bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Inactivation of Apc in the Mouse Prostate Causes Prostate Carcinoma
Authors: Bruxvoort Katia J. , Charbonneau Holli M. , Giambernardi Troy A. , Goolsby James C. , Qian Chao-Nan , Zylstra Cassandra R. , Robinson Daniel R. , Roy-Burman Pradip , Shaw Aubie K. , Buckner-Berghuis Bree D. , Sigler Robert E. , Resau James H. , Sullivan Ruth , Bushman Wade , Williams Bart O.
Published: March 2023

Abstract
Alterations of the Wnt/β-catenin signaling pathway are positively associated with the development and progression of human cancer, including carcinoma of the prostate. To determine the role of activated Wnt/β-catenin signaling in mouse prostate carcinogenesis, we created a mouse prostate tumor model using probasin-Cre–mediated deletion of Apc. Prostate tumors induced by the deletion of Apc have elevated levels of β-catenin protein and are highly proliferative. Tumor formation is fully penetrant and follows a consistent pattern of progression. Hyperplasia is observed as early as 4.5 weeks of age, and adenocarcinoma is observed by 7 months. Continued tumor growth usually necessitated sacrifice between 12 and 15 months of age. Despite the high proliferation rate, we have not observed metastasis of these tumors to the lymph nodes or other organs. Surgical castration of 6-week-old mice inhibited tumor formation, and castration of mice with more advanced tumors resulted in the partial regression of specific prostate glands. However, significant areas of carcinoma remained 2 months postcastration, suggesting that tumors induced by Apc loss of function are capable of growth under conditions of androgen depletion. We conclude that the prostate-specific deletion of Apc and the increased expression of β-catenin associated with prostate carcinoma suggests a role for β-catenin in prostate cancer and offers an appropriate animal model to investigate the interaction of Wnt signaling with other genetic and epigenetic signals in prostate carcinogenesis. [Cancer Res 2007;67(6):2490–6]
Data from Eradication of Tumor Colonization and Invasion by a B Cell–Specific Immunotoxin in a Murine Model for Human Primary Intraocular Lymphoma
Authors: Li Zhuqing , Mahesh Sankaranarayana P. , Shen De Fen , Liu Baoying , Siu Willie O. , Hwang Frank S. , Wang Qing-Chen , Chan Chi-Chao , Pastan Ira , Nussenblatt Robert B.
Published: March 2023

Abstract
Human primary intraocular lymphoma (PIOL) is predominantly a B cell–originated malignant disease with no appropriate animal models and effective therapies available. This study aimed to establish a mouse model to closely mimic human B-cell PIOL and to test the therapeutic potential of a recently developed immunotoxin targeting human B-cell lymphomas. Human B-cell lymphoma cells were intravitreally injected into severe combined immunodeficient mice. The resemblance of this tumor model to human PIOL was examined by fundoscopy, histopathology, immunohistochemistry, and evaluated for molecular markers. The therapeutic effectiveness of immunotoxin HA22 was tested by injecting the drug intravitreally. Results showed that the murine model resembles human PIOL closely. Pathologic examination revealed that the tumor cells initially colonized on the retinal surface, followed by infiltrating through the retinal layers, expanding preferentially in the subretinal space, and eventually penetrating through the retinal pigment epithelium into the choroid. Several putative molecular markers for human PIOL were expressed in vivo in this model. Tumor metastasis into the central nervous system was also observed. A single intravitreal injection of immunotoxin HA22 after the establishment of the PIOL resulted in complete regression of the tumor. This is the first report of a murine model that closely mimics human B-cell PIOL. This model may be a valuable tool in understanding the molecular pathogenesis of human PIOL and for the evaluation of new therapeutic approaches. The results of B cell–specific immunotoxin therapy may have clinical implications in treating human PIOL. (Cancer Res 2006; 66(21): 10586-93)
Data from MSF-A Interacts with Hypoxia-Inducible Factor-1α and Augments Hypoxia-Inducible Factor Transcriptional Activation to Affect Tumorigenicity and Angiogenesis
Authors: Amir Sharon , Wang Ruoxiang , Matzkin Haim , Simons Jonathan W. , Mabjeesh Nicola J.
Published: March 2023

Abstract
Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor in the signaling pathway that controls the hypoxic responses of cancer cells. Activation of the HIF system has been observed in carcinogenesis and numerous cancers. We found an interaction between a member of the mammalian septin gene family (MSF-A) and the HIF system. MSF-A is a nuclear protein that interacts with HIF-1α protein to prevent its ubiquitination and degradation, thus activating the HIF transcriptome. Cells overexpressing MSF-A protein exhibit increased HIF transcriptional activity and higher proliferation rates in vitro and in vivo. Xenograft-derived human tumors from these cells were larger and more vascular. These findings link a function of a septin protein with angiogenesis through activation of the HIF pathway. (Cancer Res 2006; 66(2): 856-66)
Data from Tumorigenic Conversion of Primary Human Esophageal Epithelial Cells Using Oncogene Combinations in the Absence of Exogenous Ras
Authors: Kim Seok-Hyun , Nakagawa Hiroshi , Navaraj Arunasalam , Naomoto Yoshio , Klein-Szanto Andres J.P. , Rustgi Anil K. , El-Deiry Wafik S.
Published: March 2023

