bluuebunny/crossref_metadata_2025_split huggingface dataset:
N-myc Can Substitute for Insulin-Like Growth Factor Signaling in a Mouse Model of Sonic Hedgehog–Induced Medulloblastoma
Authors: Browd Samuel R. , Kenney Anna M. , Gottfried Oren N. , Yoon Joon Won , Walterhouse David , Pedone Carolyn A. , Fults Daniel W. 
Published: March 2006

Abstract
Medulloblastoma is a malignant brain tumor that arises in the cerebellum in children, presumably from granule neuron precursors (GNP). Advances in patient treatment have been hindered by a paucity of animal models that accurately reflect the molecular pathogenesis of human tumors. Aberrant activation of the Sonic hedgehog (Shh) and insulin-like growth factor (IGF) pathways is associated with human medulloblastomas. Both pathways are essential regulators of GNP proliferation during cerebellar development. In cultured GNPs, IGF signaling stabilizes the oncogenic transcription factor N-myc by inhibiting glycogen synthase kinase 3β–dependent phosphorylation and consequent degradation of N-myc. However, determinants of Shh and IGF tumorigenicity in vivo remain unknown. Here we report a high frequency of medulloblastoma formation in mice following postnatal overexpression of Shh in cooperation with N-myc. Overexpression of N-myc, alone or in combination with IGF signaling mediators or with the Shh target Gli1, did not cause tumors. Thus, Shh has transforming functions in addition to induction of N-myc and Gli1. This tumor model will be useful for testing novel medulloblastoma therapies and providing insight into mechanisms of hedgehog-mediated transformation. (Cancer Res 2006; 66(5): 2666-72)
Degradation of Fibrillar Collagen in a Human Melanoma Xenograft Improves the Efficacy of an Oncolytic Herpes Simplex Virus Vector
Authors: McKee Trevor D. , Grandi Paola , Mok Wilson , Alexandrakis George , Insin Numpon , Zimmer John P. , Bawendi Moungi G. , Boucher Yves , Breakefield Xandra O. , Jain Rakesh K. 
Published: March 2006

Abstract
Oncolytic viral therapy provides a promising approach to treat certain human malignancies. These vectors improve on replication-deficient vectors by increasing the viral load within tumors through preferential viral replication within tumor cells. However, the inability to efficiently propagate throughout the entire tumor and infect cells distant from the injection site has limited the capacity of oncolytic viruses to achieve consistent therapeutic responses. Here we show that the spread of the oncolytic herpes simplex virus (HSV) vector MGH2 within the human melanoma Mu89 is limited by the fibrillar collagen in the extracellular matrix. This limitation seems to be size specific as nanoparticles of equivalent size to the virus distribute within tumors to the same extent whereas smaller particles distribute more widely. Due to limited viral penetration, tumor cells in inaccessible regions continue to grow, remaining out of the range of viral infection, and tumor eradication cannot be achieved. Matrix modification with bacterial collagenase coinjection results in a significant improvement in the initial range of viral distribution within the tumor. This results in an extended range of infected tumor cells and improved virus propagation, ultimately leading to enhanced therapeutic outcome. Thus, fibrillar collagen can be a formidable barrier to viral distribution and matrix-modifying treatments can significantly enhance the therapeutic response. (Cancer Res 2006; 66(5): 2509–13)
Hepatocyte Growth Factor and Inducible Nitric Oxide Synthase Are Involved in Multidrug Resistance–Induced Angiogenesis in Hepatocellular Carcinoma Cell Lines
Authors: Lasagna Nadia , Fantappiè Ornella , Solazzo Michela , Morbidelli Lucia , Marchetti Serena , Cipriani Greta , Ziche Marina , Mazzanti Roberto 
Published: March 2006

