tumor rejection. Therapeutic effects, however, required coadministration of paired TLR agonists and DC-tumor fusion hybrids. The administration of TLR agonists alone or with fusion vaccine induced transient splenomegaly but without apparent toxicity. The therapeutic effects of this immunization regimen were significantly abrogated through the neutralization of IL-12p70, indicating that production of this third signal was essential to the observed tumor regression. These results show the profound functional consequences of TLR cooperativity and further highlight the critical role of IL-12 in antitumor immunity. [Cancer Res 2008;68(11):4045–9]
Wnt/β-Catenin Signaling Contributes to Activation of Normal and Tumorigenic Liver Progenitor Cells
Authors: Yang Wen , Yan He-Xin , Chen Lei , Liu Qiong , He Ya-Qin , Yu Le-Xing , Zhang Shu-Hui , Huang Dan-Dan , Tang Liang , Kong Xiao-Ni , Chen Chao , Liu Shu-Qin , Wu Meng-Chao , Wang Hong-Yang 
Published: June 2008

Abstract
Adult hepatic progenitor (oval) cells are facultative stem cells in liver, which participate in a range of human liver diseases, including hepatocellular carcinoma (HCC). However, the molecular pathways regulating the expansion and differentiation of these cells are poorly understood. We show that active Wnt/β-catenin signaling occurs preferentially within the oval cell population, and forced expression of constitutively active β-catenin mutant promotes expansion of the oval cell population in the regenerated liver. More importantly, we identify a subpopulation of less differentiated progenitor-like cells in HCC cell lines and primary HCC tissues, which are defined by expression of the hepatic progenitor marker OV6 and endowed with endogenously active Wnt/β-catenin signaling. These OV6+ HCC cells possess a greater ability to form tumor in vivo and show a substantial resistance to standard chemotherapy compared with OV6− tumor cells. The fraction of tumor cells expressing OV6 is enriched after Wnt pathway activation, whereas inhibition of β-catenin signaling leads to a decrease in the proportion of OV6+ cells. In addition, the chemoresistance of OV6+ HCC progenitor-like cells can be reversed by lentivirus-delivered stable expression of microRNA targeting β-catenin. These results highlight the importance of the Wnt/β-catenin pathway in activation and expansion of oval cells in normal rodent models and human HCCs. OV6+ tumor cells may represent the cellular population that confers HCC chemoresistance, and therapies targeted to the Wnt/β-catenin signaling may provide a specific method to disrupt this resistance mechanism to improve overall tumor control with chemotherapy. [Cancer Res 2008;68(11):4287–95]
Genome-Wide Copy Number Analysis in Esophageal Adenocarcinoma Using High-Density Single-Nucleotide Polymorphism Arrays
Authors: Nancarrow Derek J. , Handoko Herlina Y. , Smithers B. Mark , Gotley David C. , Drew Paul A. , Watson David I. , Clouston Andrew D. , Hayward Nicholas K. , Whiteman David C. ,   for the Australian Cancer Study and the Study of Digestive Health
Published: June 2008

Abstract
We applied whole-genome single-nucleotide polymorphism arrays to define a comprehensive genetic profile of 23 esophageal adenocarcinoma (EAC) primary tumor biopsies based on loss of heterozygosity (LOH) and DNA copy number changes. Alterations were common, averaging 97 (range, 23–208) per tumor. LOH and gains averaged 33 (range, 3–83) and 31 (range, 11–73) per tumor, respectively. Copy neutral LOH events averaged 27 (range, 7–57) per EAC. We noted 126 homozygous deletions (HD) across the EAC panel (range, 0–11 in individual tumors). Frequent HDs within FHIT (17 of 23), WWOX (8 of 23), and DMD (6 of 23) suggest a role for common fragile sites or genomic instability in EAC etiology. HDs were also noted for known tumor suppressor genes (TSG), including CDKN2A, CDKN2B, SMAD4, and GALR1, and identified PDE4D and MGC48628 as potentially novel TSGs. All tumors showed LOH for most of chromosome 17p, suggesting that TSGs other than TP53 may be targeted. Frequent gains were noted around MYC (13 of 23), BCL9 (12 of 23), CTAGE1 (14 of 23), and ZNF217 (12 of 23). Thus, we have confirmed previous reports indicating frequent changes to FHIT, CDKN2A, TP53, and MYC in EAC and identified additional genes of interest. Meta-analysis of previous genome-wide EAC studies together with the data presented here highlighted consistent regions of gain on 8q, 18q, and 20q and multiple LOH regions on 4q, 5q, 17p, and 18q, suggesting that more than one gene may be targeted on each of these chromosome arms. The focal gains and deletions documented here are a step toward identifying the key genes involved in EAC development. [Cancer Res 2008;68(11):4163–72]
Twist Is Required for Thrombin-Induced Tumor Angiogenesis and Growth
Authors: Hu Liang , Roth Jennifer M. , Brooks Peter , Ibrahim Sherif , Karpatkin Simon 
Published: June 2008