Abstract
To investigate pathways of human esophageal squamous cell transformation, we generated esophageal tumor cells using human telomerase– and SV40-immortalized primary esophageal epithelial cells (EPC2) by overexpression of selected combinations of oncogenes. H-Ras, c-Myc, or Akt, but not epidermal growth factor receptor (EGFR), induced transformed colonies in soft agar. By contrast, bioluminescence imaging of genetically altered immortalized esophageal cells revealed that Akt, EGFR, or H-Ras, but not c-Myc, resulted in tumor formation in immunodeficient mice. H-Ras-driven tumors showed highly tumorigenic phenotypes with 2.6 ± 0.6 days for doubling, whereas Akt and EGFR tumors doubled every 9.5 ± 1.6 and 6.1 ± 1.2 days, respectively. H-Ras-driven tumors expressed the hypoxia-inducible factor target Glut1, whereas Akt- or EGFR-driven tumors had evidence of angiogenesis and no detectable Glut1 expression. Proliferation rates among these tumors were similar, but there was reduced apoptosis in the more aggressive H-Ras-driven tumors that also developed aneuploidy and multiple centrosomes. c-Myc overexpression did not result in tumorigenic conversion but introduction of Bcl-XL into c-Myc-expressing cells generated tumors. Although cytokeratin expression was typical of squamous carcinoma, gene expression profiling was done to compare the four different types of engineered tumors with human esophageal squamous cell carcinomas and adenocarcinomas. Interestingly, c-Myc plus Bcl-XL transformants mimicked squamous carcinomas, whereas H-Ras-, EGFR-, and Akt-driven tumors were similar to adenocarcinomas in their molecular profiles. These genetically engineered models may provide new platforms for understanding human esophagus cancer and may assist in the evaluation of new therapies. (Cancer Res 2006; 66(21): 10415-24)
Data from Identification of EZH2 as a Molecular Marker for a Precancerous State in Morphologically Normal Breast Tissues
Authors: Ding Lei , Erdmann Christine , Chinnaiyan Arul M. , Merajver Sofia D. , Kleer Celina G.
Published: March 2023

Abstract
The discovery of molecular markers to detect the precancerous state would have profound implications in the prevention of breast cancer. We report that the expression of the Polycomb group protein EZH2 increases in histologically normal breast epithelium with higher risk of developing cancer. We identify EZH2 as a potential marker for detecting preneoplastic lesions of the breast in vivo and as a possible target for preventative intervention. (Cancer Res 2006; 66(8): 4095-9)
Data from Androgens Modulate Expression of Transcription Intermediary Factor 2, an Androgen Receptor Coactivator whose Expression Level Correlates with Early Biochemical Recurrence in Prostate Cancer
Authors: Agoulnik Irina U. , Vaid Ajula , Nakka Manjula , Alvarado Misty , Bingman William E. , Erdem Halime , Frolov Anna , Smith Carolyn L. , Ayala Gustavo E. , Ittmann Michael M. , Weigel Nancy L.
Published: March 2023

Abstract
Prostate cancer is an androgen-dependent disease; metastatic prostate cancer is typically treated by androgen receptor (AR) blockade. Recurrence after androgen ablation and evidence that AR continues to play a role in many prostate cancers has led to an examination of other factors that potentiate AR activity. AR is a ligand-activated transcription factor whose activity is regulated not only by hormone but also by the levels of coactivators recruited by AR to facilitate transcription. We sought to assess the consequences of reducing expression of the transcription intermediary factor 2 (TIF2) coactivator on prostate cancer cell growth and AR action in cell lines to examine TIF2 expression in prostate cancer and to correlate expression with clinical outcome. Depletion of TIF2 reduced expression of AR-induced target genes and slowed proliferation of AR-dependent and AR-independent prostate cancer cells. Remarkably, we found that TIF2 expression is directly repressed by high levels of androgens in multiple AR-expressing cell lines. Expression of a reporter containing 5′-flanking region of the TIF2 was repressed both by androgens and by the antagonist, Casodex. Expression of TIF2 correlates with biochemical (prostate-specific antigen) recurrence (P = 0.0136). In agreement with our in vitro findings, the highest expression of TIF2 was found in patients whose cancer relapsed after androgen ablation therapy, supporting the idea that AR blockade might activate pathways that lead to stimulation of AR-dependent and AR-independent proliferation of prostate epithelium. The elevated expression of TIF2 at low hormone levels likely aids in inducing AR activity under these conditions; treatment with Casodex has the potential to counteract this induction. (Cancer Res 2006; 66(21): 10594-602)
Data from Bone Morphogenetic Protein 7 in the Development and Treatment of Bone Metastases from Breast Cancer
Authors: Buijs Jeroen T. , Henriquez Nico V. , van Overveld Petra G.M. , van der Horst Geertje , Que Ivo , Schwaninger Ruth , Rentsch Cyrill , ten Dijke Peter , Cleton-Jansen Anne-Marie , Driouch Keltouma , Lidereau Rosette , Bachelier Richard , Vukicevic Slobodan , Clézardin Philippe , Papapoulos Socrates E. , Cecchini Marco G. , Löwik Clemens W.G.M. , van der Pluijm Gabri
Published: March 2023

Abstract
Bone morphogenetic protein 7 (BMP7) counteracts the physiological epithelial-to-mesenchymal transition (EMT), a process that is indicative of epithelial plasticity. Because EMT is involved in cancer, we investigated whether BMP7 plays a role in breast cancer growth and metastasis. In this study, we show that decreased BMP7 expression in primary breast cancer is significantly associated with the formation of clinically overt bone metastases in patients with ≥10 years of follow-up. In line with these clinical observations, BMP7 expression is inversely related to tumorigenicity and invasive behavior of human breast cancer cell lines. Moreover, BMP7 decreased the expression of vimentin, a mesenchymal marker associated with invasiveness and poor prognosis, in human MDA-MB-231 (MDA-231)-B/Luc+ breast cancer cells under basal and transforming growth factor-β (TGF-β)–stimulated conditions. In addition, exogenous addition of BMP7 to TGF-β–stimulated MDA-231 cells inhibited Smad-mediated TGF-β signaling. Furthermore, in a well-established bone metastasis model using whole-body bioluminescent reporter imaging, stable overexpression of BMP7 in MDA-231 cells inhibited de novo formation and progression of osteolytic bone metastases and, hence, their metastatic capability. In line with these observations, daily i.v. administration of BMP7 (100 μg/kg/d) significantly inhibited orthotopic and intrabone growth of MDA-231-B/Luc+ cells in nude mice. Our data suggest that decreased BMP7 expression during carcinogenesis in the human breast contributes to the acquisition of a bone metastatic phenotype. Because exogenous BMP7 can still counteract the breast cancer growth at the primary site and in bone, BMP7 may represent a novel therapeutic molecule for repression of local and bone metastatic growth of breast cancer. [Cancer Res 2007;67(18):8742–51]
Data from Increased Levels of the FoxM1 Transcription Factor Accelerate Development and Progression of Prostate Carcinomas in both TRAMP and LADY Transgenic Mice
Authors: Kalin Tanya V. , Wang I-Ching , Ackerson Timothy J. , Major Michael L. , Detrisac Carol J. , Kalinichenko Vladimir V. , Lyubimov Alexander , Costa Robert H.
Published: March 2023