Abstract
Based on literature, it is possible to hypothesize that multidrug resistance (MDR) and angiogenic phenotypes are linked to each other in human liver cancer cells. Our goal is to assess whether MDR cells trigger angiogenesis and to study the possible molecular mechanisms involved. Conditioned medium from parental drug-sensitive P5 cells (P5-CM) and MDR-positive P1(0.5) cells [P1(0.5)-CM] stimulated human umbilical vein endothelial cells (HUVEC) survival, proliferation, migration, and microtubular structure formation, but P1(0.5)-CM had a significantly greater effect than P5-CM. Cell implants were done in the rabbit avascular cornea to measure angiogenesis in vivo: P1(0.5) cells induced an important neovascular response in rabbit cornea after 1 week, whereas P5 cells had no effect. P1(0.5) and P5 cells produced vascular endothelial growth factor, but only P1(0.5) secreted hepatocyte growth factor (HGF) into the medium, and small interfering RNA specific for MDR1 clearly reduced HGF production in P1(0.5) cells. The transcription factor Ets-1 and the HGF receptor c-Met were up-regulated in P1(0.5) cells and in HUVEC cultured in P1(0.5)-CM. Inducible nitric oxide synthase (iNOS) seemed to play a major role in the proangiogenic effect of P1(0.5), and its inhibition by 1400W blunted the capacity of P1(0.5) cells to stimulate HUVEC proliferation, migration, and Ets-1 expression. In conclusion, these data show that development of MDR and angiogenic phenotypes are linked to each other in MDR cells. HGF production, Ets-1 and c-Met up-regulation, and iNOS expression can be part of the molecular mechanisms that enhance the angiogenic activity of the MDR-positive hepatocellular carcinoma cell line. (Cancer Res 2006; 66(5): 2673-82)
Normoxic Stabilization of Hypoxia-Inducible Factor-1α by Modulation of the Labile Iron Pool in Differentiating U937 Macrophages: Effect of Natural Resistance–Associated Macrophage Protein 1
Authors: Knowles Helen J. , Mole David R. , Ratcliffe Peter J. , Harris Adrian L. 
Published: March 2006

Abstract
Hypoxia-inducible factor (HIF) is a transcription factor with major roles in many cellular and systemic responses to hypoxia. Activation of HIF pathways under hypoxia is mediated by suppression of the Fe2+- and O2-dependent HIF hydroxylase enzymes that normally inactivate HIFα subunits. Mechanisms underlying induction of HIF in normoxic conditions are less clearly understood. In human cancers, infiltrating macrophages show up-regulation of HIF and it has recently been shown that normoxic expression of HIF-1α is essential for macrophage function. Here, we report studies of HIF-1α induction following phorbol-12-myristate 13-acetate (PMA)–induced differentiation of monocytic U937 and THP1 cells. HIF-1α was markedly up-regulated under normoxia in this setting and this involved failure of HIF-1α prolyl hydroxylation despite the presence of O2. Fluorescence measurements showed that differentiation was associated with marked reduction of the labile iron pool. Both the reduction in labile iron pool and the up-regulation of HIF-1α were suppressed by RNA interference–mediated down-regulation of the iron transporter natural resistance–associated macrophage protein 1. Up-regulation of HIF-1α following PMA-induced differentiation was also abolished by addition of Fe2+ or ascorbate. These results indicate that physiologic changes in macrophage iron metabolism have an important effect on HIF hydroxylase pathways and suggest means by which the system could be manipulated for therapeutic benefit. (Cancer Res 2006; 66(5): 2600-7)
Chromosomal Instability in MYH- and APC-Mutant Adenomatous Polyps
Authors: Cardoso Joana , Molenaar Lia , de Menezes Renee X. , van Leerdam Monique , Rosenberg Carla , Möslein Gabriela , Sampson Julian , Morreau Hans , Boer Judith M. , Fodde Riccardo 
Published: March 2006

Abstract
The vast majority of colorectal cancers display genetic instability, either in the chromosomal instability (CIN) or microsatellite instability (MIN) forms. Although CIN tumors are per definition aneuploid, MIN colorectal cancers, caused by loss of mismatch repair function, are usually near diploid. Recently, biallelic germ line mutations in the MYH gene were found to be responsible for MYH-associated polyposis (MAP), an autosomal recessive predisposition to multiple colorectal polyps, often indistinguishable from the dominant familial adenomatous polyposis (FAP) syndrome caused by inherited APC mutations. Here, we analyzed MYH- and APC-mutant polyps by combining laser capture microdissection, isothermal genomic DNA amplification, and array comparative genomic hybridization. Smoothed quantile regression methods were applied to the MAP and FAP genomic profiles to discriminate chromosomes predominantly affected by gains and losses. Up to 80% and 60% of the MAP and FAP polyps showed aneuploid changes, respectively. Both MAP and FAP adenomas were characterized by frequent losses at chromosome 1p, 17, 19, and 22 and gains affecting chromosomes 7 and 13. The aneuploid changes detected at early stages of MYH-driven tumorigenesis may underlie accelerated tumor progression, increased cancer risk, and poor prognosis in MAP. (Cancer Res 2006; 66(5): 2514-9)
Induction of Nevi and Skin Tumors in Ink4a/Arf Xpa Knockout Mice by Neonatal, Intermittent, or Chronic UVB Exposures
Authors: van Schanke Arne , van Venrooij Gemma M.C.A.L. , Jongsma Marjan J. , Banus H. Alexander , Mullenders Leon H.F. , van Kranen Henk J. , de Gruijl Frank R. 
Published: March 2006