Abstract
Twist, a master regulator of embryonic morphogenesis, induces functions that are also required for tumor invasion and metastasis. Because thrombin contributes to the malignant phenotype by up-regulating tumor metastasis, we examined its effect on Twist in five different tumor cell lines and two different endothelial cell lines. Thrombin up-regulated Twist mRNA and protein in all seven cell lines. Down-regulation of Twist in B16F10 tumor cell lines led to a ∼3-fold decrease in tumor growth on a chorioallantoic membrane assay and ∼2-fold decrease in syngeneic mice. Angiogenesis was decreased ∼45% and 36%, respectively. The effect of Twist on angiogenesis was further examined and compared with the effect of thrombin. In studies using a Twist-inducible plasmid, several identical vascular growth factors and receptors were up-regulated ∼2- to 3-fold in tumor cells as well as human umbilical vascular endothelial cells by both Twist as well as thrombin (vascular endothelial growth factor, KDR, Ang-2, matrix metalloproteinase 1, GRO-α, and CD31). Thrombin-induced endothelial cell chemotaxis and Matrigel endothelial cell tubule formation were similarly regulated by Twist. Thus, thrombin up-regulates Twist, which is required for thrombin-induced angiogenesis as measured by endothelial cell migration, Matrigel tubule formation, and tumor angiogenesis. [Cancer Res 2008;68(11):4296–302]
Epigenetic Inactivation of the Groucho Homologue Gene TLE1 in Hematologic Malignancies
Authors: Fraga Mario F. , Berdasco Maria , Ballestar Esteban , Ropero Santiago , Lopez-Nieva Pilar , Lopez-Serra Lidia , Martín-Subero José I. , Calasanz Maria J. , de Silanes Isabel Lopez , Setien Fernando , Casado Sara , Fernandez Agustin F. , Siebert Reiner , Stifani Stefano , Esteller Manel 
Published: June 2008

Abstract
An undifferentiated status and the epigenetic inactivation of tumor-suppressor genes are hallmarks of transformed cells. Promoter CpG island hypermethylation of differentiating genes, however, has rarely been reported. The Groucho homologue Transducin-like Enhancer of Split 1 (TLE1) is a multitasked transcriptional corepressor that acts through the acute myelogenous leukemia 1, Wnt, and Notch signaling pathways. We have found that TLE1 undergoes promoter CpG island hypermethylation–associated inactivation in hematologic malignancies, such as diffuse large B-cell lymphoma and AML. We also observed a mutual exclusivity of the epigenetic alteration of TLE1 and the cytogenetic alteration of AML1. TLE1 reintroduction in hypermethylated leukemia/lymphoma cells causes growth inhibition in colony assays and nude mice, whereas TLE1-short hairpin RNA depletion in unmethylated cells enhances tumor growth. We also show that these effects are mediated by TLE1 transcriptional repressor activity on its target genes, such as Cyclin D1, Colony-Stimulating Factor 1 receptor, and Hairy/Enhancer of Split 1. These data suggest that TLE1 epigenetic inactivation contributes to the development of hematologic malignancies by disrupting critical differentiation and growth-suppressing pathways. [Cancer Res 2008;68(11):4116–22]