Abstract
The proliferation-specific Forkhead Box M1 (FoxM1 or FoxM1b) transcription factor is overexpressed in a number of aggressive human carcinomas. Mouse hepatocytes deficient in FoxM1 fail to proliferate and are highly resistant to developing carcinogen-induced liver tumors. We previously developed a transgenic (TG) mouse line in which the ubiquitous Rosa26 promoter was used to drive expression of the human FoxM1b cDNA transgene in all mouse cell types. To investigate the role of FoxM1b in prostate cancer progression, we bred Rosa26-FoxM1b mice with both TRAMP and LADY TG mouse models of prostate cancer. We show that increased expression of FoxM1b accelerated development, proliferation, and growth of prostatic tumors in both TRAMP and LADY double TG mice. Furthermore, development of prostate carcinomas in TRAMP/Rosa26-FoxM1b double TG mice required high levels of FoxM1 protein to overcome sustained expression of the alternative reading frame tumor suppressor, a potent inhibitor of FoxM1 transcriptional activity. Depletion of FoxM1 levels in prostate cancer cell lines PC-3, LNCaP, or DU-145 by small interfering RNA transfection caused significant reduction in proliferation and anchorage-independent growth on soft agar. This phenotype was associated with increased nuclear levels of the cyclin-dependent kinase inhibitor protein p27Kip1 and diminished expression of S-phase promoting cyclin A2 and M-phase promoting cyclin B1 proteins. Finally, we show that elevated levels of FoxM1 protein correlate with high proliferation rates in human prostate adenocarcinomas. Our results suggest that the FoxM1 transcription factor regulates development and proliferation of prostate tumors, and that FoxM1 is a novel target for prostate cancer treatment. Cancer Res 2006; 66(3): 1712-20
Data from Increased Efficacy and Safety in the Treatment of Experimental Liver Cancer with a Novel Adenovirus-Alphavirus Hybrid Vector
Authors: Guan Min , Rodriguez-Madoz Juan R. , Alzuguren Pilar , Gomar Celia , Kramer M. Gabriela , Kochanek Stefan , Prieto Jesus , Smerdou Cristian , Qian Cheng
Published: March 2023

Abstract
An improved viral vector for cancer gene therapy should be capable of infecting tumors with high efficiency, inducing specific and high-level expression of transgene in the tumor and selectively destroying tumor cells. In the design of such a vector to treat hepatocellular carcinoma, we took advantage of (a) the high infectivity of adenoviruses for hepatic cells, (b) the high level of protein expression and proapoptotic properties that characterize Semliki Forest virus (SFV) replicon, and (c) tumor selectivity provided by α-fetoprotein (AFP) promoter. We constructed a hybrid viral vector composed of a helper-dependent adenovirus containing an SFV replicon under the transcriptional control of AFP promoter and a transgene driven by SFV subgenomic promoter. Hybrid vectors containing murine interleukin-12 (mIL-12) genes or reporter gene LacZ showed very specific and high-level expression of transgenes in AFP-expressing hepatocellular carcinoma cells, both in vitro and in an in vivo hepatocellular carcinoma animal model. Infected hepatocellular carcinoma cells were selectively eliminated due to the induction of apoptosis by SFV replication. In a rat orthotopic liver tumor model, treatment of established tumors with a hybrid vector carrying mIL-12 gene resulted in strong antitumoral activity without accompanying toxicity. This new type of hybrid vectors may provide a potent and safe tool for cancer gene therapy. (Cancer Res 2006; 66(3): 1620-9)
Data from Multiple Adaptive Mechanisms to Chronic Liver Disease Revealed at Early Stages of Liver Carcinogenesis in the Mdr2-Knockout Mice
Authors: Katzenellenbogen Mark , Pappo Orit , Barash Hila , Klopstock Naama , Mizrahi Lina , Olam Devorah , Jacob-Hirsch Jasmine , Amariglio Ninette , Rechavi Gidi , Mitchell Leslie Ann , Kohen Ron , Domany Eytan , Galun Eithan , Goldenberg Daniel
Published: March 2023

Abstract
Molecular events preceding the development of hepatocellular carcinoma were studied in the Mdr2-knockout (Mdr2-KO) mice. These mice lack the liver-specific P-glycoprotein responsible for phosphatidylcholine transport across the canalicular membrane. Portal inflammation ensues at an early age followed by hepatocellular carcinoma development after the age of 1 year. Liver tissue samples of Mdr2-KO mice in the early and late precancerous stages of liver disease were subjected to histologic, biochemical, and gene expression profiling analysis. In an early stage, multiple protective mechanisms were found, including induction of many anti-inflammatory and antioxidant genes and increase of total antioxidant capacity of liver tissue. Despite stimulation of hepatocyte DNA replication, their mitotic activity was blocked at this stage. In the late stage of the disease, although the total antioxidant capacity of liver tissue of Mdr2-KO mice was normal, and inflammation was less prominent, many protective genes remained overexpressed. Increased mitotic activity of hepatocytes resulted in multiple dysplastic nodules, some of them being steatotic. Expression of many genes regulating lipid and phospholipid metabolism was distorted, including up-regulation of choline kinase A, a known oncogene. Many other oncogenes, including cyclin D1, Jun, and some Ras homologues, were up-regulated in Mdr2-KO mice at both stages of liver disease. However, we found no increase of Ras activation. Our data suggest that some of the adaptive mechanisms induced in the early stages of hepatic disease, which protect the liver from injury, could have an effect in hepatocarcinogenesis at later stages of the disease in this hepatocellular carcinoma model. (Cancer Res 2006; 66(8): 4001-10)
Data from DNAX Accessory Molecule-1 Mediated Recognition of Freshly Isolated Ovarian Carcinoma by Resting Natural Killer Cells
Authors: Carlsten Mattias , Björkström Niklas K. , Norell Håkan , Bryceson Yenan , van Hall Thorbald , Baumann Bettina C. , Hanson Mikael , Schedvins Kjell , Kiessling Rolf , Ljunggren Hans-Gustaf , Malmberg Karl-Johan
Published: March 2023