Abstract
Nevi and melanomas correlate to childhood and intermittent solar UV exposure, xeroderma pigmentosum patients run increased risk, and p16Ink4a expression is often lost in malignant progression. To ascertain the effect of these risk factors, pigmented hairless Ink4a/Arf−, Xpa− knockout mice were subjected to various combinations of neonatal [7,12-dimethylbenz(a)anthracene (DMBA) or UVB exposure] and adult treatments (12-O-tetradecanoylphorbol-13-acetate or subacute daily UVB exposure or intermittent overexposure). Nevi occurred earliest, grew largest, and were most numerous in mice exposed to DMBA followed by intermittent UVB overexposure [effect of six minimal edemal doses (MED), 1×/2 weeks &gt; 4 MED 1×/wk]. Neonatal UV exposure enhanced nevus induction but lost its effect after 200 days. The Xpa−/− mice proved exquisitely sensitive to UV-driven nevus induction, indicating the involvement of pyrimidine dimer DNA lesions, but Xpa+/+ mice developed many more nevi (&gt;40 per mouse) at high UV dosages not tolerated by Xpa−/− mice. Ink4a/Arf−/− mice developed most skin tumors faster, but surprisingly developed nevi slower than their heterozygous counterparts especially after neonatal UV exposure. Despite raising &gt;1,600 nevi, only six melanomas arose in our experiments with Ink4a/Arf knockout mice (five of which in Xpa+/+ mice at high UV dosages). In contrast to human nevi, these nevi lacked hotspot mutations in Braf or Ras genes, possibly explaining the lack of malignant progression in the Ink4a/Arf−/− mice. Hence, although our experiments did not effectively emulate human melanoma, they provided clear evidence that intermittent UV overexposure strongly stimulates and the Ink4a/Arf−/− genotype may actually impair nevus development. (Cancer Res 2006; 66(5): 2608-15)
FHIT Is Up-Regulated by Inflammatory Stimuli and Inhibits Prostaglandin E2–Mediated Cancer Progression
Authors: Mimori Koshi , Ishii Hideshi , Nagahara Hisashi , Sudo Tomoya , Yamashita Keishi , Inoue Hiroshi , Barnard Graham F. , Mori Masaki 
Published: March 2006

Abstract
The FHIT gene is known to be susceptible to environmental carcinogens. Formation of prostaglandin E2 (PGE2) is catalyzed by cyclooxygenase-2 (COX-2) and may influence malignant phenotype in colorectal cancer. We explored whether FHIT might play a role in progression of colorectal cancer through inflammation-associated PGE2 activity. Immunohistochemical study of COX-2 and FHIT expression was done in 92 colorectal cancer tumors. We also used a FHIT-expressing cancer cell line (H460) induced by ponasterone A and two FHIT small interfering RNA–treated colorectal cancer cell lines (CCK81 and DLD1). After PGE2 stimulation, we compared synthesis of PGE2 (ELISA assay) and cell proliferation [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay]. Immunohistochemistry showed a significant association between COX-2 and FHIT expression in colorectal cancers (P &lt; 0.01). In a subset of 41 COX-2–expressing tumors, 12 FHIT− tumors showed deeper cancer invasion than 29 FHIT+ tumors (P &lt; 0.01). Experimental study, however, showed there was no direct interaction between FHIT and COX-2. Considered with results from another experiment with epidermal growth factor receptor (EGFR), we hypothesize that FHIT and COX-2 might be regulated by a common molecule, such as EGFR. Additionally, there was an inverse and direct correlation between PGE2 synthesis and FHIT in vitro, suggesting that FHIT's postulated antiaggressive effect on tumor goes through PGE2 but not COX-2. Loss of FHIT expression in colorectal cancer suggests higher malignant potential. We conclude that FHIT suppressed cancer cell proliferation in this malignancy by directly inhibiting synthesis of PGE2 but not affecting that of COX-2. (Cancer Res 2006; 66(5): 2683-90)
Genetic Polymorphisms in Antioxidant Enzymes Modulate Hepatic Iron Accumulation and Hepatocellular Carcinoma Development in Patients with Alcohol-Induced Cirrhosis
Authors: Sutton Angela , Nahon Pierre , Pessayre Dominique , Rufat Pierre , Poiré Aurélie , Ziol Marianne , Vidaud Dominique , Barget Nathalie , Ganne-Carrié Nathalie , Charnaux Nathalie , Trinchet Jean-Claude , Gattegno Liliane , Beaugrand Michel 
Published: March 2006