Abstract
Although natural killer (NK) cells are well known for their ability to kill tumors, few studies have addressed the interactions between resting (nonactivated) NK cells and freshly isolated human tumors. Here, we show that human leukocyte antigen class Ilow tumor cells isolated directly from patients with advanced ovarian carcinoma trigger degranulation by resting allogeneic NK cells. This was paralleled by induction of granzyme B and caspase-6 activities in the tumor cells and significant tumor cell lysis. Ovarian carcinoma cells displayed ubiquitous expression of the DNAX accessory molecule-1 (DNAM-1) ligand PVR and sparse/heterogeneous expression of the NKG2D ligands MICA/MICB and ULBP1, ULBP2, and ULBP3. In line with the NK receptor ligand expression profiles, antibody-mediated blockade of activating receptor pathways revealed a dominant role for DNAM-1 and a complementary contribution of NKG2D signaling in tumor cell recognition. These results show that resting NK cells are capable of directly recognizing freshly isolated human tumor cells and identify ovarian carcinoma as a potential target for adoptive NK cell–based immunotherapy. [Cancer Res 2007;67(3):1317–25]
Data from Credentialing Preclinical Pediatric Xenograft Models Using Gene Expression and Tissue Microarray Analysis
Authors: Whiteford Craig C. , Bilke Sven , Greer Braden T. , Chen Qingrong , Braunschweig Till A. , Cenacchi Nicola , Wei Jun S. , Smith Malcolm A. , Houghton Peter , Morton Christopher , Reynolds C. Patrick , Lock Richard , Gorlick Richard , Khanna Chand , Thiele Carol J. , Takikita Mikiko , Catchpoole Daniel , Hewitt Stephen M. , Khan Javed
Published: March 2023

Abstract
Human tumor xenografts have been used extensively for rapid screening of the efficacy of anticancer drugs for the past 35 years. The selection of appropriate xenograft models for drug testing has been largely empirical and has not incorporated a similarity to the tumor type of origin at the molecular level. This study is the first comprehensive analysis of the transcriptome of a large set of pediatric xenografts, which are currently used for preclinical drug testing. Suitable models representing the tumor type of origin were identified. It was found that the characteristic expression patterns of the primary tumors were maintained in the corresponding xenografts for the majority of samples. Because a prerequisite for developing rationally designed drugs is that the target is expressed at the protein level, we developed tissue arrays from these xenografts and corroborated that high mRNA levels yielded high protein levels for two tested genes. The web database and availability of tissue arrays will allow for the rapid confirmation of the expression of potential targets at both the mRNA and the protein level for molecularly targeted agents. The database will facilitate the identification of tumor markers predictive of response to tested agents as well as the discovery of new molecular targets. [Cancer Res 2007;67(1):32–40]
Data from Epigenetic Regulation of Tumor Endothelial Cell Anergy: Silencing of Intercellular Adhesion Molecule-1 by Histone Modifications
Authors: Hellebrekers Debby M.E.I. , Castermans Karolien , Viré Emmanuelle , Dings Ruud P.M. , Hoebers Nicole T.H. , Mayo Kevin H. , oude Egbrink Mirjam G.A. , Molema Grietje , Fuks François , van Engeland Manon , Griffioen Arjan W.
Published: March 2023

Abstract
Tumors can escape from immunity by repressing leukocyte adhesion molecule expression on tumor endothelial cells and by rendering endothelial cells unresponsive to inflammatory activation. This endothelial cell anergy is induced by angiogenic growth factors and results in reduced leukocyte-vessel wall interactions, thereby attenuating infiltration of leukocytes into the tumor. This report describes a novel mechanism of endothelial cell anergy regulation. We recently reported that DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors have angiostatic activity. Here, we studied whether epigenetic mechanisms regulate this angiogenesis-mediated escape from immunity. We found that DNMT inhibitors 5-aza-2′-deoxycytidine and zebularine, as well as HDAC inhibitor trichostatin A, reexpressed intercellular adhesion molecule-1 (ICAM-1) on tumor-conditioned endothelial cells in vitro, resulting in restored leukocyte-endothelial cell adhesion. In addition, treatment with DNMT or HDAC inhibitors in vivo also restored ICAM-1 expression on tumor endothelial cells from two different mouse tumor models. Furthermore, leukocyte-vessel wall interactions in mouse tumors were increased by these compounds, as measured by intravital microscopy, resulting in enhanced leukocyte infiltration. We show that ICAM-1 down-regulation in tumor endothelial cells is associated with ICAM-1 promoter histone H3 deacetylation and loss of histone H3 Lys4 methylation but not with DNA hypermethylation. In conclusion, our data show that ICAM-1 is epigenetically silenced in tumor endothelial cells by promoter histone modifications, which can be overcome by DNMT and HDAC inhibitors, suggesting a new molecular mechanism based on which novel therapeutic approaches for cancer can be pursued. (Cancer Res 2006; 66(22): 10770-7)
Data from Phospholipase C-δ1 Is a Critical Target for Tumor Necrosis Factor Receptor–Mediated Protection against Adriamycin-Induced Cardiac Injury
Authors: Lien Yu-Chin , Noel Teresa , Liu Hua , Stromberg Arnold J. , Chen Kuey-Chu , St. Clair Daret K.
Published: March 2023

Abstract
The clinical application of adriamycin, an exceptionally good chemotherapeutic agent, is limited by its dose-related cardiomyopathy. Our recent study showed that tumor necrosis factor-α (TNF-α) receptors mediated cytoprotective signaling against adriamycin-induced mitochondrial injury and cardiomyocyte apoptosis. In the present study, we investigated the potential targets of TNF receptor–mediated cytoprotective signaling by global genome microarray analysis using wild-type and TNF receptor–deficient mice. Microarray analysis revealed that adriamycin treatment induced the down-regulation of several mitochondrial functions and energy production–related genes in double TNF receptor–deficient mice, notably, phospholipase C-δ1, a protein involved in fatty acid metabolism and calcium regulation. The role of phospholipase C-δ1 in TNF receptor–mediated cardioprotection against adriamycin-induced injury was evaluated by measuring changes in cardiac function using high-frequency ultrasound biomicroscopy. Selective inhibition of phospholipase C activity in wild-type mice by its inhibitor, U73122, exacerbated adriamycin-induced cardiac dysfunction. Inhibition of phospholipase C-δ1 resulted in the significant decrease of left ventricular ejection fraction and fractional shortening, and the decreased levels were similar to those observed in adriamycin-treated double TNF receptor–deficient mice. The data derived from the global genome analysis identified phospholipase C-δ1 as an important target for TNF receptors and revealed the critical role of TNF receptor signaling in the protection against adriamycin-induced cardiotoxicity. (Cancer Res 2006; 66(8): 4329-38)
Data from Cell Adhesion Molecule L1 Disrupts E-Cadherin-Containing Adherens Junctions and Increases Scattering and Motility of MCF7 Breast Carcinoma Cells
Authors: Shtutman Michael , Levina Elina , Ohouo Patrice , Baig Mirza , Roninson Igor B.
Published: March 2023

Abstract
The first steps of invasion and metastasis include the dissociation of adherens junctions and the induction of migratory phenotype, through a program that resembles epithelial-mesenchymal transition (EMT). The L1 cell adhesion molecule, which is normally found primarily in the brain, was recently shown to be expressed in different types of cancer and to have tumor-promoting activity. We now find that L1 mediates EMT-like events in MCF7 breast carcinoma cells. MCF7 predominantly expresses the nonneuronal isoform of L1, as do 16 of 17 other cell lines derived from different types of cancer. L1 protein expression in MCF7 cells, which form E-cadherin-containing adherens junctions, is inversely related to cell density. Analysis of MCF7 cells with overexpression or knockdown of nonneuronal L1 isoform revealed that L1 expression leads to the disruption of adherens junctions and increases β-catenin transcriptional activity. As a result, L1 expression promotes the scattering of epithelial cells from compact colonies. Expression of the full-length L1 protein, but not of its soluble extracellular moiety, increases the motility of the MCF7 epithelial monolayer in a wound-healing assay, in which L1 expression is preferentially observed and required in cells leading the movement of the monolayer. Based on these results, we propose a model for the role of L1 as a trigger of EMT-like events in transformed epithelial cells. (Cancer Res 2006; 66(23): 11370-80)
Data from Knockdown of Contactin-1 Expression Suppresses Invasion and Metastasis of Lung Adenocarcinoma
Authors: Su Jen-Liang , Yang Ching-Yao , Shih Jin-Yuan , Wei Lin-Hung , Hsieh Chang-Yao , Jeng Yung-Ming , Wang Ming-Yang , Yang Pan-Chyr , Kuo Min-Liang
Published: March 2023

Abstract
Numerous genetic changes are associated with cancer cell metastasis and invasion. In search for key regulators of invasion and metastasis, a panel of lung cancer cell lines with different invasive ability was screened. The gene for contactin-1 was found to play an essential role in tumor invasion and metastasis. Suppression of contactin-1 expression abolished the ability of lung adenocarcinoma cells to invade Matrigel in vitro as well as the polymerization of filamentous-actin and the formation of focal adhesion structures. Furthermore, knockdown of contactin-1 resulted in extensive inhibition of tumor metastasis and in increased survival in an animal model. RhoA but not Cdc42 or Rac1 was found to serve a critical role in contactin-1–mediated invasion and metastasis. Contactin-1–specific RNA interference resulted in loss of metastatic and invasive capacity in both in vitro and in vivo models. This loss was overturned by constitutive expression of the active form of RhoA. Contactin-1 was differentially expressed in tumor tissues, and its expression correlated with tumor stage, lymph node metastasis, and patient survival. Contactin-1 is proposed to function importantly in the invasion and metastasis of lung adenocarcinoma cells via RhoA-mediated mechanisms. (Cancer Res 2006; 66(5): 2553-61)
Data from Gene Expression Profile of Metastatic Human Pancreatic Cancer Cells Depends on the Organ Microenvironment
Authors: Nakamura Toru , Fidler Isaiah J. , Coombes Kevin R.
Published: March 2023

Abstract
To determine the influence of the microenvironment on changes in gene expression, we did microarray analysis on three variant lines of a human pancreatic cancer (FG, L3.3, and L3.6pl) with different metastatic potentials. The variant lines were grown in tissue culture in the subcutis (ectopic) or pancreas (orthotopic) of nude mice. Compared with tissue culture, the number of genes of which the expression was affected by the microenvironment was up-regulated in tumors growing in the subcutis and pancreas. In addition, highly metastatic L3.6pl cells growing in the pancreas expressed significantly higher levels of 226 genes than did the L3.3 or FG variant cells. Growth of the variant lines in the subcutis did not yield similar results, indicating that the orthotopic microenvironment significantly influences gene expression in pancreatic cancer cells. These data suggest that investigations of the functional consequence of gene expression require accounting for experimental growth conditions. [Cancer Res 2007;67(1):139–48]
Data from Human Arrest Defective 1 Acetylates and Activates β-Catenin, Promoting Lung Cancer Cell Proliferation
Authors: Lim Ji-Hong , Park Jong-Wan , Chun Yang-Sook
Published: March 2023