AbstractManganese superoxide dismutase (MnSOD) converts the superoxide anion into H2O2, which, unless it is detoxified by glutathione peroxidase 1 (GPx1), can increase hepatic iron and can react with iron to form genotoxic compounds. We investigated the role of Ala/Val-MnSOD and Pro/Leu-GPx1 polymorphisms on hepatic iron accumulation and hepatocellular carcinoma development in patients with alcoholic cirrhosis. Genotypes were determined in 162 alcoholic patients with cirrhosis but without hepatocellular carcinoma initially, who were prospectively followed up for hepatocellular carcinoma development. We found that patients with two Val-MnSOD alleles (slow H2O2 production) and two Pro-GPx1 alleles (presumably quick H2O2 detoxification) had a lower risk of hepatocellular carcinoma development than other patients (χ2 trend test, P = 0.001; log-rank, P = 0.0009). Indeed, hepatocellular carcinoma percentage was 0% in subjects with this “2Val-MnSOD/2Pro-GPx1” genotype versus 16%, 27%, and 32% in “2Val-MnSOD/1or2Leu-GPx1,” “1or2Ala-MnSOD/2Pro-GPx1,” and “1or2Ala-MnSOD/1or2Leu-GPx1” patients, respectively. The percentage of patients with stainable hepatic iron increased progressively with these genotypic associations: 22%, 28%, 50%, and 53%, respectively (χ2 trend test, P = 0.005). Stainable iron was a risk factor for hepatocellular carcinoma (log-rank, P = 0.0002; relative risk, 3.40). In conclusion, polymorphisms in antioxidant enzymes modulate hepatic iron accumulation and hepatocellular carcinoma development in French alcoholic patients with cirrhosis. (Cancer Res 2006; 66(5): 2844-52)
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 2006

AbstractNumerous 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)
Functional Diversity of DNA Methyltransferase Inhibitors in Human Cancer Cell Lines
Authors: Stresemann Carlo , Brueckner Bodo , Musch Tanja , Stopper Helga , Lyko Frank 
Published: March 2006

Abstract
DNA methyltransferase inhibitors represent promising new drugs for cancer therapies. The first of these compounds (5-azacytidine, Vidaza) has recently been approved as an antitumor agent, and others are presently in various stages of their preclinical or clinical development. Most of the archetypal inhibitors have been established and characterized in different experimental systems, which has thus far precluded their direct comparison. We have now established defined experimental conditions that allowed a comparative analysis of the six most widely known DNA methyltransferase inhibitors: 5-azacytidine (5-aza-CR), 5-aza-2′-deoxycytidine (5-aza-CdR), zebularine, procaine, (−)-epigallocatechin-3-gallate (EGCG), and RG108. Of these, 5-aza-CR, 5-aza-CdR, zebularine, and EGCG were found to exhibit significant cytotoxicity in human cancer cell lines. 5-aza-CdR and EGCG were also found to be genotoxic, as evidenced by the induction of micronuclei. In addition, 5-aza-CR, 5-aza-CdR, zebularine, and RG108 caused concentration-dependent demethylation of genomic DNA, whereas procaine and EGCG failed to induce significant effects. Finally, the experiments in cancer cell lines were complemented by a cell-free in vitro assay with purified recombinant DNA methyltransferase, which indicated that RG108 is the only drug capable of direct enzyme inhibition. These results show a substantial diversity in the molecular activities of DNA methyltransferase inhibitors and provide valuable insights into the developmental potential of individual drugs. (Cancer Res 2006; 66(5): 2794-800)
Matrix Metalloproteinases Play an Active Role in Wnt1-Induced Mammary Tumorigenesis
Authors: Blavier Laurence , Lazaryev Alisa , Dorey Frederick , Shackleford Gregory M. , DeClerck Yves A. 
Published: March 2006