Abstract
Arrest defective 1 (ARD1), an acetyltransferase, is essential for the yeast life cycle. Although its human homologue (hARD1) has been identified, its biological functions in human cells remain unclear. In the present study, we examined the biological function of hARD1. In H1299 and A549 lung cancer cells, hARD1-silencing RNA inhibited cell proliferation and induced G1 arrest. Cyclin D1 was also found to be down-regulated in these growth-arrested cells, and the ectopic expression of cyclin D1 rescued cell growth. hARD1 knockdown repressed the promoter activity of the cyclin D1 gene, which inhibited the transcription of cyclin D1. Moreover, hARD1 knockdown reduced the binding of β-catenin/TCF4 transcription factor to cyclin D1 promoter and repressed its transcriptional activity. Inversely, hARD1 expression increased the transcriptional activity of β-catenin. Both endogenous and ectopically expressed hARD1 was coimmunoprecipitated with β-catenin. hARD1 knockdown did not affect β-catenin expression or degradation but noticeably reduced acetylated β-catenin. The β-catenin binding and acetylation by hARD1 were observed in vitro. Therefore, it is suggested that hARD1 participates in proliferation of lung cancer cells via the activation of β-catenin. (Cancer Res 2006; 66(22): 10677-82)
Data from Identification of the IFITM Family as a New Molecular Marker in Human Colorectal Tumors
Authors: Andreu Pauline , Colnot Sabine , Godard Cécile , Laurent-Puig Pierre , Lamarque Dominique , Kahn Axel , Perret Christine , Romagnolo Béatrice
Published: March 2023

Abstract
We analyzed the expression profiles of intestinal adenomas from a new murine familial adenomatous polyposis model (ApcΔ14/+) using suppression subtractive hybridization to identify novel diagnostic markers of colorectal carcinogenesis. We identified 18 candidate genes having increased expression levels in the adenoma. Subsequent Northern blotting, real-time reverse transcription-PCR, and in situ hybridization analysis confirmed their induction in β-catenin-activated epithelial cells of murine adenomas. We showed that most of the genes also have altered expression levels in human colonic adenomas and carcinomas. We focused on the IFITM genes that encode IFN-inducible transmembrane proteins. Serial analyses of gene expression levels revealed high levels of expression in early and late intestinal neoplasm in both mice and humans. Using a conditional mouse model of Apc inactivation and a human colon carcinoma cell line, we showed that IFITM gene expression is rapidly induced after activation of the β-catenin signaling. Using a large-scale analysis of human tumors, we showed that IFITM gene expression is significantly up-regulated specifically in colorectal tumors and thus may be a useful diagnostic tool in these tumors. (Cancer Res 2006; 66(4): 1949-55)
Data from Patterns of Known and Novel Small RNAs in Human Cervical Cancer
Authors: Lui Weng-Onn , Pourmand Nader , Patterson Bruce K. , Fire Andrew
Published: March 2023

Abstract
Recent studies suggest that knowledge of differential expression of microRNAs (miRNA) in cancer may have substantial diagnostic and prognostic value. Here, we use a direct sequencing method to characterize the profiles of miRNAs and other small RNA segments for six human cervical carcinoma cell lines and five normal cervical samples. Of 166 miRNAs expressed in normal cervix and cancer cell lines, we observed significant expression variation of six miRNAs between the two groups. To further show the biological relevance of our findings, we examined the expression level of two significantly varying miRNAs in a panel of 29 matched pairs of human cervical cancer and normal cervical samples. Reduced expression of miR-143 and increased expression of miR-21 were reproducibly displayed in cancer samples, suggesting the potential value of these miRNAs as tumor markers. In addition to the known miRNAs, we found a number of novel miRNAs and an additional set of small RNAs that do not meet miRNA criteria. [Cancer Res 2007;67(13):6031–43]
Data from Aldose Reductase Regulates Growth Factor-Induced Cyclooxygenase-2 Expression and Prostaglandin E2 Production in Human Colon Cancer Cells
Authors: Tammali Ravinder , Ramana Kota V. , Singhal Sharad S. , Awasthi Sanjay , Srivastava Satish K.
Published: March 2023

Abstract
Inhibition of prostaglandin E2 (PGE2) and cyclooxygenase (COX)-2 by nonsteroidal anti-inflammatory drugs reduces the progression of colon cancer. Inhibition of aldose reductase (AR; EC. 1.1.1.21.) by sorbinil or by antisense ablation prevented fibroblast growth factor–induced and platelet-derived growth factor–induced up-regulation of PGE2 synthesis in human colon cancer cells, Caco-2. AR besides reducing aldo-sugars efficiently reduces toxic lipid aldehydes and their conjugates with glutathione. Inhibition of AR prevented growth factor-induced COX-2 activity, protein, and mRNA and significantly decreased activation of nuclear factor-κB and protein kinase C (PKC) and phosphorylation of PKC-β2 as well as progression of Caco-2 cell growth but had no effect on COX-1 activity. Cell cycle analysis suggests that inhibition of AR prevents growth factor-induced proliferation of Caco-2 cells at S phase. Treatment of Caco-2 cells with the most abundant and toxic lipid aldehyde 4-hydroxy-trans-2-nonenal (HNE) or its glutathione-conjugate [glutathionyl-HNE (GS-HNE)] or AR-catalyzed product of GS-HNE, glutathionyl-1,4-dihydroxynonane (GS-DHN), resulted in increased COX-2 expression and PGE2 production. Inhibition of AR prevented HNE- or GS-HNE-induced but not GS-DHN-induced up-regulation of COX-2 and PGE2. More importantly, in vivo studies showed that administration of AR-small interfering RNA (siRNA), but not control siRNA, to nude mice bearing SW480 human colon adenocarcinoma cells completely arrested tumor progression. Collectively, these observations suggest that AR is an obligatory mediator of growth factor-induced up-regulation of COX-2, PGE2, and growth of Caco-2 cells, indicating that inhibition of AR may be a novel therapeutic approach in preventing the progression of colon cancer. (Cancer Res 2006; 66(19): 9705-13)
Data from Enhanced Hepatocyte Growth Factor Signaling by Type II Transforming Growth Factor-β Receptor Knockout Fibroblasts Promotes Mammary Tumorigenesis
Authors: Cheng Nikki , Chytil Anna , Shyr Yu , Joly Alison , Moses Harold L.
Published: March 2023

Abstract
Transforming growth factor-β (TGF-β) plays complex dual roles as an inhibitor and promoter of tumor progression. Although the influence of the stromal microenvironment on tumor progression is well recognized, little is known about the functions of TGF-β signaling in the stroma during tumor progression. Using cre-lox technology, expression of the type II TGF-β receptor was selectively knocked out in fibroblasts (Tgfbr2FspKO). In a co-xenograft model, we show that Tgfbr2FspKO fibroblasts enhance mammary carcinoma growth and metastasis in mice while increasing hepatocyte growth factor (HGF) expression and c-Met signaling downstream pathways including signal transducers and activators of transcription 3 (Stat3) and p42/44 mitogen-activated protein kinase (MAPK). Treatment of tumor-bearing mice with a pharmacologic inhibitor (EXEL-7592) of c-Met blocks tumor progression and reduces levels of phospho-Stat3 and phospho-p42/44 MAPK. Similarly, small interfering RNA knockdown of c-Met expression in mammary tumor cells reduces metastasis and c-Met signaling caused by Tgfbr2FspKO fibroblasts. The results show that TGF-β signaling in fibroblasts suppresses tumor metastasis by antagonizing HGF/c-Met signaling within tumor epithelial cells. Furthermore, this co-xenograft model represents a unique context to study stromal TGF-β and HGF signaling in mammary tumorigenesis. [Cancer Res 2007;67(10):4869–77]
Data from Attenuation of Mitogen- and Stress-Activated Protein Kinase-1–Driven Nuclear Factor-κB Gene Expression by Soy Isoflavones Does Not Require Estrogenic Activity
Authors: Vanden Berghe Wim , Dijsselbloem Nathalie , Vermeulen Linda , Ndlovu 'Matladi N. , Boone Elke , Haegeman Guy
Published: March 2023

Abstract
We have analyzed in molecular detail how soy isoflavones (genistein, daidzein, and biochanin A) suppress nuclear factor-κB (NF-κB)–driven interleukin-6 (IL6) expression. In addition to its physiologic immune function as an acute stress cytokine, sustained elevated expression levels of IL6 promote chronic inflammatory disorders, aging frailty, and tumorigenesis. Our results in estrogen-unresponsive fibroblasts, mitogen- and stress-activated protein kinase (MSK) knockout cells, and estrogen receptor (ER)–deficient breast tumor cells show that phytoestrogenic isoflavones can selectively block nuclear NF-κB transactivation of specific target genes (in particular IL6), independently of their estrogenic activity. This occurs via attenuation of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK activity, which further down-regulates MSK-dependent NF-κB p65 and histone H3 phosphorylation. As constitutive NF-κB and MSK activity are hallmarks of aggressive metastatic ER-deficient breast cancer, the MSK signaling pathway may become an attractive target for chemotherapy. (Cancer Res 2006; 66(9): 4852-62)
Data from Daxx Cooperates with the Axin/HIPK2/p53 Complex to Induce Cell Death
Authors: Li Qinxi , Wang Xuan , Wu Xiaoling , Rui Yanning , Liu Wei , Wang Jifeng , Wang Xinghao , Liou Yih-Cherng , Ye Zhiyun , Lin Sheng-Cai
Published: March 2023

Abstract
Daxx, a death domain–associated protein, has been implicated in proapoptosis, antiapoptosis, and transcriptional regulation. Many factors known to play critically important roles in controlling apoptosis and gene transcription have been shown to associate with Daxx, including the Ser/Thr protein kinase HIPK2, promyelocytic leukemia protein, histone deacetylases, and the chromatin remodeling protein ATRX. Although it is clear that Daxx may exert multiple functions, the underlying mechanisms remain far from clear. Here, we show that Axin, originally identified for its scaffolding role to control β-catenin levels in Wnt signaling, strongly associates with Daxx at endogenous levels. The Daxx/Axin complex formation is enhanced by UV irradiation. Axin tethers Daxx to the tumor suppressor p53, and cooperates with Daxx, but not DaxxΔAxin, which is unable to interact with Axin, to stimulate HIPK2-mediated Ser46 phosphorylation and transcriptional activity of p53. Interestingly, Axin and Daxx seem to selectively activate p53 target genes, with strong activation of PUMA, but not p21 or Bax. Daxx-stimulated p53 transcriptional activity was significantly diminished by small interfering RNA against Axin; Daxx fails to inhibit colony formation in Axin−/− cells. Moreover, UV-induced cell death was attenuated by the knockdown of Axin and Daxx. All these results show that Daxx cooperates with Axin to stimulate p53, and implicate a direct role for Axin, HIPK2, and p53 in the proapoptotic function of Daxx. We have hence unraveled a novel aspect of p53 activation and shed new light on the ultimate understanding of the Daxx protein, perhaps most pertinently, in relation to stress-induced cell death. [Cancer Res 2007;67(1):66–74]
Data from Targeting the Lymphotoxin-β Receptor with Agonist Antibodies as a Potential Cancer Therapy
Authors: Lukashev Matvey , LePage Doreen , Wilson Cheryl , Bailly Véronique , Garber Ellen , Lukashin Alex , Ngam-ek Apinya , Zeng Weike , Allaire Norman , Perrin Steve , Xu Xianghong , Szeliga Kendall , Wortham Kathleen , Kelly Rebecca , Bottiglio Cindy , Ding Jane , Griffith Linda , Heaney Glenna , Silverio Erika , Yang William , Jarpe Matt , Fawell Stephen , Reff Mitchell , Carmillo Amie , Miatkowski Konrad , Amatucci Joseph , Crowell Thomas , Prentice Holly , Meier Werner , Violette Shelia M. , Mackay Fabienne , Yang Dajun , Hoffman Robert , Browning Jeffrey L.
Published: March 2023