Abstract
The Wnt signaling transduction pathway plays a critical role in the pathogenesis of several murine and human epithelial cancers. Here, we have used mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice, which develop spontaneous mammary adenocarcinoma, to examine whether matrix metalloproteinases (MMPs)—a family of extracellular proteases implicated in multiple steps of cancer progression—contributed to Wnt1-induced tumorigenesis. An analysis of the expression of several MMPs by RT-PCR and in situ hybridization revealed an increase in the expression of MMP-2, MMP-3, MMP-9, MMP-13, and MT1-MMP (MMP-14) in hyperplastic glands and in mammary tumors of MMTV-Wnt1 transgenic mice. Interestingly, whereas MMP-2, MMP-3, and MMP-9 were exclusively expressed by stromal cells in mammary tumors, MMP-13 and MT1-MMP were expressed by transformed epithelial cells in addition to the tumor stroma. To determine whether these MMPs contributed to tumorigenesis, MMTV-Wnt1 mice were crossed with transgenic mice overexpressing tissue inhibitor of metalloproteinase-2—a natural MMP inhibitor—in the mammary gland. In the double MMTV-Wnt1/tissue inhibitor of metalloproteinases-2 transgenic mice, we observed an increase in tumor latency and a 26.3% reduction in tumor formation. Furthermore, these tumors grew at a slower rate, exhibited an 18% decrease in proliferative rate, and a 12.2% increase in apoptotic rate of the tumor cells in association with a deficit in angiogenesis when compared with tumors from MMTV-Wnt1 mice. Thus, for the first time, the data provides evidence for the active role of MMPs in Wnt1-induced mammary tumorigenesis. (Cancer Res 2006; 66(5): 2691-9)
Lysophosphatidic Acid Is a Major Regulator of Growth-Regulated Oncogene α in Ovarian Cancer
Authors: Lee Zendra , Swaby Ramona F. , Liang Yuewei , Yu Shuangxing , Liu Shuying , Lu Karen H. , Bast Robert C. , Mills Gordon B. , Fang Xianjun 
Published: March 2006

AbstractGrowth-regulated oncogene α (GROα), a member of the chemokine superfamily, is commonly expressed in transformed cells and contributes to angiogenesis and tumorigenesis. Here, we report that increased GROα levels are detected in the plasma and ascites of ovarian cancer patients. Ovarian cancer cell lines in culture express and secrete GROα. However, when they are starved in serum-free medium, ovarian cancer cells ceased producing GROα, suggesting that GROα is not constitutively expressed but rather is produced in response to exogenous growth factors in ovarian cancer cells. The prototype peptide growth factors present in serum such as platelet-derived growth factor, insulin-like growth factor I, and insulin do not stimulate GROα production by ovarian cancer cells. In contrast, lysophosphatidic acid (LPA), a glycerol backbone phospholipid mediator present in serum and ascites of ovarian cancer patients, is a potent inducer of GROα expression in ovarian cancer cell lines. Treatment of ovarian cancer cells with LPA leads to transcriptional activation of the GROα gene promoter and robust accumulation of GROα protein in culture supernatants. The action of LPA on GROα expression is mediated by LPA receptors, particularly the LPA2 receptor in that ectopic expression of these receptors restores the LPA-dependent GROα production in nonresponsive cells. Down-regulation of LPA2 expression by small interfering RNA (siRNA) in ovarian cancer cells desensitizes GROα production in response to LPA. The effect of serum on GROα production is also significantly decreased by siRNA inhibition of LPA2 expression. These studies identify LPA as a primary regulator of GROα expression in ovarian cancer. (Cancer Res 2006; 66(5): 2740-8)
Prognostic Value of an Activation State Marker for Epidermal Growth Factor Receptor in Tissue Microarrays of Head and Neck Cancer
Authors: Kong Anthony , Leboucher Pierre , Leek Russell , Calleja Véronique , Winter Stuart , Harris Adrian , Parker Peter J. , Larijani Banafshé 
Published: March 2006

Abstract
Overexpression and mutation of epidermal growth factor receptors (EGFR) have been shown to be important in the prognosis of several cancers, including head and neck cancers. However, our inability to define the activation status of these and other receptors limits our ability to assess the importance of these pathways and to exploit effectively new molecularly targeted treatments directed at their catalytic activities. Here we describe the use of automated, high-throughput fluorescence lifetime imaging microscopy to measure EGFR autophosphorylation status by fluorescence resonance energy transfer (FRET) in head and neck tumors. We have correlated FRET efficiency with the clinical and survival data. The results from head and neck arrays show that high FRET efficiency is correlated with worsening disease-free survival but not with overall survival. This powerful tool could be exploited as a new independent quantitative prognostic factor in clinical decisions and cancer management. (Cancer Res 2006; 66(5): 2834-43)