Abstract
The lymphotoxin-β receptor (LTβR) is a tumor necrosis factor receptor family member critical for the development and maintenance of various lymphoid microenvironments. Herein, we show that agonistic anti-LTβR monoclonal antibody (mAb) CBE11 inhibited tumor growth in xenograft models and potentiated tumor responses to chemotherapeutic agents. In a syngeneic colon carcinoma tumor model, treatment of the tumor-bearing mice with an agonistic antibody against murine LTβR caused increased lymphocyte infiltration and necrosis of the tumor. A pattern of differential gene expression predictive of cellular and xenograft response to LTβR activation was identified in a panel of colon carcinoma cell lines and when applied to a panel of clinical colorectal tumor samples indicated 35% likelihood a tumor response to CBE11. Consistent with this estimate, CBE11 decreased tumor size and/or improved long-term animal survival with two of six independent orthotopic xenografts prepared from surgical colorectal carcinoma samples. Targeting of LTβR with agonistic mAbs offers a novel approach to the treatment of colorectal and potentially other types of cancers. (Cancer Res 2006; 66(19): 9617-24)
Data from Mouse Dendritic-Endothelial Cell Hybrids and 4-1BB Costimulation Elicit Antitumor Effects Mediated by Broad Antiangiogenic Immunity
Authors: Ko Eric , Luo Wei , Peng Liaomin , Wang Xinhui , Ferrone Soldano
Published: March 2023

Abstract
Antiangiogenic immunotherapy, which targets molecules critical to tumor angiogenesis, is expected to counteract the negative effect of tumor cell genetic instability on the outcome of immunotherapy targeting tumor antigens. Previously, targeting of individual angiogenic molecules has been shown to inhibit tumor angiogenesis and limit tumor growth. Nevertheless, this approach may be bypassed by redundant angiogenic pathways. To overcome this limitation, we have developed an immunization strategy targeting multiple molecules critical to angiogenesis. To this end, hybrids of dendritic cells (DC) and syngeneic endothelial cells (EC) were used as immunogens, because (a) whole EC express multiple molecules involved in angiogenesis and (b) DC tumor cell hybrids are effective in generating self-antigen–specific immune responses. The immunization strategy included the administration of an agonist 4-1BB–specific monoclonal antibody (mAb), because it augments self-antigen–specific immune responses elicited by DC hybrids. Immunization of mice with DC-EC hybrids and 4-1BB–specific mAb inhibited the growth of B16.F10 melanoma and MC38 colon adenocarcinoma tumors. This effect is mediated by EC-specific CD4+ and CD8+ T-cell responses, which markedly inhibited tumor angiogenesis. No therapy-related side effects, except minor and transient hematologic changes, were observed. Our findings represent a useful background for the design of antiangiogenic immunotherapeutic strategies to control tumor growth in a clinical setting. [Cancer Res 2007;67(16):7875–84]
Data from Enhanced Spontaneous and Benzo(a)pyrene-Induced Mutations in the Lung of Nrf2-Deficient gpt Delta Mice
Authors: Aoki Yasunobu , Hashimoto Akiko H. , Amanuma Kimiko , Matsumoto Michi , Hiyoshi Kyoko , Takano Hirohisa , Masumura Ken-ichi , Itoh Ken , Nohmi Takehiko , Yamamoto Masayuki
Published: March 2023

Abstract
The lung is an organ that is sensitive to mutations induced by chemicals in ambient air, and transgenic mice harboring guanine phosphoribosyltransferase (gpt) gene as a target gene are a well-established model system for assessing genotoxicity in vivo. Transcription factor Nrf2 mediates inducible and constitutive expression of cytoprotective enzymes against xenobiotics and mutagens. To address whether Nrf2 is also involved in DNA protection, we generated nrf2+/−::gpt and nrf2−/−::gpt mice. The spontaneous mutation frequency of the gpt gene in the lung was approximately three times higher in nrf2-null (nrf2−/−) mice than nrf2 heterozygous (nrf2+/−) and wild-type (nrf2+/+) mice, whereas in the liver, the mutation frequency was higher in nrf2−/− and nrf2+/− mice than in nrf2+/+ wild-type mice. By contrast, no difference in mutation frequency was observed in testis among the three genotypes. A single intratracheal instillation of benzo(a)pyrene (BaP) increased the lung mutation frequency 3.1- and 6.1-fold in nrf2+/− and nrf2−/− mice, respectively, compared with BaP-untreated nrf2+/− mice, showing that nrf2−/− mice are more susceptible to genotoxic carcinogens. Surprisingly, mutation profiles of the gpt gene in BaP-treated nrf2+/− mice was substantially different from that in BaP-untreated nrf2−/− mice. In nrf2−/− mice, spontaneous and BaP-induced mutation hotspots were observed at nucleotides 64 and 140 of gpt, respectively. These results thus show that Nrf2 aids in the prevention of mutations in vivo and suggest that Nrf2 protects genomic DNA against certain types of mutations. [Cancer Res 2007;67(12):5643–8]